Tomas L. Griebling

Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer

Prostate cancer is the second leading cause of cancer death in the United States and, thus far, there has been no effective therapy for the treatment of hormone-refractory disease. Recently, the androgen receptor (AR) has been shown to play a critical role in the development and progression of the disease. In this report, we showed that knocking down the AR protein level by a small interfering RNA (siRNA) approach resulted in a significant apoptotic cell death as evidenced by an increased annexin V binding, reduced mitochondrial potential, caspase-3/6 activation, and DFF45 and poly(ADP-ribose) polymerase cleavage. The apoptotic response was specifically observed in those siRNA-transfected cells that harbor a native AR gene. No cell death was found in the AR-null prostate cancer cell PC-3 or its subline that has been reconstituted with an exogenous AR gene, as well as two breast cancer cell lines that are AR positive. Moreover, in parallel with the siRNA-induced AR silencing, the antiapoptotic protein Bcl-xL was significantly reduced, which might account for the apoptotic cell death because ectopic enforced expression of Bcl-xL protein partially inhibited apoptosis after AR silencing. Taken together, our data showed that knocking down the AR protein level in prostate cancer cells leads to apoptosis by disrupting the Bcl-xL–mediated survival signal downstream of AR-dependent survival pathway.

Postoperative urinary retention.

Postoperative urinary retention (PUR) is a common complication of surgery and anesthesia. The risk of retention is especially high after anorectal surgery, hernia repair, and orthopedic surgery and increases with advancing age. Certain anesthetic and analgesic modalities, particularly spinal anesthesia with long-acting local anesthetics and epidural analgesia, promote the development of urinary retention. Portable ultrasound provides rapid and accurate assessment of bladder volume and aids in the diagnosis and management of PUR. Catheterization is recommended when bladder volume exceeds 600 mL to prevent the negative sequelae of prolonged bladder overdistention.

Results of a Prospective, Randomized, Multicenter Study Evaluating Sacral Neuromodulation With InterStim Therapy Compared to Standard Medical Therapy at 6-Months in Subjects With Mild Symptoms of Overactive Bladder

This prospective, randomized, multicenter trial evaluated the 6‐month success rate of sacral neuromodulation (SNM) with InterStim® Therapy versus standard medical therapy (SMT) for overactive bladder (OAB).

Effect of fesoterodine in vulnerable elderly subjects with urgency incontinence: A double-blind, placebo controlled trial

PURPOSE We evaluated the efficacy and safety of flexible dose fesoterodine in medically complex vulnerable elderly subjects with urgency urinary incontinence. MATERIALS AND METHODS In this 12-week, randomized, double-blind, flexible dose, placebo controlled trial, subjects were community dwelling men and women 65 years old or older. Subjects had scores of 3 or more on the VES-13 (Vulnerable Elders Survey) and 20 or more on the MMSE (Mini-Mental State Examination), and 2 to 15 urgency urinary incontinence episodes and 8 or more micturitions per 24 hours on 3-day baseline diaries. Subjects randomized to fesoterodine received 4 mg once daily for 4 weeks and could then increase to 8 mg based on discussion with the investigator. Subjects receiving 8 mg could decrease the dose to 4 mg at any time (sham escalation and de-escalation for placebo). The primary outcome measure was change in daily urgency urinary incontinence episodes. Secondary outcomes included changes in other diary variables and patient reported quality of life measures. Safety evaluations included self-reported symptoms and post-void residual volume. RESULTS A total of 562 patients were randomized (mean age 75 years, 50.4% age 75 years or greater). Subjects had high rates of comorbidities, polypharmacy and functional impairment. At week 12 the fesoterodine group had significantly greater improvements in urgency urinary incontinence episodes per 24 hours (-2.84 vs -2.20, p = 0.002) and most other diary variables and quality of life, as well as a higher diary dry rate (50.8% vs 36.0%, p = 0.002). Adverse effects were generally similar to those of younger populations including risk of urinary retention. CONCLUSIONS To our knowledge this is the first antimuscarinic study in a community based, significantly older, medically complex elderly population with urgency urinary incontinence. Flexible dose fesoterodine significantly improved urgency urinary incontinence episodes and other outcomes vs placebo, and was generally well tolerated.

