Ralph W. deVere White

BACKGROUND: Despite aggressive local therapy, patients with locally advanced bladder cancer are at significant risk for metastases. We evaluated the ability of neoadjuvant chemotherapy to improve the outcome in patients with locally advanced bladder cancer who were treated with radical cystectomy. METHODS: Patients were enrolled if they had muscle-invasive bladder cancer (stage T2 to T4a) and were to be treated with radical cystectomy. They were stratified according to age (less than 65 years vs. 65 years or older) and stage (superficial muscle invasion vs. more extensive disease) and were randomly assigned to radical cystectomy alone or three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy. RESULTS: We enrolled 317 patients over an 11-year period, 10 of whom were found to be ineligible; thus, 154 were assigned to receive surgery alone and 153 to receive combination therapy. According to an intention-to-treat analysis, the median survival among patients assigned to surgery alone was 46 months, as compared with 77 months among patients assigned to combination therapy (P=0.06 by a two-sided stratified log-rank test). In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38 percent vs. 15 percent, P<0.001). CONCLUSIONS: As compared with radical cystectomy alone, the use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy increases the likelihood of eliminating residual cancer in the cystectomy specimen and is associated with improved survival among patients with locally advanced bladder cancer.

Although prostate cancer (CaP) is the most frequently diagnosed malignant tumor and the second leading cause of cancer deaths in American men, the mechanisms explaining the development and progression of CaP remain largely unknown. Recent studies have shown that some aberrantly expressed microRNAs (miRNAs) are involved in tumorigenesis. Although aberrant expression of certain miRNAs has been discovered in CaP, their function in this disease has not yet been defined. In this study, we found differential expression of miR-125b in androgen-dependent and independent CaP cells, as well as in benign and malignant prostate tissues. Furthermore, androgen signaling was able to up-regulate the expression of miR-125b. In addition, transfection of synthetic miR-125b stimulated androgen-independent growth of CaP cells and down-regulated the expression of Bak1. Our results suggest that miR-125b acts as an oncogene, contributing to the pathogenesis of CaP.

An androgen receptor (AR) gene mutation identified in the androgen-dependent human prostate cancer xenograft, CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT for histidine to TAT for tyrosine and abolished a restriction site for the endonuclease SfaNI. SfaNI digestion of AR exon H DNA from normal but not from prostate cancer tissue indicated H874Y is a somatic mutation that occurred before the initial tumor transplant. CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in size to the AR mRNA in human benign prostatic hyperplasia. AR protein is present in cell nuclei by immunostaining as in other androgen-responsive tissues. Transcriptional activity of recombinant H874Y transiently expressed in CV1 cells in the presence of testosterone or dihydrotestosterone was similar to that of wild type AR. With dihydrotestosterone at a near physiological concentration (0.01 nM), H874Y and wild type AR induced 2-fold greater luciferase activity than did the LNCaP mutant AR T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100 nM) with H874Y stimulated a 3- to 8-fold greater response than with wild type AR and at 100 nM the response was similar with the LNCaP mutant. H874Y, like the LNCaP cell mutant, was more responsive to estradiol and progesterone than was wild type AR. The antiandrogen hydroxyflutamide (10 nM) had greater agonist activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR mutations that alter ligand specificity may influence tumor progression subsequent to androgen withdrawal by making the AR more responsive to adrenal androgens or antiandrogens.

PURPOSE: We investigated patient satisfaction with the artificial urinary sphincter and established criteria for a successful outcome by inquiring about patient perceived satisfaction, continence achieved and comparison with the surgeon office records. MATERIALS AND METHODS: During 9 years 65 patients with post-prostatectomy incontinence underwent placement of the AMS800 artificial urinary sphincter. Review of charts and a telephone questionnaire were conducted to determine patient perceived satisfaction. RESULTS: A total of 50 patients participated in the survey. Median followup was 23.4 months. Preoperative incontinence was severe. Of the patients 90% reported continuous leakage, and 70% wore an average of 6 diapers and 24% wore an average of 7.4 pads daily. The long-term complete continence rate was 20%. Of the patients with wetness 55% had leakage of a few drops daily and 22% had leakage of less than a teaspoon. Of all patients 50% had leakage daily, 24% had leakage 1 or more times a week and wore an average of 1.5 pads per day, and 6% reported changing clothes due to wetness. A total of 90% of the patients reported satisfaction with the artificial urinary sphincter and 96% stated that they would recommend or had recommended the artificial urinary sphincter to a friend. In retrospect, 92% of the patients would have the artificial urinary sphincter placed again, 90% of those undergoing revision reported no change in satisfaction and 14% reported improved sexual activity. CONCLUSIONS: Patient satisfaction with the artificial urinary sphincter for post-prostatectomy incontinence is uniformly high. Although postoperative continence was not 100%, relative improvement in continence was the most significant factor affecting patient perceived outcome. Using these parameters criteria for a successful outcome can be established, and patient concerns regarding the artificial urinary sphincter can be dispelled.

OBJECTIVES: We compare the Bard BTA (bladder tumor antigen) test to voided cytology studies in patients undergoing surveillance cystoscopy for recurrent bladder cancer. MATERIALS AND METHODS: A prospective, blinded, multicenter trial was performed. RESULTS: A total of 499 patients underwent 1,014 cystoscopic examinations and tumor was identified in 151. The bladder tumor antigen test was more sensitive than cytology studies in detecting recurrent cancer (p < 0.001), being positive in 61 cases versus 25 for cytology. The trial in healthy volunteers and nonurological patients estimates bladder tumor antigen test specificity to be 95.9%. CONCLUSIONS: The bladder tumor antigen test is a simple, rapid and inexpensive adjunct to cystoscopy, and the results are equivalent or superior to those of voided cytology as performed in this trial.