Sandip Vasavada

Transobturator tape compared with tension-free vaginal tape for the treatment of stress urinary incontinence: A randomized controlled trial

OBJECTIVE: To compare the safety and efficacy of the transobturator tape to tension-free vaginal tape (TVT) in the treatment of stress urinary incontinence in patients with and without concurrent pelvic organ prolapse. METHODS: One-hundred seventy women with urodynamic stress incontinence, including those with and those without pelvic organ prolapse, from three academic medical centers were randomized to receive TVT or transobturator tape. Subjects with detrusor overactivity or previous sling surgery were excluded. The primary outcome was the presence or absence of abnormal bladder function, a composite outcome defined as the presence of any the following: incontinence symptoms of any type, a positive cough stress test, or retreatment for stress incontinence or postoperative urinary retention assessed 1 year after surgery. This study is a noninferiority study design. RESULTS: Of 180 women who enrolled in the study, 170 underwent surgery and 168 returned for follow-up, with a mean follow-up of 18.2±6 months. Mean operating time, length of stay, and postoperative pain scores were similar between the two groups. Bladder perforations occurred more frequently in the TVT group (7% compared with 0%, P=.02); otherwise, the incidence of perioperative complications was similar. Abnormal bladder function occurred in 46.6% of TVT patients and 42.7% of transobturator tape patients, with a mean absolute difference of 3.9% favoring transobturator tape (95% confidence interval –11.0% to 18.6%.). The P value for the one-sided noninferiority test was .006, indicating that transobturator tape was not inferior to TVT. CONCLUSION: The transobturator tape is not inferior to TVT for the treatment of stress urinary incontinence and results in fewer bladder perforations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00475839 LEVEL OF EVIDENCE: I

The Effect of Obstruction on the Developing Bladder

Congenital bladder obstruction causes significant immediate and long-term consequences yet its pathophysiology remains poorly understood. A model of early fetal bladder obstruction in sheep has been developed to study the response of the developing bladder to high grade obstruction, with particular emphasis on the regulation of growth and development. Congenital bladder obstruction was produced in fetal sheep at 60 days of gestation and studied at 95 days of gestation (14 sheep) or term (12 sheep). A total of 24 age-matched normal sheep served as controls. Bladders were analyzed by total weight, stereological estimation of smooth muscle cell size, number and total mass, deoxyribonucleic acid concentration, muscarinic cholinergic receptor density, myosin isoform analysis and/or passive cystometrics. Congenital bladder obstruction caused a 4.6 times increase in bladder weight at term reflecting a 5.8 times increase in smooth muscle mass. This increase was predominantly that of cellular hypertrophy and less so of hyperplasia, based upon increased cell volume, increased protein-to-deoxyribonucleic acid ratio, and no significant increase in total cell number. Muscarinic cholinergic receptor number per smooth muscle cell increased 3.2 times but it did not change relative to myosin content. The ratio of myosin heavy chain isoforms SM1:SM2 is developmentally regulated and was seen to change from 1.6 at 100 days of gestation to 1.13 at term in normals. After 5 weeks of obstruction SM1:SM2 was 1.27 and it was 1.25 at term, indicating an effect on the developmental regulation of smooth muscle. Rapid fill cystometry in vivo measured the rate of stress relaxation to assess accommodative properties. The half-decay time was increased in all 3 obstructed bladders tested to greater than 15 seconds at 50% capacity (normal less than 5 seconds), suggesting reduced compliance. This study shows that an in utero model of bladder obstruction is feasible. Congenital bladder obstruction produces a variety of structural, biochemical and functional changes in the developing bladder indicative of alterations in the regulation of growth and differentiation.

