Synergistic Antitumor Effects of Combined Treatment with HSP90 Inhibitor and PI3K/mTOR Dual Inhibitor in Cisplatin-Resistant Human Bladder Cancer Cells.

PURPOSE: The current study aimed to investigate the synergistic antitumor effect of combined treatment with 17-DMAG (HSP90 inhibitor) and NVP-BEZ235 (PI3K/mTOR dual inhibitor) on cisplatin-resistant human bladder cancer cells. MATERIALS AND METHODS: Human bladder cancer cells exhibiting cisplatin resistance (T24R2) were exposed to escalating doses of 17-DMAG (2.5-20 nM) with or without NVP-BEZ236 (0.5-4 µM) in combination with cisplatin. Antitumor effects were assessed by CCK-8 analysis. Based on the dose-response study, synergistic interactions between the two regimens were evaluated using clonogenic assay and combination index values. Flow cytometry and Western blot were conducted to analyze mechanisms of synergism. RESULTS: Dose- and time-dependent antitumor effects for 17-DMAG were observed in both cisplatin-sensitive (T24) and cisplatin-resistant cells (T24R2). The antitumor effect of NVP-BEZ235, however, was found to be self-limiting. The combination of 17-DMAG and NVP-BEZ235 in a 1:200 fixed ratio showed a significant antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range, and clonogenic assay showed compatible results with synergy tests. Three-dimensional analysis revealed strong synergy between the two drugs with a synergy volume of 201.84 µM/mL²%. The combination therapy resulted in G1-phase cell cycle arrest and caspase-dependent apoptosis confirmed by the Western blot. CONCLUSION: HSP90 inhibitor monotherapy and in combination with the PI3K/mTOR survival pathway inhibitor NVP-BEZ235 shows a synergistic antitumor effect in cisplatin-resistant bladder cancers, eliciting cell cycle arrest at the G1 phase and induction of caspase-dependent apoptotic pathway.

Effect of Early Sacral Neuromodulation on Bladder Function in a Rat Model of Incomplete Spinal Cord Injury Due to Focal Contusion.

OBJECTIVES: Incomplete spinal cord injury (SCI) accounts for two-thirds of all SCIs in clinical practice. Preclinical research on the effect of sacral neuromodulation (SNM) on bladder function, however, has been focused only on animal models of complete SCI. We aimed to evaluate the effect of early SNM on bladder responses in a rat model of incomplete SCI. MATERIALS AND METHODS: Altogether, 21 female Sprague-Dawley rats were equally assigned to control (CTR), SCI + sham stimulation (SHAM), and SCI + SNM (SNM) groups. In the SHAM and SNM groups, incomplete SCI was created by producing a moderate contusion with an NYU-MASCIS impactor at the T9-T10 level of the spine, with needle electrodes implanted bilaterally into the S2 or S3 sacral foramen. Only SNM group underwent electrical stimulation for 28 days, beginning on day 7 after SCI. Cystometry was performed 35 days after SCI. RESULTS: Although the interval between voiding contractions was significantly longer in the SHAM group than the CTR group (25.5 ± 1.4 vs. 12.5 ± 1.7 min; p < 0.05), there were no significant differences between the SNM group (16.5 ± 1.5 min) and the CTR group. Maximum voiding contraction pressure did not differ among the groups. The SNM group had a significantly lower frequency (3.5 ± 0.5 vs. 14.6 ± 2.0; p < 0.05) and maximum pressure (11.4 ± 6.2 vs. 21.3 ± 1.8 cmH2 O; p < 0.05) of nonvoiding contractions than the SHAM group. CONCLUSIONS: Our results provide experimental evidence that early SNM treatment may prevent or diminish bladder dysfunctions (e.g., detrusor overactivity, abnormal micturition reflex) in a clinical condition of incomplete SCI.

Intermediate PSA half-life after neoadjuvant hormone therapy predicts reduced risk of castration-resistant prostate cancer development after radical prostatectomy.

