Faculty Bibliography

Approximately 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastatic disease, which is almost invariably lethal. However, our understanding of pathways that drive aggressive behavior of MIBC is incomplete. Members of the FOXA subfamily of transcription factors are implicated in normal urogenital development and urologic malignancies. FOXA proteins are implicated in normal urothelial differentiation, but their role in bladder cancer is unknown. We examined FOXA expression in commonly used in vitro models of bladder cancer and in human bladder cancer specimens, and used a novel in vivo tissue recombination system to determine the functional significance of FOXA1 expression in bladder cancer. Logistic regression analysis showed decreased FOXA1 expression is associated with increasing tumor stage (p<0.001), and loss of FOXA1 is associated with high histologic grade (p<0.001). Also, we found that bladder urothelium that has undergone keratinizing squamous metaplasia, a precursor to the development of squamous cell carcinoma (SCC) exhibited loss of FOXA1 expression. Furthermore, 81% of cases of SCC of the bladder were negative for FOXA1 staining compared to only 40% of urothelial cell carcinomas. In addition, we showed that a subpopulation of FOXA1 negative urothelial tumor cells are highly proliferative. Knockdown of FOXA1 in RT4 bladder cancer cells resulted in increased expression of UPK1B, UPK2, UPK3A, and UPK3B, decreased E-cadherin expression and significantly increased cell proliferation, while overexpression of FOXA1 in T24 cells increased E-cadherin expression and significantly decreased cell growth and invasion. In vivo recombination of bladder cancer cells engineered to exhibit reduced FOXA1 expression with embryonic rat bladder mesenchyme and subsequent renal capsule engraftment resulted in enhanced tumor proliferation. These findings provide the first evidence linking loss of FOXA1 expression with histological subtypes of MIBC and urothelial cell proliferation, and suggest an important role for FOXA1 in the malignant phenotype of MIBC.

Retraction of the bowels during abdominal surgery is generally facilitated by the use of a combination of various retractors along with surgical towels or sponges. The use of surgical towels and sponges may lead to retained foreign bodies or adhesions. In addition, these towels and sponges often require manipulation during long surgical procedures. The ideal way to avoid these problems in abdominal surgery is to develop a technique for retraction of the abdominal contents that eliminates the requirement for these foreign bodies. This article presents the results of a small trial for Lap Pak (Seguro Surgical, Columbia, MD), a disposable radio-opaque device that is made of silicone and retracts the bowels in a cephalad orientation without the need for towels or sponges.

Muscle invasive and recurrent nonmuscle invasive bladder cancers have been traditionally treated with a radical cystectomy and urinary diversion. The urinary diversion is generally accomplished through the creation of an incontinent ileal conduit, continent catheterizable reservoir, or orthotopic neobladder utilizing small or large intestine. While radical extirpation of the bladder is often successful from an oncological perspective, there is a significant morbidity associated with enteric interposition within the genitourinary tract. Therefore, there is a great opportunity to decrease the morbidity of the surgical management of bladder cancer through utilization of novel technologies for creating a urinary diversion without the use of intestine. Clinical trials using neourinary conduits (NUC) seeded with autologous smooth muscle cells are currently in progress and may represent a significant surgical advance, potentially eliminating the complications associated with the use of gastrointestinal segments in the urinary reconstruction, simplifying the surgical procedure, and greatly facilitating recovery from cystectomy.

BACKGROUND AND PURPOSE/OBJECTIVE:Patients who are undergoing laparoscopic ablative therapy (LAT) are often older with more comorbidities in comparison with patients who are undergoing laparoscopic partial nephrectomy (LPN). A matched control study was performed to compare the surgical and functional outcomes of LPN and LAT. PATIENTS AND METHODS/METHODS:A prospectively maintained database of 250 patients who underwent nephron-sparing surgery was explored. Fifty-one LAT patients (21 and 30 laparoscopic radiofrequency and cryoablation, respectively) were matched with 51 LPN patients. A comparison of preoperative, operative, and postoperative outcomes was performed. RESULTS:The groups were similar in age, sex, body mass index, preoperative estimated glomerular filtration rate (eGFR), number of comorbidities and tumor size. Patients who were undergoing LAT had a lower incidence of endophytic tumor and higher incidence of upper pole and midpolar tumors. Hilar vessels clamping was performed in LPN (47/51 patients). Mean estimated blood loss and operative time were higher in those undergoing LPN (P<0.01). There was no significant difference in transfusion rate and hospital stay, however. Mean follow-up was 27 and 18 months in LAT and LPN, respectively (P<0.01). The mean percent decline of eGFR at the last follow-up was 10 (95% confidence interval [CI]: 4-15) and 7.5 (95% CI: 4-11), respectively (P<0.43). In comparison with baseline, eGFR declined significantly (P<0. 01), but there was no difference between the groups. CONCLUSION/CONCLUSIONS:Despite renal ischemia, longer operative time, and higher blood loss associated with LPN, the hospital stay and long-term functional outcomes are similar to those of LAT in a matched control study.

