Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure.

PURPOSE: Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10% and 30%. Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes. Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation. We now report the results of a phase II trial to assess efficacy. MATERIALS AND METHODS: This study was an investigator initiated, single center, single arm, phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Guérin failed. Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was evaluated with cystoscopy, biopsy, cytology and imaging. If complete response was achieved, patients were treated with full dose monthly maintenance treatments for 6 months. RESULTS: A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of these responses remained durable after maintenance therapy. At a mean followup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their bladders without progression or distant metastases. A single patient had progression to muscle invasive disease at radical cystectomy. Treatment related adverse events were noted in 9 of 28 (32.1%) patients and were limited to grade 1 or 2. CONCLUSIONS: Intravesical nab-paclitaxel has minimal toxicity and a 35.7% response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Guérin failure. Complete response remained durable at 1 year followup in this heavily pretreated patient population.

The role of preoperative prostatic urethral biopsy in clinical decision-making at the time of radical cystectomy.

INTRODUCTION: Involvement of the prostatic urethra by bladder cancer directly impacts prognosis, risk of urethral recurrence, and timing of radical cystectomy (RC); it also affects the type of urinary diversion chosen. Both cold cup biopsies and transurethral (TUR) loop biopsies have been used to evaluate the status of the prostatic urethra. We report our 20 year experience with preoperative and intro-operative prostatic urethral biopsies in order to determine relative efficacy and associated treatment implications. MATERIALS AND METHODS: The Columbia University urologic oncology database was reviewed and yielded 234 men who underwent preoperative endoscopic biopsies of the prostatic urethra before RC between 1990 and 2010. Two techniques were described: 1) cold cup biopsy, and 2) TUR loop biopsy. We evaluated the sensitivity, specificity, and predictive values for these respective techniques relative to the final pathological status of the prostatic urethra (PU) in the RC specimen. RESULTS: Of the 234 urethral biopsies 115 (49.1%) were cold cup and 96 (41.1%) were TUR loop biopsies. In the remaining 9.8% of patients, the technique could not be determined. Eighty-one preoperative biopsies (34.6%) revealed involvement of the urethra. No differences were observed in predictive values, sensitivity, and specificity between the two preoperative techniques. The negative predictive value (NPV) was higher than positive predictive value (PPV) for both preoperative approaches. Thirty-eight patients (16.2%) had a urethral frozen section analysis done intra-operatively. Only 1 patient (3%) had an abnormality on frozen section, being the negative predictive value (NPV) higher than the positive predictive value (PPV) for the test's ability to predict the status of the final urethral margin. Urethrectomy was performed at cystectomy in 52 patients with a positive biopsy; 15 (28.8%) of these patients ultimately had a negative PU on final pathology. Only 2/182 (1%) of the patients with an intact urethra presented with a urethral recurrence with a median follow up of 30.5 months. CONCLUSIONS: Preoperative prostatic urethral biopsy does not adequately predict final prostatic urethral status at radical cystectomy. No differences in predictive capacity could be detected with either cold cup biopsy or TUR biopsy. Intra-operative biopsy of the prostatic urethra is predictive of a negative urethral margin. Simultaneous radical urethrectomy should not be performed based up on preoperative prostatic urethral biopsy results alone.

High expression of the PAX3-FKHR oncoprotein is required to promote tumorigenesis of human myoblasts.

PAX3-FKHR is a fusion oncoprotein generated by the 2;13 chromosomal translocation in alveolar rhabdomyosarcoma (ARMS), a cancer associated with the skeletal muscle lineage. Previous studies determined that high-level PAX3-FKHR expression is a consistent feature in ARMS tumors. To investigate the relationship between expression and phenotype in human myogenic cells, PAX3-FKHR was introduced into immortalized human myoblasts to produce a low overall PAX3-FKHR expression level. Although PAX3-FKHR alone failed to exert transforming activity, a combination of PAX3-FKHR and MYCN induced transforming activity in cell culture assays. Furthermore, myoblasts expressing PAX3-FKHR with or without MYCN formed tumors in SCID mice. These tumors demonstrated invasive features and expressed myogenic markers, consistent with rhabdomyosarcoma. Comparisons of tumor and parental cells revealed that only a subset of parental cells developed into tumors and that tumor cells expressed high PAX3-FKHR levels compared with transduced parental cells. Subcloning of parental PAX3-FKHR/MYCN-transduced myoblasts identified rare high PAX3-FKHR-expressing subclones with high transforming and tumorigenic activity; however, most subclones expressed low PAX3-FKHR and showed neither transforming nor tumorigenic activity. Finally, RNA interference experiments in myoblast-derived tumor and ARMS cells revealed that high PAX3-FKHR expression plays a crucial role in regulating proliferation, transformation, and differentiation. These findings support the premise that high PAX3-FKHR-expressing cells are selected during tumorigenesis.