Risk Factors for De Novo Overactive Bladder After Midurethral Sling.

IMPORTANCE: The low incidence of de novo overactive bladder (OAB) symptoms after a midurethral sling (MUS) procedure better informs preoperative counseling. OBJECTIVE: The study aimed to measure the incidence and risk factors for de novo OAB after MUS. STUDY DESIGN: This was a retrospective cohort study of de novo OAB symptoms in patients who underwent MUS surgery in a health maintenance organization between January 1, 2008, and September 30, 2016. Patients were identified using Current Procedural Terminology codes for MUS and International Classification of Diseases, Tenth Revision codes for urinary urgency, frequency, nocturia, OAB, and urgency urinary incontinence (UUI). The cohort of patients was identified by the absence of these International Classification of Diseases, Tenth Revision codes 12 months preoperatively and the presence of these codes within 6 months after surgery. This cohort was used to calculate the rate of de novo OAB after MUS surgery. Clinical and demographic factors were abstracted. Statistical analysis was performed using descriptive, χ2 , simple logistic, and multiple logistic regression. RESULTS: During the study period, 13,893 patients underwent MUS surgery and 6,634 met the inclusion criteria. The mean age was 56.9 years, mean parity was 2.76, and mean body mass index was 28.9 (calculated as weight in kilograms divided by height in meters squared). Of these, 410 (6.1%) developed de novo OAB within 12 months. The most common symptoms were urgency (65.4%), UUI (42.2%), and frequency (19.8%). On multivariable regression modeling, de novo urgency and UUI were not associated with concurrent surgery ( P < 0.05). Increasing age and body mass index were associated with an increased risk of nocturia ( P < 0.05). CONCLUSIONS: The incidence of de novo OAB after MUS surgery was 6.1%. This aligns with current literature and critically informs preoperative counseling for MUS surgery.

Fecal Putative Uropathogen Abundance and Antibiotic Resistance Gene Carriage in Women With Refractory Recurrent Urinary Tract Infection Treated With Fecal Microbiota Transplantation.

OBJECTIVE: The aims of this study were to describe the fecal relative abundance of potentially uropathogenic bacteria and to analyze antibiotic resistance genes before and after fecal microbiota transplantation in women with recurrent urinary tract infection (UTI). METHODS: Shotgun sequencing was performed on fecal samples from 3 donors and 4 women with recurrent UTI who underwent transplantation. Recipient samples were sequenced at baseline and at 4 time points through 6 months postintervention. Relative fecal uropathogen abundance was analyzed by species and participant using descriptive statistics. Antibiotic resistance gene abundance was assigned, normalized, and compared between donors and recipients at baseline and postintervention using an abundance bar plot, nonmetric multidimensional scaling, and pairwise permutational multivariate analysis of variance. RESULTS: The median (range) relative abundance of Escherichia coli in all fecal samples from women with recurrent UTI was 0% (0%-5.10%); Enterococcus faecalis, 0% (0%-0.20%); Enterococcus faecium, 0% (0%-1.90%); Klebsiella pneumoniae, 0% (0%-0.10%); and Pseudomonas aeruginosa, 0% (0%-0.10%). Gut microbes carried genes conferring resistance to antibiotics used for UTI. No significant difference was seen in antibiotic resistance gene carriage after transplantation compared with baseline (P=0.22, R2=0.08 at 3 months). Antibiotic gene composition and abundance were significantly associated with the individual from whom the sample came (P=0.004, R2=0.78 at 3 months). CONCLUSIONS: Exploratory analysis of gut microbiomes in women with recurrent UTI identifies no or low relative putative uropathogen abundance for all species examined. Antibiotic resistance gene carriage persisted after fecal microbiota transplantation, although conclusions are limited by small sample size.

Knowledge of pelvic floor disorders in women seeking primary care: a cross-sectional study.