BACKGROUND: The magnitude and rapidity of the tumor response to androgen deprivation is known to predict the durability of the therapy. We have investigated the predictive value of categorizing patients by the half-life of PSA under neoadjuvant androgen deprivation therapy in patients with biochemical recurrence after radical prostatectomy. METHODS: Medical records of 317 patients who received neoadjuvant androgen deprivation therapy before radical prostatectomy and developed biochemical recurrence were analyzed. The patients were categorized into five groups according to PSA half-life. Risk of developing castration resistance was evaluated by Kaplan-Meier analysis and by Cox proportional risk regression analysis. RESULTS: The median follow-up duration was 50.1 months (IQR 31.8-68.7) and median PSA half-life was 22.1 days (IQR 12.7-38.4). Comparison of survival curves revealed that patients in the intermediate response group showed significantly lower 5-year castration-resistant prostate cancer rate (37.5%) compared to non-response and ultra-rapid response groups (63.6%, p = 0.007; 56.1%, p = 0.031; respectively). In the multivariate regression model, intermediate response compared to non-response was associated with significantly reduced risk of castration resistance development (hazard ratio 0.397, 95% confidence interval 0.191-0.823, p = 0.013) and overall mortality (hazard ratio 0.138, 95% confidence interval 0.033-0.584, p = 0.007). When subcategorized by Gleason score, Kaplan-Meier curve revealed that, in the high Gleason score stratum, 5-year castration-resistant prostate cancer rate for intermediate response group (44.0%) was exceptionally lower than that in non-response group (66.7%, p = 0.047), while castration resistance increased in other groups. CONCLUSION: Short PSA half-life as well as no response after androgen deprivation is associated with increased risk of treatment failure compared to intermediate PSA half-life.

Impact of lymphovascular invasion on lymph node metastasis for patients undergoing radical prostatectomy with negative resection margin.

BACKGROUND: The association between lymphovascular invasion and lymphatic or hematogenous metastasis has been suspected, with conflicting evidence. We have investigated the association between the risk of biochemical recurrence and lymphovascular invasion in resection margin negative patients, as well as its association with lymph node metastasis. METHODS: One thousand six hundred thirty four patients who underwent radical prostatectomy from 2005 to 2014 were selected. Patients with bone or distant organ metastasis at the time of operation were excluded. Survival analysis was performed to assess biochemical recurrence, metastasis and mortality risks by Kaplan-Meier analysis and multivariate Cox proportional hazard regression. Odds of lymph node metastasis were evaluated by Logistic regression. RESULTS: LVI was detected in 118 (7.4%) patients. The median follow-up duration was 33.1 months. In the Kaplan-Meier analysis, lymphovascular invasion was associated with significantly increased 5-year and 10-year BCR rate (60.2% vs. 39.1%, 60.2% vs. 40.1%, respectively; p < 0.001), 10-year bone metastasis rate and cancer specific mortality (16.9% vs. 5.1%, p = 0.001; 6.8% vs. 2.7%, p = 0.034, respectively) compared to patients without LVI. When stratified by T stage and resection margin status, lymphovascular invasion resulted in significantly increased 10-year biochemical recurrence rate in T3 patients both with and without positive surgical margin (p = 0.008, 0.005, respectively). In the multivariate Cox regression model lymphovascular invasion resulted in 1.4-fold BCR risk and 1.7-fold metastasis risk increase (95% CI 1.045-1.749, 1.024-2.950; p = 0.022, 0.040, respectively). Lymphovascular invasion was revealed to be strongly associated with lymph node metastasis in the multivariate Logistic regression (OR 4.317, 95% CI 2.092-8.910, p < 0.001). CONCLUSION: Lymphovascular invasion increases the risk of recurrence in T3 patients regardless of margin status, by accelerating lymph node metastasis and distant organ metastasis.

The prognostic significance of postoperative neutrophil-to-lymphocyte ratio after radical prostatectomy for localized prostate cancer.

