Sheng-Mou Hsiao

IL-6 Trans-Signaling in Formation and Progression of Malignant Ascites in Ovarian Cancer

Classic signaling by the proinflammatory cytokine interleukin 6 (IL-6) involves its binding to target cells that express the membrane-bound IL-6 receptor α. However, an alternate signaling pathway exists in which soluble IL-6 receptor (sIL-6Rα) can bind IL-6 and activate target cells that lack mIL-6Rα, such as endothelial cells. This alternate pathway, also termed trans-signaling, serves as the major IL-6 signaling pathway in various pathologic proinflammatory conditions including cancer. Here we report that sIL-6Rα is elevated in malignant ascites from ovarian cancer patients, where it is associated with poor prognosis. IL-6 trans-signaling on endothelial cells prevented chemotherapy-induced apoptosis, induced endothelial hyperpermeability, and increased transendothelial migration of ovarian cancer cells. Selective blockade of the MAPK pathway with ERK inhibitor PD98059 reduced IL-6/sIL-6Rα-mediated endothelial hyperpermeability. ERK activation by the IL-6/sIL-6Rα complex increased endothelial integrity via Src kinase activation and Y685 phosphorylation of VE-cadherin. Selective targeting of IL-6 trans-signaling in vivo reduced ascites formation and enhanced the taxane sensitivity of intraperitoneal human ovarian tumor xenografts in mice. Collectively, our results show that increased levels of sIL-6Rα found in ovarian cancer ascites drive IL-6 trans-signaling on endothelial cells, thereby contributing to cancer progression. Selective blockade of IL-6 trans-signaling may offer a promising therapeutic strategy to improve the management of patients with advanced ovarian cancer.

An alternative intervention for urinary incontinence: Retraining diaphragmatic, deep abdominal and pelvic floor muscle coordinated function

This study was a randomized controlled trial to investigate the effect of treating women with stress or mixed urinary incontinence (SUI or MUI) by diaphragmatic, deep abdominal and pelvic floor muscle (PFM) retraining. Seventy women were randomly allocated to the training (n = 35) or control group (n = 35). Women in the training group received 8 individual clinical visits and followed a specific exercise program. Women in the control group performed self-monitored PFM exercises at home. The primary outcome measure was self-reported improvement. Secondary outcome measures were 20-min pad test, 3-day voiding diary, maximal vaginal squeeze pressure, holding time and quality of life. After a 4-month intervention period, more participants in the training group reported that they were cured or improved (p < 0.01). The cure/improved rate was above 90%. Both amount of leakage and number of leaks were significantly lower in the training group (p < 0.05) but not in the control group. More aspects of quality of life improved significantly in the training group than in the control group. Maximal vaginal squeeze pressure, however, decreased slightly in both groups. Coordinated retraining diaphragmatic, deep abdominal and PFM function could improve symptoms and quality of life. It may be an alternative management for women with SUI or MUI.

Risk Factors Affecting Cure After Mid-urethral Tape Procedure for Female Urodynamic Stress Incontinence: Comparison of Retropubic and Transobturator Routes

OBJECTIVES To identify the risk factors affecting cure after the tension-free vaginal tape procedure (TVT) or transobturator tape procedure (TOT). METHODS A total of 121 women with urodynamically proved stress incontinence underwent TVT (n = 61) or TOT (n = 60). We analyzed all data with univariate and multivariate logistic regression analyses. RESULTS Univariate analysis revealed that a larger postvoid residual urine volume, greater pad weight test, and lower maximal flow rate were associated with a greater risk of failure to be cured after TVT. A lower maximal urethral closure pressure (MUCP) was associated with a greater risk of failure after the TOT procedure. With additional analysis, we found that a MUCP of <or=40 cm H(2)O (odds ratio [OR] 9.21, P = .004) was associated with a significantly greater risk of failure to be cured after the TOT procedure but not a MUCP of <o=50 cm H(2)O (OR 2.24, P = .21). Multivariate analysis revealed that preoperative detrusor overactivity was an independent risk factor affecting cure after TVT (OR 113.1, 95% confidence interval 1.84-6592.77, P = .02) or TOT (OR 23.7, 95% confidence interval 1.63-344.53, P = .02), and MUCP <o=40 cm H(2)O (OR 8.34, 95% confidence interval 1.52-45.65, P = .01) was another risk factor for TOT. CONCLUSIONS The risk factors affecting cure after mid-urethral tape procedures were preoperative detrusor overactivity for TVT and TOT and MUCP <o=40 cm H(2)O for TOT.

Comparisons of urodynamic effects, therapeutic efficacy and safety of solifenacin versus tolterodine for female overactive bladder syndrome

Aim:  To evaluate the urodynamic effects, therapeutic efficacy and safety of solifenacin versus tolterodine treatment for women with overactive bladder syndrome.

Histone Deacetylase 6 Regulates Estrogen Receptor α in Uterine Leiomyoma

Histone deacetylase 6 (HDAC) 6 is a regulatory factor in the endocrine traffic network that controls growth factor receptor stability. Histone deacetylase 6 expression and its pathogenic role in the uterine leiomyoma have not been studied. Here, we demonstrated that there was a consistent pattern of increasing HDAC6 and estrogen receptor (ER) α expression in leiomyoma samples. For all individual cases, expression of HDAC6 in the normal myometrium or leiomyoma positively correlated with ERα expression. The spearman’s rho (ρ) was .53 (P = .008) between HDAC6 and ERα in normal myometrium and, more significantly, the spearman rho was .80 (P < .001) between HDAC6 and ERα in leiomyoma. In ELT-3 leiomyoma cells, silencing HDAC6 expression substantially reduced ERα expression, lowered estrogen response, and inhibited ELT-3 cell growth. Our results, taken together, are the first to provide experimental evidence suggesting that HDAC6 may be an essential molecular therapeutic target in controlling leiomyoma growth.