BACKGROUND: Pelvic floor disorders including urinary incontinence (UI) and pelvic organ prolapse (POP) are common conditions; however, most women with these symptoms do not seek care. Failure to seek care may be related to misconceptions about these conditions. The aim of this study was to assess the baseline knowledge of UI and POP among adult women presenting to primary care clinics, as well as factors associated with knowledge levels. METHODS: A survey with questions from previously validated UI and POP knowledge questionnaires (PIKQ-UI and PIKQ-POP, respectively) was self-administered to a cross-sectional group of adult female patients presenting to three primary care clinics: geriatric, community-based, and hospital-based. Participants' demographics and medical histories were compared using ANOVA or Kruskal-Wallis for continuous variables and Chi-square test or Fisher's exact test for categorical variables. In order to compare various covariates with knowledge non-proficiency on PIKQ-UI and PIKQ-POP scales, unadjusted and adjusted ORs with 95% CIs were calculated using bivariate analysis and multivariate logistic regression, respectively. RESULTS: Of 346 participants, knowledge non-proficiency was similar and consistent across clinic sites and reached 72.0% for UI and 53.6% for POP. On multivariate analysis, lower educational attainment, being unaware of UI or POP as medical conditions, and having no history of care-seeking for these conditions were significantly associated with knowledge non-proficiency on UI, POP, or both. CONCLUSIONS: Knowledge non-proficiency for UI and POP is common among women presenting for primary care. For UI, healthcare providers should assess patients' actual understanding of the disease, especially among those with lower educational attainment, to eliminate any possible misconceptions. For POP, the focus should be on increasing awareness of this disease, as many women may have not previously heard of this condition. Simple strategies may increase knowledge in these areas and change care-seeking behaviors. STUDY REGISTRATION: None.

An Internet-based survey to evaluate the comfort and need for further pubovaginal sling training.

INTRODUCTION AND HYPOTHESIS: The pubovaginal sling (PVS) dates to the 1940s as an efficacious surgical treatment for stress urinary incontinence (SUI). Recently, it has been replaced by the midurethral sling (MUS). Since 2008, international regulatory agencies increased regulation and issued warnings on vaginal mesh for repair of pelvic organ prolapse (POP), which has led to increased scrutiny of the MUS. Thus, the need for surgical comfort with PVS is resurfacing. We sought to evaluate the surgical practice patterns among international urogynecologists for the treatment of SUI and identify whether a need and interest for more training exists. METHODS: We developed a short, Internet-based survey for members of the International Urogynecological Association (IUGA). Descriptive analyses, binomial and multivariate logistic regressions were calculated to determine significant associations. RESULTS: Among 556 members who responded to the survey, 72% did not offer PVS in practice. Among those who did, there was as significant relationship between offering PVS and practicing in the United States, board-certification in urogynecology, PVS exposure in training, increasing number of PVS performed during training, and comfort with PVS. Members interested in further PVS training were younger, less comfortable with PVS, performed fewer PVS, or had no exposure in training. CONCLUSION: Most IUGA members do not offer PVS in clinical practice. As would be expected, members who performed more PVS in training and were more comfortable with PVS were likely to offer it to patients. Our results highlight a learning gap, especially among younger providers who are not comfortable with PVS and desire further training in this procedure.

Intravesical instillations for the treatment of refractory recurrent urinary tract infections.

BACKGROUND: Treatment options for refractory recurrent urinary tract infections (UTI) are limited; therefore, we sought to determine if intravesical instillations with heparin effectively treat recurrent UTIs. METHODS: Patients at an academic medical center who received intravesical instillations with heparin for recurrent UTIs/chronic cystitis between January 2011 and December 2015 were identified via International Classification of Diseases, Ninth Revision (ICD-9) and Current Procedural Terminology (CPT) procedure codes. All cases were analyzed for frequency of UTIs during the treatment phase as well as for the subsequent 6 months after completion of therapy. Demographic, clinical and treatment related factors were then collected from the medical records to draw associations with success or failure of treatment. RESULTS: Thirty-nine women were treated with heparin intravesical instillations for recurrent UTIs. The average age of the cohort was 68.38 years [range 25-88, standard deviation (SD) 12.92], with mean parity 2.38 (range 0-7, SD 1.55) and mean body mass index 27.85 (range 19.5-37.9, SD 4.84). A total of 84.6% completed the recommended 6-week treatment course while 69.2% went on to an additional maintenance phase. Twelve patients (30.8%) had a culture-proven UTI during the treatment phase. In the 6-month follow-up period, 46.2% of patients had at least one UTI with only seven patients (17.9%) meeting criteria for recurrent UTIs (two or more UTIs in 6 months). On univariable assessment, development of recurrent UTIs after completion of instillation therapy was associated with increasing age and vaginal estrogen use during the instillation treatment course. CONCLUSIONS: Intravesical instillation with heparin is an effective option to consider for the treatment of refractory recurrent UTIs.