BACKGROUND: The pretreatment neutrophil-to-lymphocyte ratio has prognostic value after radical prostatectomy for treating localized prostate cancer. However, the use of postoperative neutrophil-to-lymphocyte ratio has not been evaluated in this population. We investigated the prognostic significance of early postoperative neutrophil-to-lymphocyte ratio after radical prostatectomy for prostate cancer. METHODS: We retrospectively reviewed clinical data from 2,302 patients with localized prostate cancer who underwent radical prostatectomy at our institution between years 2000 and 2010. Only patients with pre- and postoperative complete blood counts with differential results were included. Patients who received neoadjuvant or postoperative adjuvant treatment and those without adequate medical records were excluded. Kaplan-Meier analyses were performed to analyze biochemical recurrence-free survival and overall survival rates. Univariate and multivariate Cox regression models were used for each endpoint. RESULTS: Kaplan-Meier curves showed that high postoperative neutrophil-to-lymphocyte ratio (>3.5) was significantly associated with decreased biochemical recurrence-free survival (p = 0.009) and overall survival (p = 0.010). In the univariate and multivariate Cox regression analyses, high postoperative neutrophil-to-lymphocyte ratio was a significant predictor of biochemical recurrence (hazard ratio 1.270, p = 0.008) and overall survival (hazard ratio 1.437, p = 0.033). CONCLUSIONS: Our results demonstrate that postoperative neutrophil-to-lymphocyte ratio is an independent factor for biochemical recurrence and overall survival in patients who underwent radical prostatectomy for prostate cancer. These findings suggest that neutrophil-to-lymphocyte ratio can be a potentially valuable tool for stratifying high-risk patients and facilitating choices of postoperative therapy in patients with prostate cancer.

Prognostic Significance of the Proportion of Ductal Component in Ductal Adenocarcinoma of the Prostate.

PURPOSE: In prostate cancer ductal adenocarcinoma is mixed with the usual acinar adenocarcinoma. However, to our knowledge whether the proportion of the ductal component affects oncologic outcomes is currently unknown. We investigated whether the proportion of the ductal component predicts oncologic outcomes in ductal adenocarcinoma. MATERIALS AND METHODS: We retrospectively reviewed clinical data on 3,038 patients with prostate cancer who underwent radical prostatectomy at our institution between 2005 and 2014. We excluded patients who received neoadjuvant or adjuvant treatment. Patients were stratified based on the proportion of the ductal component. We compared the probability of biochemical recurrence between groups and investigated how the proportion of the ductal component influences biochemical recurrence using Kaplan-Meier estimates and Cox regression models, respectively. RESULTS: Of 2,648 patients 101 (3.8%) had ductal adenocarcinoma and 2,547 (96.2%) had acinar adenocarcinoma. Freedom from biochemical recurrence in patients with ductal adenocarcinoma was significantly lower than in those with acinar adenocarcinoma (p <0.001). When ductal cases were stratified by the proportion of the ductal component, freedom from biochemical recurrence in the high ductal component group was significantly lower compared to that in the low ductal component group (30% or greater vs less than 30%, p = 0.023). On univariate and multivariate Cox regression analyses, a high ductal component was a significant predictor of biochemical recurrence (p <0.001). CONCLUSIONS: The prognosis for ductal adenocarcinoma can be stratified by the proportion of the ductal component. This marker could potentially be used as a surrogate for poor prognosis or as a determinant for adjuvant therapy.

Prognostic Significance of Vas Deferens Invasion After Radical Prostatectomy in Patients with Pathological Stage T3b Prostate Cancer.