The identification of patients with high-risk bladder cancer is important for the timely and appropriate treatment of this lethal disease. The understanding of the natural history of bladder cancer has improved; however, the criteria used to define high-risk disease and the relevant treatment strategies have remained the same for the past several decades, despite multiple large, randomized, prospective clinical trials that have evaluated the use of intravesical, surgical and systemic therapies. The genetic signature of high-risk bladder cancer has been a focus of investigation and has led to the discovery of potential molecular targets for disease identification, risk stratification and therapy. These advances, combined with a comprehensive risk assessment profile that incorporates available pathological and clinical characteristics, might improve the diagnosis and treatment of patients with bladder cancer.

OBJECTIVE:Patients with bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the bladder are candidates for intravesical (IVe) valrubicin. This post-hoc analysis of data from the pivotal phase 3, prospective, open-label study of valrubicin evaluated the effects of patient characteristics and past treatments on the response to valrubicin. METHODS:Enrolled patients had non-muscle-invasive CIS with or without concurrent papillary disease stage Ta and/or T1 for which papillary tumors had been resected before treatment, and had previously received ≥ 2 courses of IVe therapy (≥ 1 BCG course). Patients received a course of valrubicin, which consisted of 6 weekly IVe treatments of valrubicin (800 mg). Complete response was defined as no evidence of disease by urine cytology, cystoscopy, and biopsy at 3 and 6 months posttreatment. Patient characteristics, baseline urinary symptoms, and number and type of previous treatment courses and instillations were compared for complete versus nonresponders (including partial responders) to valrubicin. RESULTS:Ninety patients enrolled; 87 patients with positive biopsy at initiation completed a valrubicin course and underwent the 3-month assessment. Five had missing data at 6 months. Of the remaining 82 patients, 18 demonstrated a complete response; 64 demonstrated partial or no response. For complete responders versus partial or nonresponders, differences in patient characteristics, baseline urinary symptoms, and number of previous courses or instillations of BCG or other types of treatment were not significant (P > 0.05). More complete responders had evidence of inflammation before or during valrubicin treatment (P = 0.005 vs nonresponders). CONCLUSIONS:In these patients with BCG-refractory CIS, complete responders to valrubicin did not differ significantly from partial or nonresponders in the number of prior courses or instillations. The results suggest that therapy with valrubicin may be considered in appropriate candidates who have not responded to prior therapies. Cystectomy should be reconsidered when valrubicin treatment fails.

BACKGROUND AND PURPOSE/OBJECTIVE:Patients with Gleason (GL) 6 prostate cancer in one or two biopsy cores can be upgraded and/or upstaged at the time of surgery, which may adversely impact long-term outcome. A novel model for prediction of adverse pathologic outcomes was developed using preoperative characteristics. PATIENTS AND METHODS/METHODS:Between 2003 and 2007, 1159 patients underwent robot-assisted radical prostatectomy (RARP) at our institution. GL 6 prostate cancer in one or two biopsy cores was identified in 416 (36%) patients. Logistic regression analyses were used to assess the rate of GL ≥7 and/or extraprostatic extension at RARP. Covariates consisted of age, body mass index (BMI), number of positive cores, greatest percent of cancer in a core (GPC), clinical stage, and preoperative prostate-specific antigen (PSA) level. After backward variable selection, the developed model was internally validated using the area under the curve and subjected to methods of calibration. RESULTS:Respectively, 278 (67%) and 138 (33%) patients had one or two positive biopsy cores. At RARP, 90 (22%) patients were upgraded to GL ≥7 and 37 (9%) had extraprostatic extension. The novel model relied on age, BMI, preoperative PSA level, and GPC for prediction of adverse pathologic outcomes and was 69% accurate. Calibration plot revealed a virtually perfect relationship between predicted and observed probabilities. CONCLUSIONS:In patients with GL 6 prostate cancer in one or two biopsy cores, 25% have more ominous pathology at RARP. The model provides an individual assessment of adverse outcomes at surgery. Consequently, it may be considered when counseling patients regarding their management options.

OBJECTIVES/OBJECTIVE:To present outcomes of a contemporary series of patients undergoing radical cystectomy (RC) for bladder cancer after previous treatment for localized cancer of the prostate (CaP). METHODS:A retrospective review of more than 1000 RCs performed for bladder cancer between 1995 and 2008 identified 49 patients previously treated for localized CaP. Patients were stratified according to the type of primary therapy received for CaP: any form of primary or adjuvant radiotherapy (brachytherapy or external beam radiotherapy) versus radical prostatectomy (RP) monotherapy. Perioperative data were analyzed and compared between the 2 groups. RESULTS:Of 49 patients, 40 (82%) underwent primary or adjuvant radiotherapy and 9 (18%) RP alone. Eleven (22%) patients received a continent diversion. Mean estimated blood loss (EBL) and hospital stay were 979 mL and 12 days, respectively. Extravesical disease (≥pT3a) was present in 23 patients (57.5%) in the radiotherapy group and in 2 patients (22%) in the RP group. Ten patients (all in the radiotherapy group) had a positive margin, 9 (90%) of whom had pathologic T4 disease. The overall major perioperative complication rate was 41%. Of the 6 patients with an ONB (all after RP), 4 had severe incontinence. CONCLUSIONS:Patients undergoing RC after previous treatment for localized CaP are at increased risk for perioperative morbidity. Patients should be counseled that orthotopic diversion after RP may be associated with significant incontinence. Extravesical disease is more prevalent in patients treated with previous radiation. We observed a high rate of positive margins associated with pathologic T4 disease in this cohort.