Pathologic features associated with resolution of complex atypical hyperplasia and grade 1 endometrial adenocarcinoma after progestin therapy.

OBJECTIVE: To determine the response of complex atypical hyperplasia (CAH) and well differentiated endometrioid adenocarcinoma of the uterus (WDC) to progestin therapy and whether pre-treatment estrogen and progesterone receptor status predicts outcome. METHODS: We performed a retrospective review encompassing women treated with progestin therapy for CAH or WDC at two institutions. Clinicopathologic, treatment, and recurrence data were recorded. Pre/post-treatment pathologic evaluation was performed. SAS 9.2 was used for statistical analyses. RESULTS: Forty-six patients were included. The median age was 35, and median BMI was 36.9. Thirty-seven percent were diagnosed with CAH and 63% had WDC. Megestrol acetate was the most commonly used agent (89%); 24% received multiple progestin therapies. Median treatment length was 6 months (range, 1-84); 36% of the patients underwent eventual hysterectomy, and 17.4% had carcinoma in their uterine specimens (8 primary endometrial, 1 primary ovarian). After a median follow-up of 35 months (range, 2-162), 65% experienced a complete response (CR), 28% had persistent or progressive disease, and 23% had a CR followed by recurrence. On univariate analysis, decreased post-treatment glandular cellularity (p = 0.0006), absence of post-treatment mitotic figures (p = 0.0008), and use of multiple progestin agents (p = 0.025) were associated with CR; however, only decreased glandular cellularity was significant on multivariate analysis (p = 0.007). Estrogen and progesterone receptor expression was not associated with treatment response. CONCLUSION: In women with CAH or WDC, the overall response rate to progestin therapy was 65%; pre-treatment estrogen/progesterone receptor status did not predict response to treatment.

The NF-κB pathway mediates lysophosphatidic acid (LPA)-induced VEGF signaling and cell invasion in epithelial ovarian cancer (EOC).

OBJECTIVES: Our previous report has implicated the involvement of VEGF-VEGFR-2 h signaling in LPA-induced EOC invasion. However, the mechanism by which LPA regulates VEGF and VEGFR-2 expression remains to be elucidated. In the present study, we systematically examined the signal transduction pathways activated by LPA and further evaluated whether LPA's effect on VEGF-VEGFR-2 signaling and EOC invasion was mediated by the activation of NF-κB pathway. METHODS: Using a signal transduction PathwayFinder PCR array, we examined the expression change of 86 key genes representing 18 signal transduction pathways in DOV13 and SKOV3 cells upon LPA (20 µM) treatment. We also used quantitative PCR, Western blotting and ELISA to evaluate the effect of NF-κB pathway inhibition on VEGF(121), VEGF(165) and VEGFR-2 mRNA and protein expression/secretion with or without the presence of LPA (20 µM) in SKOV3. Cell invasion under various treatment conditions was assessed by Matrigel invasion assay and MMP-2 secretion was detected by gelatin zymography. RESULTS: Our results showed that in both DOV13 and SKOV3, several of the NF-κB pathway components, such as TNF, are consistently activated by LPA stimulation. In addition, treatment with an NF-κB pathway activation inhibitor, at 10 µM, significantly decreased LPA-induced VEGF(121), VEGF(165) and VEGFR-2 mRNA expression and VEGF secretion, as well as LPA-induced SKOV3 invasion (p<0.05). When combined with an EGFR inhibitor, NF-κB pathway inhibition exhibited a significantly stronger effect than used alone (p<0.05) on reducing LPA-induced VEGF secretion and cell invasion. Additionally, NF-κB inhibition also decreased LPA-induced MMP-2 secretion and MMP-1 expression (p<0.05). CONCLUSIONS: These results suggest that the NF-κB pathway plays an important role in LPA-induced VEGF signaling and EOC invasion and targeting this pathway may reveal potential therapeutic options for metastatic EOC.

Biomarkers for ovarian cancer detection and therapy.

Despite advances in surgical technologies and the development of more effective chemotherapeutics, epithelial ovarian cancer (EOC) remains the leading cause of death in women with gynecologic malignancies. The high mortality and morbidity associated with EOC is mostly attributed to the inability to detect the disease before it is widely disseminated throughout the abdominal cavity. In the past decade, tremendous efforts have been taken to search for novel biomarkers that will detect EOC at an early stage, which may also serve as new targets for the prevention and control of metastasis. Here, we review recent developments in EOC early detection and targeted therapy, as well as new technologies for the discovery of novel biomarkers.