BACKGROUND: Seminal vesicle invasion (SVI) is associated with adverse clinical outcomes in prostate cancer (PCa) patients. Despite its anatomical similarity and close proximity to the seminal vesicle, the prognostic significance of vas deferens invasion (VDI) by PCa has not been elucidated. For these reasons, we investigated the impact of VDI on the oncological outcome of pT3b PCa in association with SVI. METHODS: We retrospectively reviewed the medical records of 3359 patients who had undergone a radical prostatectomy at our institution between January 2000 and December 2014 for PCa. Patients who received neoadjuvant or adjuvant treatment (radiation, androgen deprivation therapy, or both) and those without adequate medical records were excluded. A Kaplan-Meier analysis was performed to analyze biochemical recurrence-free survival (BCRFS), and a Cox regression model was used to test the influence of VDI on biochemical recurrence (BCR). RESULTS: Of 350 patients with pathologically confirmed SVI (pT3b), 87 (24.9%) had VDI, while the remaining 263 patients (75.1%) had isolated SVI. Compared with SVI patients without VDI, SVI patients with VDI were noted to have a significantly worse 5-year BCRFS (25.1 vs. 17.1%, respectively). VDI was a significant predictor of BCR in multivariate Cox regression analysis (hazard ratio 1.39, 95% confidence interval 1.02-1.90; p = 0.039). CONCLUSIONS: Our results shows that the prognosis of PCa with SVI might be further stratified by VDI status, thus suggesting the role of VDI either as a surrogate for poor prognosis or as a determinant for adjuvant therapy.

Effect of Preoperative Risk Group Stratification on Oncologic Outcomes of Patients with Adverse Pathologic Findings at Radical Prostatectomy.

BACKGROUND: Current National Comprehensive Cancer Network guidelines recommend postoperative radiation therapy based only on adverse pathologic findings (APFs), irrespective of preoperative risk group. We assessed whether a model incorporating both the preoperative risk group and APFs could predict long-term oncologic outcomes better than a model based on APFs alone. METHODS: We retrospectively reviewed 4,404 men who underwent radical prostatectomy (RP) at our institution between 1992 and 2014. After excluding patients receiving neoadjuvant therapy or with incomplete pathological or follow-up data, 3,092 men were included in the final analysis. APFs were defined as extraprostatic extension (EPE), seminal vesicle invasion (SVI), or a positive surgical margin (PSM). The adequacy of model fit to the data was compared using the likelihood-ratio test between the models with and without risk groups, and model discrimination was compared with the concordance index (c-index) for predicting biochemical recurrence (BCR) and prostate cancer-specific mortality (PCSM). We performed multivariate Cox proportional hazard model and competing risk regression analyses to identify predictors of BCR and PCSM in the total patient group and each of the risk groups. RESULTS: Adding risk groups to the model containing only APFs significantly improved the fit to the data (likelihood-ratio test, p <0.001) and the c-index increased from 0.693 to 0.732 for BCR and from 0.707 to 0.747 for PCSM. A RP Gleason score (GS) ≥8 and a PSM were independently associated with BCR in the total patient group and also each risk group. However, only a GS ≥8 and SVI were associated with PCSM in the total patient group (GS ≥8: hazard ratio [HR] 5.39 and SVI: HR 3.36) and the high-risk group (GS ≥8: HR 6.31 and SVI: HR 4.05). CONCLUSION: The postoperative estimation of oncologic outcomes in men with APFs at RP was improved by considering preoperative risk group stratification. Although a PSM was an independent predictor for BCR, only a RP GS ≥8 and SVI were associated with PCSM in the total patient and high-risk groups.

Association of Anterior and Lateral Extraprostatic Extensions with Base-Positive Resection Margins in Prostate Cancer.

