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Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive and fatal disease, with most patients succumbing within 1-2 years despite undergoing multiple treatments. Androgen-receptor (AR) inhibitors, including enzalutamide (ENZ), are used for the treatment of mCRPC; however, most patients develop resistance to ENZ. Herein, we propose that the repression of SLC22A3 by AR-V7/YAP1/TAZ conferred ENZ resistance in mCRPC. SLC22A3 expression is specifically downregulated in the ENZ-resistant C4-2B MDVR cells, and when YAP1/TAZ is hyperactivated by AR full-length or AR-V7, these proteins interact with DNMT1 to repress SLC22A3 expression. We observed low SLC22A3 expression and high levels of TAZ or YAP1 in mCRPC patient tissues harbouring AR-V7 and the opposite expression patterns in normal patient tissues. Our findings suggest a mechanism underlying ENZ resistance by providing evidence that the AR-V7/YAP1/TAZ axis represses SLC22A3, which could be a potential treatment target in prostate cancer.

Background The anti-cancer activities of curcumin are well-documented from preclinical studies using prostate cancer models. Our objective was to evaluate the anti-cancer activity of oral curcumin in patients with prostate cancer. Methods This randomized, double-blind, placebo-controlled trial was performed on patients with prostate cancer who received intermittent androgen deprivation (IAD). Participants who finished the first on-treatment period of IAD were randomized into a curcumin or placebo group. The patients took oral curcumin (1440 mg/day) or placebo for six months and were followed up until the beginning of the second on-treatment. The primary end-point was duration of the first off-treatment. The secondary end-points were change in PSA and testosterone levels during 6 months, PSA progression rate, and health-related quality of life (HRQOL) scores at 6 months. Safety assessments included adverse event, adverse drug reaction, and serious adverse event. Results A total of 97 participants were randomized 1:1 to curcumin (n = 49) and placebo (n = 48) groups. Among them, 82 patients (84.5%) were evaluable for the analysis (39 and 43 patients in the curcumin and placebo groups, respectively). The median off-treatment duration was 16.3 months (95% confidence interval [CI] 12.3-20.3 months) and 18.5 months (95% CI 12.5-23.0 months) in the curcumin and placebo groups, respectively. There was no significant difference in the curve of off-treatment duration between the two groups (P = 0.4816). The proportion of patients with PSA progression during the active curcumin treatment period (6 months) was significantly lower in the curcumin group than the placebo group (10.3% vs 30.2%, P = 0.0259). The change of PSA, testosterone levels during 6 months, and HRQOL scores at 6 months were not different between curcumin and placebo groups. Adverse events were higher in the placebo group (16 of 46 vs 7 of 45 patients, P = 0.0349). No significant differences in the adverse drug reaction were found between the two groups. Conclusions Six months' intake of oral curcumin did not significantly affect the overall off-treatment duration of IAD. However, PSA elevation was suppressed with curcumin intake during the curcumin administration period. Curcumin at this dose was well tolerated and safe.

Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is one of the main compounds present in Artemisia species. Eupatilin has both antioxidative and anti-inflammatory properties and a relaxation effect on vascular contraction regardless of endothelial function. We evaluated the relaxant effects of eupatilin on the corpus cavernosum (CC) of rabbits and the underlying mechanisms of its activity in human corpus cavernosum smooth muscle (CCSM) cells. Isolated rabbit CC strips were mounted in an organ bath system. A conventional whole-cell patch clamp technique was used to measure activation of calcium-sensitive K+ -channel currents in human CCSM cells. The relaxation effect of eupatilin was evaluated by cumulative addition (10-5 m ~ 3 × 10-4 m) to CC strips precontracted with 10-5 m phenylephrine. Western blotting analysis was performed to measure myosin phosphatase targeting subunit 1 (MYPT1) and protein kinase C-potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17-kDa (CPI-17) expression and to evaluate the effect of eupatilin on the RhoA/Rho-kinase pathway. Eupatilin effectively relaxed the phenylephrine-induced tone in the rabbit CC strips in a concentration-dependent manner with an estimated EC50 value of 1.2 ± 1.6 × 10-4 m (n = 8, p