p53, bcl-2, and Bax Expression in Renal Cell Carcinoma

OBJECTIVES Renal cell carcinomas often show a high degree of resistance to chemotherapy and radiation despite expressing normal function of the protein p53. The loss of control of apoptosis may also contribute to progression and resistance to treatment modalities and can be attributed to an interaction between p53 and the apoptotic regulators bcl-2 and Bax. To determine whether the expression of p53, bcl-2, or Bax could be correlated with outcome, we analyzed the expression pattern of these proteins in renal cell tumor samples. METHODS We examined 28 patients with clear cell renal cell carcinomas along with 7 patients with papillary renal cell carcinomas and 4 with renal oncocytomas. All renal cell carcinomas were clinically localized Stage pT2 with tumor size ranging from 4.0 to 10.3 cm (mean 6.23). Immunohistochemistry was performed on all samples and correlated with markers of outcome, including tumor grade, metastasis, recurrence, and overall survival rate. RESULTS In all clear cell tumors, the detection level of p53 expression was below the sensitivity of the assay, consistent with the reported infrequent incidence of p53 mutations in renal cell cancers. bcl-2 expression showed a significant correlation (P = 0.018) with higher tumor grade but could not be significantly correlated with other parameters examined including tumor recurrence, metastasis, or survival rate. The expression of Bax could similarly be correlated with higher tumor grade but with none of the other parameters. CONCLUSIONS At the present time, the combination of both tumor grade and stage represents the best prognostic markers available. Adjunctive use of bcl-2 and Bax staining currently plays a minimal role in helping to further stratify patients at high risk for disease progression or recurrence.

Management of iatrogenic foreign bodies of the bladder and urethra following pelvic floor surgery

Literature regarding the management of iatrogenic foreign body in the bladder and urethra following female pelvic reconstructive surgery, especially mesh erosion, are sparse. We present our recent experience with the removal of iatrogenic foreign bodies from the bladder and urethra and propose a treatment algorithm.

Urethral Diverticula in 90 Female Patients: A Study With Emphasis on Neoplastic Alterations

PURPOSE Urethral diverticula are uncommon and occur predominantly in women. We examined a large series of female urethral diverticula to determine associated neoplastic alterations and subsequent clinical outcomes. MATERIALS AND METHODS All pathological evaluations of female urethral diverticulectomies performed at our institution between 1981 and 2007 were retrospectively reviewed and the clinicopathological features were correlated. RESULTS During this period 90 women underwent urethral diverticulectomy at our institution. Patient age was 24 to 78 years (mean 45). The most common clinical finding was urinary incontinence (29 of 78 women or 37%). Diverticular size was 0.3 to 5.0 cm (mean 1.7). Neoplastic alterations identified in 5 patients (6%) were glandular in nature, including 1 clear cell and 4 invasive adenocarcinomas. Superficial changes associated with invasive carcinoma included villous adenoma in 1 case, intestinal metaplasia in 2 and high grade dysplasia in 3. An additional 3 patients had extensive intestinal metaplasia. Of the 90 patients the remaining 82 demonstrated benign findings, including nephrogenic adenoma in 10 (11%). All 5 patients with invasive carcinoma underwent anterior pelvic exenteration with urinary diversion. In 2 patients with invasive adenocarcinoma metastatic disease subsequently developed, of which they died. CONCLUSIONS Although most cases of surgically resected diverticula demonstrate benign features, approximately 10% show atypical glandular findings, including invasive adenocarcinoma. Due to the risk of malignancy in a subset of patients careful clinical examination and followup are warranted in all patients to exclude neoplastic disease.

OnabotulinumtoxinA vs Sacral Neuromodulation on Refractory Urgency Urinary Incontinence in Women: A Randomized Clinical Trial.