INTRODUCTION: Positive surgical margins (PSM) detected in the radical prostatectomy specimen increase the risk of biochemical recurrence (BCR). Still, with formidable number of patients never experiencing BCR in their life, the reason for this inconsistency has been attributed to the artifacts and to the spontaneous regression of micrometastatic site. To investigate the origin of margin positive cancers, we have looked into the influence of extraprostatic extension location on the resection margin positive site and its implications on BCR risk. MATERIALS & METHODS: The clinical information and follow-up data of 612 patients who had extraprostatic extension and positive surgical margin at the time of robot assisted radical prostatectomy (RARP) in the single center between 2005 and 2014 were modeled using Fine and Gray's competing risk regression analysis for BCR. Extraprostatic extensions were divided into categories according to location as apex, base, anterior, posterior, lateral, and posterolateral. Extraprostatic extensions were defined as presence of tumor beyond the borders of the gland in the posterior and posterolateral regions. Tumor admixed with periprostatic fat was additionally considered as having extraprostatic extension if capsule was vague in the anterior, apex, and base regions. Positive surgical margins were defined as the presence of tumor cells at the inked margin on the inspection under microscopy. Association of these classifications with the site of PSM was evaluated by Cohen's Kappa analysis for concordance and logistic regression for the odds of apical and base PSMs. RESULTS: Median follow-up duration was 36.5 months (interquartile range[IQR] 20.1-36.5). Apex involvement was found in 158 (25.8%) patients and base in 110 (18.0%) patients. PSMs generally were found to be associated with increased risk of BCR regardless of location, with BCR risk highest for base PSM (HR 1.94, 95% CI 1.40-2.68, p<0.001) after adjusting for age, initial prostate-specific antigen, pathologic Gleason score, and pathologic T stage in the multivariate model. Logistic regression for PSM site revealed no significant correlation of apex PSM with extraprostatic extension location, while base PSM was associated with increased odds of anterior (OR 2.513, 95% CI 1.425-4.430, p = 0.001) and lateral (OR 2.715, 95% CI 1.735-4.250, p<0.001) extraprostatic extension. CONCLUSION: Extension into the extraprostatic tissue on some specific locations do not share the same recur risk due to the different anatomical structures surrounding the organ. Anterior and lateral EPEs are prone to leave PSM on the base of the prostate, probably because of the lack of anatomical barricades slowing down the direct invasion process. More study on the pattern of spread of the tumors found to have extraprostatic extension is suggested for optimal planning of the operation extent and of the adjuvant radiotherapy.

Computed Tomography-Based Novel Prediction Model for the Outcome of Shockwave Lithotripsy in Proximal Ureteral Stones.

INTRODUCTION AND OBJECTIVES: Computed tomography (CT) is one of the most commonly used diagnostic modalities for urinary stone disease. In this study we developed a CT and clinical parameter-based prediction model for shockwave lithotripsy (SWL) outcome in proximal ureteral stones. MATERIALS AND METHODS: Data from 223 patients with single proximal ureteral stones treated with SWL between January 2009 and January 2015 were reviewed retrospectively. Clinical parameters including age, sex, body weight, and body mass index (BMI) were analyzed in combination with stone-related CT parameters (stone diameter, height, volume, location, Hounsfield units [HU], stone-to-skin distance [SSD]), and secondary signs (hydronephrosis, perinephric edema, and rim sign). Based on the cutoff values determined by c-statistics, a scoring system for the prediction of SWL outcome was developed. RESULTS: The success rate was 65.9% (147/223), and in a univariate analysis body weight, BMI, SSD (vertical, horizontal), HU, stone diameter, height, volume, and all secondary signs were significantly associated with the success of SWL. However, on multivariate analysis only BMI (odds ratio [OR] = 1.322, confidence interval [CI] 1.156, 1.512, p = 0.00), stone diameter (OR = 1.397, CI 1.259, 1.551, p = 0.00), and perinephric edema (grade 0-1 vs 3-4, OR = 2.831, CI 1.032, 7.764, p = 0.043) were independent predictors of SWL success. The prediction model based on the logistic regression analysis was as follows: SWL success = 1/[1 + exp (-10.165 + 0.279 × [BMI] + 0.334 × [diameter] + 1.040 [perinephric edema])], having an area under the curve of 0.881. In the prediction model based on these parameters, scores of 0, 1, 2, and 3 correlated with SWL success rates of 98.5%, 65.7%, 31.4%, and 0%, respectively. CONCLUSIONS: BMI, stone diameter, and perinephric edema were independent predictors of SWL outcome and a prediction model based on these parameters will facilitate decision-making for SWL in proximal ureteral stones.