Objective To investigate the efficacy of Holmium laser transurethral incision of the prostate (Ho-TUIP) with preoperative characteristics based on urodynamic parameters. Methods The medical records of 40 consecutive cases of Ho-TUIP in patients unresponsive to medical treatment were retrospectively reviewed. The efficacy of Ho-TUIP was analyzed according to preoperative factors, including urodynamic parameters. Treatment success was confirmed if overall efficacy demonstrated an improvement that was “good or greater” according to the criteria developed by Homma et al. Predictive factors of treatment success were analyzed using logistic regression analysis with demographics, symptom questionnaires, prostate size, and urodynamic parameters. Postoperative complications and Global Response Assessment (GRA) were investigated. Results Mean age was 60.9 years (range 37–84), mean follow-up period was 36.6 months (range 6.3–114.8), and mean prostate size was 23.5 mL (range 12.7–39.5). All patients underwent medical treatment before Ho-TUIP, and mean medication duration was 50.5 months (range 3.4–140.0). The treatment success rate was 60.0%. Treatment success rates were higher in the bladder outlet obstruction index (BOOI) ≥20 group (n = 26) than in the BOOI

Objectives To investigate the potential effects of preoperative volumetric compensation of the contralateral normal kidney on renal function after simple nephrectomy or radical nephrectomy. Methods A total of 306 patients (80 simple nephrectomy patients and 226 radical nephrectomy patients) with 1:3 propensity score matching were included between October 1996 and December 2013. Preoperative three-dimensional kidney volume was estimated from computed tomography images using a specialized volumetric program. Glomerular filtration rate assessed using the Chronic Kidney Disease Epidemiology Collaboration equations was checked preoperatively, 1 week, 3 months and 1 year after nephrectomy. Results Preoperative mean Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate was 76.5 mL/min/1.73 m2 in the simple nephrectomy group and 89.2 mL/min/1.73 m2 in the radical nephrectomy group. In simple nephrectomy patients, mean Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate showed a stable pattern up to 3 months (75.5 mL/min/1.73 m2 at 7 days and 76.2 mL/min/1.73 m2 at 3 months), and decreased slightly to 72.6 mL/min/1.73 m2 at 1 year. However, in radical nephrectomy patients, mean Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate decreased immediately to 63.4 mL/min/1.73 m2 at 7 days after surgery, and then increased gradually to 64.6 mL/min/1.73 m2 at 3 months and 65.9 mL/min/1.73 m2 at 1 year. Preoperative mean contralateral normal kidney volume was 225.7 mL in the simple nephrectomy group and 180.1 mL in the radical nephrectomy group (P < 0.001). The contralateral normal kidney volume to total normal kidney volume ratio was 0.74 in the simple nephrectomy group and 0.51 in the radical nephrectomy group (P < 0.001). Conclusions Preoperative volumetric compensation of the contralateral normal kidney is important to maintain postoperative renal function in patients undergoing nephrectomy.

Objectives To evaluate the oncological outcome and to assess prognostic factors of salvage radiotherapy alone in patients with biochemical recurrence after radical prostatectomy. Methods We reviewed our single institution, prospectively maintained database of 2043 patients who underwent radical prostatectomy between September 1995 and December 2011. In this cohort, 149 patients who developed biochemical recurrence after radical prostatectomy and received salvage radiotherapy alone after pelvic magnetic resonance imaging were included. Three-dimensional conformal radiotherapy or intensity-modulated radiotherapy was delivered with a median dose of 70.0 Gy (66.0–78.0 Gy) or 67.2 Gy (64.8–70.0 Gy). Kaplan–Meier and Cox regression analyses were carried out. Results With a median follow up of 82 months (range 20–153 months), 55 patients (36.9%) failed salvage radiotherapy. The 5-year salvage radiotherapy failure-free probability was 53.6%. On multivariate analysis, pre-salvage radiotherapy prostate-specific- antigen ≥1.0 ng/mL (P = 0.003, hazard ratio 3.592, 95% confidence interval 1.522–8.579), pathological stage ≥T3a (P = 0.004, hazard ratio 2.261, 95% confidence interval 1.290–3.833), pathological Gleason score ≥7 (P = 0.018, hazard ratio 5.501, 95% confidence interval 1.577–21.221), prostate-specific antigen doubling time