COMPARISON OF CYSTOSCOPIC AND HISTOLOGICAL FINDINGS IN PATIENTS WITH SUSPECTED INTERSTITIAL CYSTITIS

PURPOSE Although the exact etiology of interstitial cystitis remains elusive, bladder inflammation appears to be common in many patients. The National Institutes of Health (NIH) have established diagnostic criteria for interstitial cystitis based on the presence of irritative voiding symptoms in the absence of other identifiable pathology. Cystoscopic examination with hydrodistention performed in patients under anesthesia is part of the NIH diagnostic criteria. We determine if the severity of cystoscopic findings correlated with histological evidence of inflammation in patients with suspected interstitial cystitis. MATERIALS AND METHODS A total of 69 patients who met NIH symptom criteria for interstitial cystitis and underwent cystoscopy, hydrodistention and bladder biopsy under anesthesia were reviewed. There were 2 investigators blinded to the histological data who independently reviewed operative reports. A urological pathologist blinded to the clinical data reviewed biopsies for inflammation severity. Cystoscopic and histological findings were then converted to a numeric scale. Numeric data were analyzed using the Pearson correlation coefficient. RESULTS Cystoscopic examination revealed no evidence of interstitial cystitis in 6 patients (9%), mild changes in 27 (39%), moderate changes in 23 (33%) and severe changes in 13 (19%). Histological examination revealed no inflammation in 21 patients (30%), mild inflammation in 28 (41%), moderate inflammation in 11 (16%) and severe inflammation in 9 (13%). Histological scores correlated poorly with total and scaled cystoscopic severity scores (r = 0.295 and 0.349, respectively). CONCLUSIONS Severity of cystoscopic findings observed during hydrodistention with anesthesia does not appear to correlate with the degree of inflammation identified histologically in patients with suspected interstitial cystitis.

RESOLUTION OF URGE SYMPTOMS FOLLOWING SLING CYSTOURETHROPEXY

PURPOSE Persistence of urinary urge symptoms in women after pubovaginal sling cystourethropexy is a distressing problem. We assess the ability of preoperative video urodynamics to identify patients in whom urinary urge symptoms failed to resolve postoperatively. MATERIALS AND METHODS The records of 84 consecutive women who had undergone pubovaginal sling cystourethropexy were reviewed. Preoperative video urodynamics revealed stress urinary incontinence in all cases and concomitant detrusor instability in some. Cases of motor urge, defined as urge symptoms plus detrusor instability, were divided into low and high pressure categories. Patients with urge symptoms but no demonstrable detrusor instability on video urodynamics were diagnosed with sensory urge. Postoperatively complete urge resolution was defined as total absence of symptoms without pharmacological therapy. Mean followup was 26.7 months (range 2 to 62). RESULTS Of the 84 patients 41 with motor urge and 28 with sensory urge had preoperative urge symptoms. Complete resolution or improvement in urge symptoms occurred in 24 (58.5%) and 7 (17.1%) of the motor urge, and 11 (39.3%) and 9 (32.1%) of sensory urge cases, respectively. Of the 41 patients with motor urge 23 had low pressure instability, which completely resolved in 21 (91.3%) and improved in 2 (8.7%). Of the 18 remaining patients with high pressure motor urge only 5 (27. 8%) had complete resolution of urge and 5 (27.8%) had improvement. CONCLUSIONS Our results suggest that patients with low pressure motor urge are significantly more likely to experience resolution of urinary urge symptoms after pubovaginal sling cystourethropexy than those with high pressure motor urge or sensory urge.