Wunderlich syndrome as the first manifestation of an extraskeletal Ewing sarcoma.

We recently encountered an extremely rare case of spontaneous perirenal hemorrhage in a 34-year-old man. He initially had undergone radical nephrectomy owing to suspicion of renal cell carcinoma. The final diagnosis was extraskeletal Ewing sarcoma.

EphA2 Is a Potential Player of Malignant Cellular Behavior in Non-Metastatic Renal Cell Carcinoma Cells but Not in Metastatic Renal Cell Carcinoma Cells.

OBJECTIVES: To investigate the role of EphA2 in malignant cellular behavior in renal cell carcinoma (RCC) cells and whether FAK/RhoA signaling can act as downstream effectors of EphA2 on RCC cells. METHODS: Expression of EphA2 protein in non-metastatic RCC (Caki-2 and A498), metastatic RCC cells (Caki-1 and ACHN), HEK-293 cells and prostate cancer cells (PC-3 and DU-145; positive controls of EphA2 expression) was evaluated by Western blot. Changes in mRNA or protein expression of EphA2, FAK or membrane-bound RhoA following EphA2, FAK or RhoA small interfering RNA (siRNA) transfection were determined by reverse transcription polymerase chain reaction or Western blot. The effect of siRNA treatment on cellular viability, apoptosis and invasion was analyzed by cell counting kit-8, Annexin-V and modified Matrigel-Boyden assays, respectively. RESULTS: In all RCC cell lines, the expression of EphA2 protein was detectable at variable levels; however, in HEK-293 cells, EphA2 expression was very low. Treatment with EphA2 siRNA significantly reduced the expression of EphA2 mRNA and protein in all RCC cell lines. For non-metastatic RCC cells (Caki-2 and A498) but not metastatic RCC cells (Caki-1 and ACHN), cellular viability, invasiveness, resistance to apoptosis, expression of membrane-bound RhoA protein and FAK phosphorylation were significantly decreased in EphA2 siRNA-treated cells compared to the control. In non-metastatic RCC cells, FAK siRNA significantly attenuated the invasiveness, resistance to apoptosis, as well as expression of membrane-bound RhoA protein without changing protein expression of EphA2. RhoA siRNA significantly decreased the malignant cellular behavior and expression of membrane-bound RhoA protein without changing EphA2 protein expression or FAK phosphorylation. CONCLUSIONS: Our data provide the first functional evidence that the EphA2/FAK/RhoA signaling pathway plays a critical role in the malignant cellular behavior of RCC and appears to be functional particularly in the early stage of malignant progression of non-metastatic RCC.

The prescribing and dispensing of phosphodiesterase type 5 inhibitors in South Korea: a questionnaire survey of patient discomfort.

PURPOSE: This study was performed to investigate the discomfort reported by patients taking phosphodiesterase type 5 inhibitors (PDE5Is) in clinical practice. MATERIALS AND METHODS: From September 2011 to March 2012, we surveyed patients who were prescribed PDE5Is for erectile dysfunction (ED). The questionnaire elicited information concerning: patient characteristics, medication counseling received and inconveniences experienced in hospitals and at pharmacies, effects of PDE5Is, and the separation of the prescribing and the dispensing of PDE5Is. RESULTS: A total of 237 patients completed the questionnaire (mean age: 58.81±9.14 years). Among the 62 patients (26.0%) who reported having encountered some inconveniences in hospitals, the most frequently expressed concerns 'assistant staff,' including nurses (38.7%), 'testing procedures' (27.4%), and 'the issuing of prescriptions' (22.6%). Of the 137 patients (57.8%) who noted inconveniences in obtaining medications from pharmacies, 60.6% cited 'self-consciousness' as the most common reason, followed by 'insufficient medication counseling' (22.6%), and 'absence of consultation' (11.6%). In contrast, 82% of the patients were satisfied with the medication counseling that they had received in hospitals, covering drug usage, side effects, and precautions regarding PDE5Is; this proportion was only 30% for pharmacies. Further, most patients (89%) indicated that they preferred to obtain their prescriptions and medications for ED from the hospital at the same time. CONCLUSIONS: Treatment of ED is a highly private matter. According to the survey, ED patients more often felt that obtaining medication from pharmacies was inconvenient. The sociocultural aspects of ED necessitate that exceptions to separating the prescribing and the dispensing of medication be considered.