Objectives To evaluate the clinical significance of preoperative erythrocyte sedimentation rate (ESR) and neutrophil–lymphocyte ratio (NLR) as prognostic factors in patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma (UTUC). Patients and Methods A total of 410 patients were retrospectively reviewed. An elevated NLR was defined as ≥2.5 and a normal ESR was considered to be in the range of 0–22 mm/h in men and 0–27 mm/h in women. Patients were divided into three groups: those with ESR and NLR in the normal range (group 0, n = 168), those with either elevated ESR or elevated NLR (group I, n = 169), and those with both elevated ESR and elevated NLR (group II, n = 73). Results The median patient age was 64 years and the median follow-up duration was 40.2 months. In all, 35.6 and 41.2% of patients had elevated NLRs and ESRs, respectively. Group II was associated with advanced tumour status in terms of size, grade, stage, lymph node and margin status (P < 0.05). Preoperative ESR (hazard ratio [HR] 1.784, 95% confidence interval [CI] 1.173–2.712), NLR (HR 1.704, 95% CI 1.136–2.556), and prognostic grouping (HR 2.285, 95% CI 1.397–3.737 for group I; HR 2.962, 95% CI 1.719–5.102 for group II) were independent predictors of progression-free survival (PFS) in the multivariate model (P < 0.05). Prognostic grouping was also an independent prognostic factor for cancer-specific survival (CSS) and overall survival (OS). Time-dependent area under the receiver-operating characteristic curves showed that NLR plus ESR had a greater diagnostic value than NLR alone regarding oncological outcomes (P < 0.05). Conclusions Prognostic grouping using ESR and NLR was identified as an independent prognostic marker in patients with UTUC. The addition of ESR improved the prognostic value of NLR alone in predicting oncological outcomes. The combination of preoperative ESR and NLR might be a new prediction tool in patients with UTUC after radical nephroureterectomy.

In recent reports, an association between altered TRPC channel function and the development of various diabetic complications has drawn the attention of many investigators. The aim of this study was to investigate the expression of TRPC4 channels of corpus smooth muscle (CSM) cells in diabetes, and to evaluate the association between erectile dysfunction (ED) and altered TRPC4 channel function. The expression of TRPC4 in the penile tissue of human, normal and diabetic rat was investigated using RT-PCR, western blotting and immunohistochemistry (IHC). In vivo gene transfer of dominant negative (DN) TRPC4 into the CSM of rat was conducted. In vivo pelvic nerve stimulation was performed to measure erectile function. Expression of TRPC1, TRPC3, TRPC4 and TRPC6 in human and rat CSM tissues was confirmed by RT-PCR, western blot and IHC. In the diabetic rat, the expression levels of mRNA and protein of the TRPC4, and TRPC6 were significantly increased compared to control rats (p < 0.05). The change in TRPC4 expression in the diabetic rats was higher than those of the other TRPC subunits (p < 0.05). The IHC showed that only TRPC4 expression had a higher intensity in the diabetes compared to normal rats (p < 0.05). Gene transfection with TRPC4(DN) into the diabetic rats restored erectile function to levels similar to that of normal controls. Gene expression of TRPC4(DN) in CSM tissue was confirmed by RT-PCR 2 weeks after transfection. This study demonstrated that TRPC4 channel expression increased in the penile CSM cells of diabetic rats. The down-regulation of TRPC4 with DN form restored erectile function in the diabetic rats. The alteration of TRPC4 channel is one of pathophysiology of ED and could be a target for drug development for ED.