Importance Women with refractory urgency urinary incontinence are treated with sacral neuromodulation and onabotulinumtoxinA with limited comparative information. Objective To assess whether onabotulinumtoxinA is superior to sacral neuromodulation in controlling refractory episodes of urgency urinary incontinence. Design, Setting, and Participants Multicenter open-label randomized trial (February 2012-January 2015) at 9 US medical centers involving 381 women with refractory urgency urinary incontinence. Interventions Cystoscopic intradetrusor injection of 200 U of onabotulinumtoxinA (n = 192) or sacral neuromodulation (n = 189). Main Outcomes and Measures Primary outcome, change from baseline mean number of daily urgency urinary incontinence episodes over 6 months, was measured with monthly 3-day diaries. Secondary outcomes included change from baseline in urinary symptom scores in the Overactive Bladder Questionnaire Short Form (SF); range, 0-100, higher scores indicating worse symptoms; Overactive Bladder Satisfaction questionnaire; range, 0-100; includes 5 subscales, higher scores indicating better satisfaction; and adverse events. Results Of the 364 women (mean [SD] age, 63.0 [11.6] years) in the intention-to-treat population, 190 women in the onabotulinumtoxinA group had a greater reduction in 6-month mean number of episodes of urgency incontinence per day than did the 174 in the sacral neuromodulation group (-3.9 vs -3.3 episodes per day; mean difference, 0.63; 95% CI, 0.13 to 1.14; P = .01). Participants treated with onabotulinumtoxinA showed greater improvement in the Overactive Bladder Questionnaire SF for symptom bother (-46.7 vs -38.6; mean difference, 8.1; 95% CI, 3.0 to 13.3; P = .002); treatment satisfaction (67.7 vs 59.8; mean difference, 7.8; 95% CI, 1.6 to 14.1; P = .01) and treatment endorsement (78.1 vs 67.6; mean difference; 10.4, 95% CI, 4.3 to 16.5; P < .001) than treatment with sacral neuromodulation. There were no differences in convenience (67.6 vs 70.2; mean difference, -2.5; 95% CI, -8.1 to 3.0; P = .36), adverse effects (88.4 vs 85.1; mean difference, 3.3; 95% CI, -1.9 to 8.5; P = .22), and treatment preference (92.% vs 89%; risk difference, -3%; 95% CI, -16% to 10%; P = .49). Urinary tract infections were more frequent in the onabotulinumtoxinA group (35% vs 11%; risk difference, -23%; 95% CI, -33% to -13%; P < .001). The need for self-catheterization was 8% and 2% at 1 and 6 months in the onabotulinumtoxinA group. Neuromodulation device revisions and removals occurred in 3%. Conclusions and Relevance Among women with refractory urgency urinary incontinence, treatment with onabotulinumtoxinA compared with sacral neuromodulation resulted in a small daily improvement in episodes that although statistically significant is of uncertain clinical importance. In addition, it resulted in a higher risk of urinary tract infections and need for transient self-catheterizations.

Patient Perceived Effectiveness of a New Male Sling as Treatment for Post-Prostatectomy Incontinence

PURPOSE Objective measures show the AdVance() sling provides some benefit in post-prostatectomy incontinence. To our knowledge no validated, patient determined outcomes have been used to assess this procedure. We described the patient perceived effectiveness and postoperative complications. MATERIALS AND METHODS A retrospective chart review was followed by a telephone survey consisting of the Patient Global Impression of Improvement, Patient Global Impression of Severity, and questions about recommending the surgery, daily pad use and complications. Successful outcomes were Patient Global Impression of Improvement responses of very much better or much better without further incontinence treatment. Objective success is defined as pad-free or a reduction to 2 or less pads daily. RESULTS A total of 35 patients received the sling a median of 25 months after prostatectomy. Telephone surveys were administered a mean of 35 weeks after the sling procedure and 33 patients were contacted. Of the cases 18 (51.4%) and 21 (60%) were patient determined and objective successes, respectively. Of the patients with subjective treatment failure 3 would recommend the surgery to a friend and 12 were undecided or would not. Furthermore, no patients with subjective treatment failure were pad-free and 10 (58.8%) had pads that were mostly wet on changing. For the entire population a reduction in median daily pad use from 2.5 to 1 was observed as well as a strong association (p <0.01) between Patient Global Impression of Improvement and Patient Global Impression of Severity responses. Three individuals pursued further treatment with bulking agents and 3 had retention that resolved. CONCLUSIONS The AdVance sling is safe, and demonstrates similar subjective and objective outcomes. The procedure can benefit some individuals with post-prostatectomy incontinence and, therefore, may be another treatment option for this condition.

Sodium Pentosan Polysulfate Reduces Urothelial Responses to Inflammatory Stimuli Via an Indirect Mechanism

PURPOSE Sodium pentosan polysulfate has been promoted as a urothelial cytoprotective agent for treating interstitial cystitis. The nuclear transcription factor nuclear factor kappaB is thought to have a role in mediating the urothelial inflammatory response of interstitial cystitis. We further defined a possible cytoprotective effect of sodium pentosan polysulfate by characterizing the effect of the drug on the expression of nuclear factor kappaB. MATERIALS AND METHODS For cell culture human urothelial cells were incubated in various concentrations of sodium pentosan polysulfate for 16 hours in keratinocyte serum-free medium. They were subsequently treated with the known nuclear factor kappaB stimulants tumor necrosis factor-alpha, lipopolysaccaride (LPS) and double-stranded RNA (dsRNA). Each stimulant was then incubated with sodium pentosan polysulfate separately and the mixture was used to treat cultured urothelial cells. For electrophoretic mobility shift assay total cell extracts were prepared and run in electrophoretic mobility shift assays using a radiolabeled nuclear factor kappaB consensus sequence as a probe. Western blot analysis was done to assess nuclear factor kappaB activation by measuring degradation of the inhibitory subunit of the nuclear factor kappaB complex. RESULTS Nuclear factor kappaB activation by tumor necrosis factor-alpha, LPS and dsRNA was unaltered when cultured cells were incubated in sodium pentosan polysulfate before treatment. In contrast, nuclear factor kappaB activation by LPS and dsRNA was suppressed when the stimulants were incubated with sodium pentosan polysulfate before cell treatment. This suppressive effect was confirmed by Western blot analysis. CONCLUSION Sodium pentosan polysulfate may have a nonspecific effect against the viral (dsRNA) and bacterial (LPS) activation of nuclear factor kappaB. The observed clinical effect of sodium pentosan polysulfate may be mediated by nonspecific binding of sodium pentosan polysulfate molecules and the inflammatory stimulants of urothelial activation. These findings suggest a mechanism of action for sodium pentosan polysulfate that occurs in the urine rather than at the mucosal membrane by direct interaction of the drug with potential interstitial cystitis inducing inflammatory agents.