Transurethral resection of fibrotic scar tissue combined with temporary urethral stent placement for patients with in anterior urethral stricture.

INTRODUCTION: Fibrotic scar formation is a main cause of recurrent urethral stricture after initial management with direct vision internal urethrotomy (DVIU). In the present study, we devised a new technique of combined the transurethral resection of fibrotic scar tissue and temporary urethral stenting, using a thermo-expandable urethral stent (Memokath(TM) 044TW) in patients with anterior urethral stricture. MATERIALS AND METHODS: As a first step, multiple incisions were made around stricture site with cold-utting knife and Collins knife electrode to release a stricture band. Fibrotic tissue was then resected with a 13Fr pediatric resectoscope before deployment of a MemokathTM 044TW stent (40 - 60mm) on a pre-mounted sheath using 0° cystoscopy. Stents were removed within12 months after initial placement. RESULTS: We performed this technique on 11 consecutive patients with initial (n = 4) and recurrent (n = 7) anterior urethral stricture (April 2009 ­ February 2013). At 18.9 months of mean follow-up (12-34 months), mean Qmax (7.8±3.9ml/sec vs 16.8 ± 4.8ml/sec, p < 0.001), IPSS (20.7 vs 12.5, p = 0.001 ), and QoL score (4.7 vs 2.2, p < 0.001) were significantly improved. There were no significant procedure-related complications except two cases of tissue ingrowth at the edge of stent, which were amenable by transurethral resection. In 7 patients, an average 1.4 times (1-5 times) of palliative urethral dilatation was carried out and no patients underwent open surgical urethroplasty during the follow-up period. CONCLUSION: Combined transurethral resection and temporary urethral stenting is a effective therapeutic option for anterior urethral stricture. Further investigations to determine the long-term effects, and safety profile of this new technique are warranted.

Transurethral resection of fibrotic scar tissue combined with temporary urethral stent placement for patients with in anterior urethral stricture

Introduction Fibrotic scar formation is a main cause of recurrent urethral stricture after initial management with direct vision internal urethrotomy (DVIU). In the present study, we devised a new technique of combined the transurethral resection of fibrotic scar tissue and temporary urethral stenting, using a thermo-expandable urethral stent (MemokathTM 044TW) in patients with anterior urethral stricture. Materials and Methods As a first step, multiple incisions were made around stricture site with cold-cutting knife and Collins knife electrode to release a stricture band. Fibrotic tissue was then resected with a 13Fr pediatric resectoscope before deployment of a MemokathTM 044TW stent (40 – 60mm) on a pre-mounted sheath using 0° cystoscopy. Stents were removed within 12 months after initial placement. Results We performed this technique on 11 consecutive patients with initial (n = 4) and recurrent (n = 7) anterior urethral stricture (April 2009 – February 2013). At 18.9 months of mean follow-up (12-34 months), mean Qmax (7.8±3.9ml/sec vs 16.8 ± 4.8ml/sec, p < 0.001), IPSS (20.7 vs 12.5, p = 0.001 ), and QoL score (4.7 vs 2.2, p < 0.001) were significantly improved. There were no significant procedure-related complications except two cases of tissue ingrowth at the edge of stent, which were amenable by transurethral resection. In 7 patients, an average 1.4 times (1-5 times) of palliative urethral dilatation was carried out and no patients underwent open surgical urethroplasty during the follow-up period. Conclusion Combined transurethral resection and temporary urethral stenting is a effective therapeutic option for anterior urethral stricture. Further investigations to determine the long-term effects, and safety profile of this new technique are warranted. .

