The usefulness of the detection of GSTP1 methylation in urine as a biomarker in the diagnosis of prostate cancer.

PURPOSE: Prostate cancer has a unique set of problems associated with its early detection and diagnosis that might be aided by the addition of molecular markers, such as DNA hypermethylation. DNA methylation is an important epigenetic mechanism of gene regulation that has a critical role in normal developmental processes. Aberrant DNA methylation is a hallmark of carcinogenesis and GSTP1 hypermethylation is the most common molecular alteration in human prostate cancer. To our knowledge the clinical usefulness of the detection of gene methylation is yet to be established. MATERIALS AND METHODS: We evaluated GSTP1 hypermethylation in urine collected after prostatic massage and in core needle biopsies from 100 men referred for diagnostic biopsy. RESULTS: Methylation of GSTP1 in urine specimens had 75% sensitivity and 98% specificity for prostate cancer. GSTP1 methylation in the biopsy had 88% specificity and 91% sensitivity. Interestingly we observed a higher frequency of GSTP1 methylation in the urine of men with stage III vs II disease (100% vs 20%, p = 0.05). CONCLUSIONS: This study suggests that the detection of GSTP1 methylation in prediagnostic urine may improve the specificity of PSA and help distinguish men with prostate cancer from those with benign prostatic hyperplasia. This finding should be further explored in a larger, prospective screening trial.

Evaluation of mechanical bowel preparation methods in urinary diversion surgery.

OBJECTIVES: We performed the first prospective, randomized, multi-center comparison of overall quality and patient tolerability of polyethylene glycol (PEG) and sodium phosphate (NaP) solution for mechanical bowel preparation prior to urinary diversion surgery. METHODS: Between 2001 and 2003, 36 patients at six institutions underwent major urological reconstructive surgery incorporating small intestine (35 radical cystectomy with urinary diversion and 1 bladder augmentation). Patients were prospectively randomized to receive either oral polyethylene glycol (group 1, n = 16) or sodium phosphate (group 2, n = 20) for mechanical bowel preparation prior to surgery, according to our multi-institutional IRB-approved protocol. All patients completed a questionnaire the morning of surgery to assess the tolerability and side effects of each agent. Quality of the bowel preparation was recorded based on intraoperative findings of the attending surgeon, who was blinded to the preparation method. RESULTS: Both bowel cleansing regimens were safe and well tolerated. Patient-reported ease of use and subjective incidence of side effects were statistically similar in the two groups, and a statistically non-significant trend to more bloating in the PEG group was also noted (p = 0.085). Surgeon-scored overall quality of preparation adequacy revealed no significant differences between oral sodium phosphate and polyethylene glycol solutions (p = 0.555). Postoperative complications were rare for each bowel preparation agent. CONCLUSIONS: Performance characteristics of oral sodium phosphate and polyethylene glycol bowel preparations appear to be similar. Each method is safe, efficacious, and well-tolerated when used prior to urinary diversion surgery. The cost for the NaP preparation was $1.40 versus $19.70 for the PEG bowel preparation. Sodium phosphate may have a slight advantage because of its convenience and economic advantage.

CD44 and PTGS2 methylation are independent prognostic markers for biochemical recurrence among prostate cancer patients with clinically localized disease.

Up to 30% of men with clinically localized disease who receive radical prostatectomy develop a biochemical recurrence. Gene methylation in tumor tissue may distinguish men with aggressive cancer. This study evaluated methylation of GSTP1, RARb2, CD44 and PTGS2 with biochemical recurrence among 60 patients who underwent radical prostatectomy using logistic regression and Kaplan Meier time to event analysis. Methylation of GSTP1 and RARbeta2 was not associated with recurrence, however, CD44 and PTGS2 methylation were significant predictors. In multivariate models adjusting for Gleason grade, the methylation profile of CD44 and PTGS2 combined was an independent predictor of biochemical recurrence (associated with 9-fold increased risk). In addition, Kaplan Meier analysis showed CD44 and PTGS2 methylation was associated with shorter time to recurrence. CD44 and PTGS2 methylation may predict biochemical recurrence in prostate cancer patients undergoing radical prostatectomy and if validated in larger studies, may identify patients with aggressive cancer.

Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial.