Transurethral Collagen Injection for Treatment of Postprostatectomy Urinary Incontinence in Men

OBJECTIVES Transurethral injection of glutaraldehyde cross-linked bovine collagen has recently been advocated as a potentially useful treatment modality for management of urinary incontinence. The reported clinical experience with urethral collagen injection in adult males has been limited. METHODS This study summarizes the current literature and reviews the clinical results of collagen injection in a group of 25 men with incontinence after either transurethral or radical prostatectomy. RESULTS The overall results in this series were disappointing. Only 2 patients (8%) achieved significant improvement with this treatment. Eight patients (32%) experienced minimal improvement in symptoms, and 15 (60%) remained incontinent with no improvement in symptoms after collagen injection. The number of injection procedures and volume of collagen material implanted did not correlate with clinical outcome. Five patients (20%) have subsequently required placement of an artificial urinary sphincter to control their incontinence. CONCLUSIONS We conclude that transurethral injection of glutaraldehyde cross-linked bovine collagen has a limited role in the management of urinary incontinence in adult men after prostatectomy.

Expression of CD44 isoforms in human prostate tumor cell lines

We have examined the expression of the transmembrane glycoproteins CD44 in four human prostate tumor cell lines. Expression was examined at the protein level by flow cytometric analysis and Western blot, and at the mRNA level by reverse transcription‐polymerase chain reaction (RT‐PCR). All four cell lines (DU145, LNCaP, PC3, and ND1) expressed the standard CD44 isoform (CD44s) at the mRNA level and all cell lines except LNCaP expressed CD44s at the protein level. All four cell lines contained one or more isoforms containing the v6 region (exon 10) at the mRNA level, which has been associated with metastatic potential. However, a subpopulation of LNCaP and ND1 cells showed protein expression of v6. In addition, soluble CD44 isoforms were identified in cultured supernatants from all cell lines except LNCaP. These results show that CD44 isoforms are expressed on human prostate tumor cell lines, including the expression of variant isoforms containing the v6 region, and provide a rationale for the further study of this cellular adhesion molecule in prostate cancer. In addition, preliminary results indicate altered expression of CD44 in human prostatic adenocarcinomas examined immunohistochemically.

Three-year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated With Sacral Neuromodulation

OBJECTIVE To evaluate the therapeutic success rate, and changes in quality of life (QOL) and safety in subjects using sacral neuromodulation (InterStim System) at 36 months. Subjects with bothersome symptoms of overactive bladder (OAB) including urinary urge incontinence (UI) and/or urgency frequency (UF), who had failed at least 1 anticholinergic medication, and had at least 1 untried medication were included. METHODS Subjects with successful test stimulation received an InterStim implant. Therapeutic success and quality of life through 36 months was evaluated in implanted subjects with data at baseline and follow-up. Safety was evaluated using reported adverse events. RESULTS A total of 340 subjects received test stimulation resulting in 272 implanted subjects. Demographics include 91% female, mean age of 57 years, and baseline symptom severity of 3.1 ± 2.7 leaks/day (UI) and 12.6 ± 4.5 voids/day (UF). The analysis showed an OAB therapeutic success rate of 83% (95% confidence interval: 78%-88%). UI subjects had a mean reduction from baseline of 2.3 ± 2.3 leaks/day whereas UF subjects had a mean reduction of 5.3 ± 4.0 voids/day (both P < .0001). Statistically significant improvements were observed in all measures of the International Consultation on Incontinence Modular Questionnaire-OABqol (all P < .0001). Eighty percent of subjects reported improvements in their urinary symptom interference. Device-related adverse events occurred in 47% (127/272) of subjects post-implant; 91% were resolved at the time of this analysis. CONCLUSION The 36-month follow-up data from the multicenter study demonstrate sustained safety, effectiveness, and improved QOL in subjects implanted with InterStim, without requiring failure of all medications.

Results of a prospective, multicenter study evaluating quality of life, safety, and efficacy of sacral neuromodulation at twelve months in subjects with symptoms of overactive bladder

This prospective, multicenter post‐approval study evaluated the success rate of sacral neuromodulation (SNM) with the InterStim® System at 12‐months. Subjects with bothersome symptoms of overactive bladder (OAB) including urinary urge incontinence (UI) or urgency‐frequency (UF), who failed at least one anticholinergic medication and had at least one not tried were included.