Synergistic antitumor effect of NVP-BEZ235 and sunitinib on docetaxel-resistant human castration-resistant prostate cancer cells.

According to recent studies, mTOR (mammalian target of rapamycin) inhibitor and tyrosine kinase inhibitor (TKI) can be used as combinational agents to enhance the antitumor effect or overcome resistance to one of the agents. In the present study, we investigated the synergistic interaction between NVP-BEZ235, a PI3K (phosphoinositide 3-kinase)/mTOR dual inhibitor, and sunitinib, a TKI, in castration-resistant prostate cancer (CRPC) cells with docetaxel resistance. Prostate cancer cells with different sensitivities to hormones and docetaxel levels were exposed to escalating doses of NVP-BEZ235 alone and in combination with sunitinib. The synergy between NVP-BEZ235 and sunitinib was determined by the combination index, three-dimensional model, and clonogenic assays. Flow cytometry and western blot analysis of proteins related to apoptosis and cell survival axis were performed. The combination of NVP-BEZ235 and sunitinib caused a significant synergistic antitumor effect over a wide range of doses in docetaxel-resistant CRPC cells. Furthermore, the IC50 (half-maximal inhibitory concentration) of NVP-BEZ235 and sunitinib was reduced by 7.8-fold and 6.6-fold, respectively. The three-dimensional synergy analysis resulted in a synergy volume of 182.47 µM/ml2%, indicating a strong synergistic effect of combination therapy. Combination therapy caused an induction of caspase-dependent apoptosis in docetaxel-resistant CRPC cells. Adding sunitinib did not produce any additional effect on the NVP-BEZ235-mediated inhibition of PI3K/AKT/mTOR phosphorylation. In conclusion, combining NVP-BEZ235, a dual PI3K/mTOR inhibitor, with sunitinib can synergistically potentiate the antitumor effect in CRPC cells after docetaxel failure though induction of caspase-dependent apoptosis.

Female urethral condyloma causing bladder outlet obstruction.

In women, urethral condyloma rarely leads to a bladder outlet obstruction. A 39-year-old woman who presented with frequency, urgency, and residual urine sensation was found to have a condyloma in her urethral meatus. Urodynamic study indicated bladder outlet obstruction. After condyloma excision, she returned to normal voiding, and the free maximum flow rate improved. In women, excision of urethral condylomas that cause obstruction can be an effective treatment with early recovery of voiding function.

Can treatment of nocturia increase testosterone level in men with late onset hypogonadism?

OBJECTIVE: To assess the effect of desmopressin on serum testosterone level in men with nocturia and late onset hypogonadism. METHODS: We prospectively enrolled men with nocturia and symptoms of late onset hypogonadism. Desmopressin (0.1 mg) was administered once daily to patients for 12 weeks, and we then compared serum testosterone levels, electrolytes, frequency volume chart indices, and changes in the International Prostate Symptom Score (IPSS), International Index of Erectile Function, and Aging Male's Symptom scales before and after treatment. Patients with a history of cardiovascular disease or hyponatremia, those using hypnotics, and those who had primary hypogonadism or hypogonadotrophic hypogonadism were excluded from the study. RESULTS: Sixty-two men (mean age, 68.4 years) completed pre- and post-treatment questionnaires and underwent laboratory testing. At the end of the study, the testosterone levels in men with low testosterone levels (<3.5 ng/mL) increased after the 12-week desmopressin treatment (2.85 ± 0.58 to 3.97 ± 1.44 ng/mL; P = .001). Mean scores had decreased from 17.7 to 13.9 (IPSS), 3.8 to 3.2 (IPSS-Quality of Life), and 33.7 to 31.1 (Aging Male's Symptom). On the frequency volume chart, nocturnal urine volume, nocturnal polyuria index, actual number of nocturia events, nocturia index, and nocturnal bladder capacity index were significantly decreased. CONCLUSION: Desmopressin improved nocturia and other urinary symptoms. Moreover, serum testosterone levels increased significantly in men with low testosterone levels after 12-week desmopressin treatment.