New frontiers for ovarian cancer risk evaluation: proteomics and contrast-enhanced ultrasound.

OBJECTIVE: The grim ovarian cancer statistics are attributed to the fact that most women typically present with widespread disease at the time of initial diagnosis. Our current diagnostic tools, such as pelvic examination and standard ultrasound, are inadequate to detect early-stage epithelial ovarian cancer. In recent years there has been an explosion of important advances in biomedical engineering, proteomic technologies, and computational analyses that has led to the identification of hundreds of previously unknown proteins unique to the pathophysiology of ovarian cancer, some of which are currently under clinical validation. At present, no one biomarker exists with 100% specificity and sensitivity for the accurate detection of early-stage epithelial ovarian cancer. CONCLUSION: As the search for a panel of biomarkers detecting cancer, let alone early-stage disease, progresses, diagnostic imaging will continue to play a critical role to confirm or refute these biomarker assays. Interestingly, recent studies using contrast-enhanced ultrasound have shown potential as an early-detection tool by detecting the aberrant vascularity required for tumor growth before the development of a mass. Thus, we propose that the use of proteomic-based biomarker discovery and contrast-enhanced ultrasound may serve as a promising combination to help accurately identify early-stage epithelial ovarian cancer to improve women's health care.

VEGFR-2 silencing by small interference RNA (siRNA) suppresses LPA-induced epithelial ovarian cancer (EOC) invasion.

BACKGROUND: The VEGF-VEGF receptor (VEGFR) signaling axis has emerged as a promising target for cancer therapy, attributing to its vital role in tumor angiogenesis and growth. We have previously reported the regulation of epithelial ovarian cancer (EOC) invasion and migration by VEGF and the implication of VEGF-VEGFR-2 axis in lysophosphatidic acid (LPA)-induced EOC invasion. However, the expression profile of VEGF and VEGFRs in EOC, their association with tumor aggressiveness, and their regulation by LPA remain unclear. OBJECTIVES AND METHODS: In this study, we examined the expression of VEGFR-1, VEGFR-2, neuropilin-1 (NRP-1), NRP-2, VEGF(121), and VEGF(165) in established EOC cell lines and assessed their correlation with cell invasiveness. Moreover, using an ovarian cancer tissue qPCR array, we analyzed VEGFR-2 expression across a panel of 48 tissues with different disease stages and histological grades. We also tested the effect of LPA on VEGF and VEGFR-2 expression and examined whether blocking VEGFR-2 by RNA interference (RNAi) affects LPA-induced EOC invasion. RESULTS: We show that VEGF and VEGFR-2 expression correlates with cell invasiveness and VEGFR-2 expression in ovarian cancer tissues correlate with tumor grade. In addition, LPA, at 20 muM, significantly induced the expression of VEGF(121), VEGF(165), and VEGFR-2 in SKOV3 and DOV13 cells (P<0.05). VEGFR-2 small interference RNA (siRNA) transfection remarkably decreased LPA's invasion-promoting effect (P<0.001) in SKOV3 cells without significantly decreasing SKOV3 cells' basal invasiveness. In DOV13 cells, VEGFR-2 silencing significantly decreases both the basal level cell invasion and LPA's invasion promoting effect (P<0.001). CONCLUSION: These results suggest that decreasing VEGFR-2 expression by RNAi may prove to be an effective method to reduce the metastatic potential of EOC cells exposed to elevated levels of LPA.

Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder.

Removal of toxic substances from the blood depends on patent connections between the kidney, ureters and bladder that are established when the ureter is transposed from its original insertion site in the male genital tract to the bladder. This transposition is thought to occur as the trigone forms from the common nephric duct and incorporates into the bladder. Here we re-examine this model in the context of normal and abnormal development. We show that the common nephric duct does not differentiate into the trigone but instead undergoes apoptosis, a crucial step for ureter transposition controlled by vitamin A-induced signals from the primitive bladder. Ureter abnormalities occur in 1-2% of the human population and can cause obstruction and end-stage renal disease. These studies provide an explanation for ureter defects underlying some forms of obstruction in humans and redefine the current model of ureter maturation.