Effect of Pelvic-Floor Muscle Strengthening on Bladder Neck Mobility: A Clinical Trial

Background Pelvic-floor muscle (PFM) strengthening has been widely used to treat people with urinary incontinence (UI). However, its effect on bladder neck position and stiffness is unknown. Objective The aim of the study was to investigate the effect of PFM strengthening on bladder neck mobility for women with stress UI (SUI) or mixed UI (MUI). Design This study was conducted as a single-group pretest-posttest design. Setting This study was conducted mainly at the Life Quality & Health Promotion Laboratory at National Taiwan University and partly in the Ultrasonography Room of the Department of Obstetrics and Gynecology at National Taiwan University Hospital. Patients Twenty-three patients (mean age=51.9 years, SD=6.1) participated in the study. Intervention and Measurements Each participant underwent a PFM strengthening program for 4 months. Bladder neck position at rest and during a cough, the Valsalva maneuver, and a PFM contraction was assessed by transperineal ultrasonography before and after the intervention. Severity Index score, self-reported improvement, PFM strength (force-generating capacity), and vaginal squeeze pressure were assessed for treatment effect. Results The position of the bladder neck at PFM contraction and bladder neck mobility for maximal incursion from rest to PFM contraction were elevated, with effect sizes of 0.48 and 0.84, respectively. Bladder neck position and bladder neck mobility were not changed during a cough and the Valsalva maneuver. All participants reported diminution of incontinence, and PFM strength and maximal vaginal squeeze pressure were improved after the intervention. Limitations The limitations of the present trial included the pretest-posttest design and the absence of intra-abdominal pressure measuring and exercise adherence recording. Conclusions Four months of daily PFM strengthening can significantly improve the ability of the PFM to elevate the bladder neck voluntarily, but may not improve its stiffness during a cough and the Valsalva maneuver for women with SUI and MUI.

Comparison of robot‐assisted laparoscopic myomectomy and traditional laparoscopic myomectomy

The benefit of robot‐assisted laparoscopic myomectomy (RALM) over traditional laparoscopic myomectomy (TLM) remains undetermined. The aim of this study was to reveal any potential advantage of RALM over TLM.

Phase II trial of carboplatin and distearoylphosphatidylcholine pegylated liposomal doxorubicin (Lipo-Dox) in recurrent platinum-sensitive ovarian cancer following front-line therapy with paclitaxel and platinum.

OBJECTIVE To evaluate the effectiveness and toxicity of distearoylphosphatidylcholine pegylated liposomal doxorubicin (DPLD) combined with carboplatin for the treatment of platinum-sensitive, paclitaxel-pretreated, recurrent, epithelial ovarian cancer. METHODS A phase II study of carboplatin/DPLD treatment for platinum-sensitive, paclitaxel-pretreated, recurrent, epithelial ovarian cancer was initiated in July 2002. As of March 2008, a total of 32 patients were enrolled. RESULTS Of the 32 patients, one achieved a complete response; 19 (59%) achieved a partial response. The overall objective response rate was 62% (95% confidence interval [CI], 45%-80%). The median progression-free survival and overall survival for all 32 patients was 9.1 months (95% CI, 6.4-10.4 months) and 27.9 months (95% CI, 13.9-38.6 months), respectively. Toxicity was tolerable. The most common grade 3 or 4 toxicities were anemia (n=3) and nausea/vomiting (n=3). Grade 3/4 leukopenia (n=2), grade 3/4 thrombocytopenia (n=2) and grade 4 hepatitis (n=1) occurred in five patients. CONCLUSION Carboplatin/DPLD appears to be an effective regimen with low toxicity for treatment of patients with platinum-sensitive, paclitaxel-pretreated, recurrent, epithelial ovarian cancer.

The STAT3-miRNA-92-Wnt signaling pathway regulates spheroid formation and malignant progression in ovarian cancer

Ovarian cancer spheroids constitute a metastatic niche for transcoelomic spread that also engenders drug resistance. Spheroid-forming cells express active STAT3 signaling and display stem cell-like properties that may contribute to ovarian tumor progression. In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity. Mechanistic investigations revealed that Wnt signaling was required for STAT3-mediated spheroid formation. Notably, the Wnt antagonist DKK1 was the most strikingly upregulated gene in response to STAT3 attenuation in ovarian cancer cells. STAT3 signaling maintained stemness and interconnected Wnt/β-catenin signaling via the miR-92a/DKK1-regulatory pathways. Targeting STAT3 in combination with paclitaxel synergistically reduced peritoneal seeding and prolonged survival in a murine model of intraperitoneal ovarian cancer. Overall, our findings define a STAT3-miR-92a-DKK1 pathway in the generation of cancer stem-like cells in ovarian tumors, with potential therapeutic applications in blocking their progression. Cancer Res; 77(8); 1955-67. ©2017 AACR.

Factors associated with a better therapeutic effect of solifenacin in patients with overactive bladder syndrome.

To analyze the predictors of therapeutic success after solifenacin treatment.