PURPOSE: Interstitial cystitis is a painful bladder condition of unknown etiology and poorly understood pathophysiology. Current therapies have met with limited success. Vanilloid receptor agonists such as resiniferatoxin (RTX) desensitize C-fibers that transmit pain; it is hypothesized that such drugs will be effective in the treatment of interstitial cystitis and painful bladder syndrome by decreasing the pain that leads to urinary frequency and urgency. MATERIALS AND METHODS: A randomized, double-blind, placebo controlled study was conducted in 163 patients with interstitial cystitis. Participants were randomly assigned to receive a single intravesical dose of 50 ml of either RTX 0.01 microM, 0.05 microM, 0.10 microM, or placebo. Safety and efficacy was evaluated over 12 weeks. The primary efficacy endpoint was the Global Response Assessment, a 7-point scale rating overall change in symptoms of interstitial cystitis after 4 weeks. Secondary efficacy endpoints included reduction in pain, urgency, frequency, nocturia, average void volume, and the O'Leary-Sant Symptom and Problem Indexes. RESULTS: RTX did not improve overall symptoms, pain, urgency, frequency, nocturia, or average void volume during 12 weeks followup. RTX resulted in a dose-dependent increase in the incidence of instillation pain, but was otherwise generally well tolerated. CONCLUSIONS: In the largest prospective, randomized clinical trial reported to date with intravesical vanilloid therapy, single administration of RTX at doses of 0.01 microM to 0.10 microM was not effective in patients with interstitial cystitis.

Multi-institutional experience with buccal mucosa onlay urethroplasty for bulbar urethral reconstruction.

PURPOSE: Buccal mucosa has been advocated as an ideal graft material for urethral reconstruction. We report our multicenter experience with buccal mucosa ventral onlay urethroplasty for complex bulbar urethral reconstruction in adults. MATERIALS AND METHODS: A retrospective analysis of patients who had undergone buccal onlay urethroplasty at 4 military medical treatment facilities participating in the Uniformed Services Urology Research Group was performed. The database generated included demographic data, genitourinary history, preoperative symptoms (American Urological Association symptom score), preoperative urinary flow rate, stricture length and operative statistics. Postoperative followup data included symptom score, flow rate, retrograde urethrogram results, and complications. RESULTS: A total of 53 patients (average age 32 years, range 17 to 64) underwent buccal mucosa graft urethroplasty between January, 1996 and March, 1998 for refractory strictures. Sixteen patients had undergone an average of 2.2 prior endoscopic procedures (range 1 to 7). Average stricture length was 3.6 plus or minus standard deviation 1.8 cm. (range 2 to 7.5) as measured on preoperative retrograde urethrogram. Followup averaged 25 months (range 11 to 40 months). Average symptom scores decreased from 21.2 (range 14 to 33) preoperatively to 5.4 (range 3 to 8) postoperatively (p <0.001). Average peak urinary flow rates increased from 7.9 preoperatively to 30.1 ml. per second postoperatively (p <0.001). Postoperative retrograde urethrograms were available for 34 patients and were normal in 24. The overall complication rate was 5.4%. Three patients required endoscopic incisions. One patient has a recurrent narrowing and treatment is considered a failure. There were 4 sacculations (7.5%) and 6 narrowings, 3 of which required further treatment. Of the patients 50 required no additional procedures (94.3%). CONCLUSIONS: Buccal mucosa grafts used as a ventral onlay for bulbar urethral reconstruction yield reproducibly excellent results with minimal morbidity and low complication rates. Longer followup will be required to confirm the durability of our results.

Intermediate term failure of pubovaginal slings using cadaveric fascia lata: a case series.

PURPOSE: The pubovaginal sling procedure using autologous fascia has become the gold standard for treating intrinsic sphincter deficiency and stress urinary incontinence in women. A recent modification has been the use of cadaveric fascia as the sling material. We recently reported similar results for cadaveric fascia lata in 121 women and autologous fascia lata in 46 at a mean followup of 12 months. We have now identified 8 patients who experienced intermediate term failure at 4 to 13 months using cadaveric fascia lata. MATERIALS AND METHODS: We retrospectively reviewed the records of 8 of 121 patients who received a pubovaginal sling using cadaveric fascia lata between February 1997 and June 1999 and had recurrent stress incontinence after 4 to 13 months. We reviewed the type of fascia, surgical technique, preoperative and postoperative urodynamics, surgical history and medical co-morbidities. RESULTS: We identified 8 patients who underwent a pubovaginal sling using cadaveric fascia lata and had recurrent stress urinary incontinence at a mean of 6.5 months (range 4 to 13) after the procedure. Fresh frozen fascia from a local tissue bank was used and the surgical technique was identical in all cases. Postoperatively urodynamics confirmed recurrent intrinsic sphincter deficiency. Previous incontinence surgery had been done in 7 of the 8 patients. Patient co-morbidities included neurological disease, diabetes mellitus, previous pelvic irradiation and previous pelvic surgery. CONCLUSIONS: We identified a higher than expected intermediate term failure rate using fresh frozen cadaveric fascia lata. This risk must be weighed against the advantages of decreased operative time and patient morbidity. Longer followup and larger numbers are necessary to determine how much of a problem exists and what patient characteristics are relevant when selecting cadaveric grafts.