Objectives To evaluate the efficacy and safety of tamsulosin dose increase to 0.4 mg daily in Asian patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia refractory to tamsulosin 0.2 mg treatment. Methods We carried out a 12-week, single-center, randomized, placebo-controlled trial in 220 patients. Patients treated with 0.2 mg tamsulosin daily without other lower urinary tract symptoms secondary to benign prostatic hyperplasia medication for more than 3 months and refractory to this treatment were enrolled. We defined “refractory” as an International Prostate Symptom Score of 13 or greater and a maximum flow rate of 15 or under despite medication. Patients with a surgical history related to lower urinary tract symptoms secondary to benign prostatic hyperplasia or a postvoid residual of 150 mL or greater were excluded. Eligible patients were randomly assigned to the 0.4 mg group (two tablets of 0.2 mg tamsulosin once daily) or the 0.2 mg group (one tablet of 0.2 mg tamsulosin and one tablet of placebo once daily). International Prostate Symptom Score, maximum flow rate, blood pressure, heart rate, and adverse events were compared between the two groups at 4 weeks and 12 weeks. Results A total of 220 patients were enrolled and analyzed. There were no differences in baseline characteristics between the two groups. After 12 weeks of medication, the International Prostate Symptom Score was not different between the two groups. However, the improvement in maximum flow rate was greater in the 0.4 mg group than the 0.2 mg group (3.0 ± 0.48 mL/s vs −0.25 ± 0.30 mL/s, P

There has been little data regarding the role of intracavernosal injection (ICI) treatment, its discontinuation rate and the reasons of withdrawal in patients with erectile dysfunction (ED) in the era of phosphodiesterase type 5 (PDE5) inhibitors. The aim of this study was to investigate the rate of withdrawal and its associated reasons in patients undergoing ICI therapy. Patients who were prescribed with ICI treatment two times or more were included since the introduction of sildenafil in Korea in 1999. Telephone surveys were performed to evaluate intercourse rates, withdrawal rates and their associated reasons, adverse events and the patients' satisfaction with their sex lives after the ICI treatments. Two hundred and ninety-four men were contacted by telephone. The mean age was 61.8 ± 7.9 years with a follow-up duration of 25.6 ± 32.1 months. At the last follow-up, 79.9% had discontinued the treatment. Most patients had previously failed PDE5 inhibitor treatment prior to the ICI therapy, and more than half had two or more risk factors of ED. Adequate penile rigidity after ICI therapy was restored in 60.2% of patients. The reasons for discontinuation of ICI were poor response (43.1%), inconvenience of use (18.3%), switch to other treatments (10.7%), loss of libido (6.7%), adverse events (5.5%) and return of spontaneous erection (2.8%). Pain was the most common adverse event in the withdrawal group, whereas prolonged erection was most common in the continuing group. Following ICI treatment, PDE5 inhibitors were the most common therapeutic option (63.1%). The overall satisfaction rate regarding sex life was significantly high in the treatment-continuing group. In conclusion, patients on ICI treatment had severe ED and high withdrawal rates in the era of PDE5 inhibitors. The most common reason for treatment discontinuation was poor response. Before initiating ICI treatments, sufficient counselling is necessary.

Pelvic organ prolapse and lower urinary tract fistulas are two disorders frequently managed in female urology. New techniques have been adapted and improved to decrease morbidity and improve clinical outcomes of these disorders. The adaptation of minimally-invasive approaches for the management of pelvic organ prolapse and lower urinary tract fistulas began with laparoscopy. However, laparoscopic surgery has not gained widespread popularity as a result of the associated technical challenges, such as intracorporeal suturing and pelvic dissection. Robotic surgery has been widely carried out in urological oncology since 2001, and has been widely adapted because of its advantages over conventional laparoscopy for the management of pelvic organ prolapse and lower urinary tract fistulas. The current literature has shown the safety, feasibility and favorable clinical outcomes of robotic surgery for the treatment of these disorders. Robotic surgery in the management of pelvic organ prolapse and lower urinary tract fistula repairs might offer a promising advancement and benefits. However, further long-term data should be followed to assess the durability of this newer, and minimally-invasive approach.