Purely Transvaginal/Perineal Management of Complications From Commercial Prolapse Kits Using a New Prostheses/Grafts Complication Classification System

PURPOSE Commercial prolapse mesh kits are increasingly used in the management of pelvic organ prolapse. We present our experience with the transvaginal/perineal management of synthetic mesh related complications from prolapse kits. In addition, we used the new ICS/IUGA (International Continence Society/International Urogynecological Association) prostheses/grafts complication classification system to report on our contemporary series. MATERIALS AND METHODS A retrospective chart review of all patients who underwent surgical removal of transvaginal mesh for mesh related complications after prolapse kit use from November 2006 to April 2010 at 1 institution was performed. We report our contemporary series of mesh complications using the new ICS/IUGA prostheses/grafts complication classification system. Postoperative pain, degree of improvement and presence of continued symptoms were reported by patients at last followup. RESULTS A total of 23 patients underwent transvaginal removal of mesh during the study period. Mean patient age was 61 years. Median period of latency to mesh related complication was 10 months (range 1 to 27). Indications for mesh removal included vaginal/pelvic pain (39%), dyspareunia (39%), vaginal mesh extrusion/exposure (26%), urinary incontinence (35%), recurrent pelvic organ prolapse (22%), bladder mesh perforation with recurrent urinary tract infection (22%), rectal mesh perforation (4%), ureteral perforation injury (4%), retained foreign body (surgical sponge) in the bladder (4%) and vesicovaginal fistula (9%), with most patients citing more than 1 reason. CONCLUSIONS Although technically difficult in some cases, purely transvaginal mesh excision appears to be safe with resolution of almost all presenting symptoms. Although slightly cumbersome, the new ICS/IUGA prostheses/graft complication classification system can be used to report and more accurately characterize mesh complications.

Subcellular localization of the von Hippel-Lindau disease gene product is cell cycle-dependent

The von Hippel‐Lindau gene product (pVHL) interacts with and inhibits the cellular transcription factor elongin. However, the subcellular localization of pVHL has remained uncertain. Naturally occurring pVHL mutants which fail to interact with elongin have been described in patients with VHL disease or sporadic renal cell carcinoma (RCC). Here, we have examined the cellular expression pattern of endogenous pVHL in different RCC cell lines by immunocytochemistry and confocal microscopy. Both anti‐N‐terminal and anti‐C‐terminal pVHL antibodies were able to recognize endogenous wild‐type pVHL expressed by the RCC cells studied. A C‐terminal truncated VHL mutant expressed by RCC cell line A498 was detected only by the N‐terminal antibody but not by the C‐terminal antibody as expected. The overall staining patterns of these cell lines are similar, with a predominant nuclear speckled pattern and a moderate cytoplasmic staining in subconfluent cell cultures. Interestingly, when cells reached confluency, more prominent nuclear staining with little or no cytoplasmic expression was observed. By using double labeling with anti‐VHL and anti‐bromodeoxyuridine (BrdU) antibodies and cell cycle analyses, we found that in the G1/G0‐phase, pVHL was localized exclusively in the nucleus associated with distinctive large subnuclear structures, whereas the majority of the cells in S‐phase of the cell cycle also showed a diffuse cytoplasmic staining. Our results indicate that subcellular localization of pVHL is regulated in a cell cycle‐dependent manner. Int. J. Cancer 78:62–69, 1998.© 1998 Wiley‐Liss, Inc.