Apalutamide for metastatic castration-sensitive prostate cancer: final analysis of the Asian subpopulation in the TITAN trial.

The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg ( n = 111) or placebo ( n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.

Apalutamide for patients with metastatic castrationsensitive prostate cancer in East Asia: a subgroup analysis of the TITAN trial.

Ethnicity might be associated with treatment outcomes in advanced prostate cancer. This study aimed to evaluate the efficacy and safety of androgen deprivation therapy (ADT) combined with apalutamide in East Asians with metastatic castration-sensitive prostate cancer (mCSPC). The original phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial was conducted at 260 sites in 23 countries. This subgroup analysis included patients enrolled in 62 participating centers in China, Japan, and Korea. Radiographic progression-free survival (PFS), time to prostate-specific antigen (PSA) progression, and PSA changes from baseline were compared between groups in the East Asian population. The intent-to-treat East Asian population included 111 and 110 participants in the apalutamide and placebo groups, respectively. The 24-month radiographic PFS rates were 76.1% and 52.3% in the apalutamide and placebo groups, respectively (apalutamide vs placebo: hazard ratio [HR] = 0.506; 95% confidence interval [CI], 0.302-0.849; P = 0.009). Median time to PSA progression was more favorable with apalutamide than placebo (HR = 0.210; 95% CI, 0.124-0.357; P < 0.001). Median maximum percentages of PSA decline from baseline were 99.0% and 73.9% in the apalutamide and placebo groups, respectively. The most common adverse event (AE) was rash in the apalutamide group, with a higher rate than that in the placebo group (37.3% vs 9.1%). The most common grade 3 or 4 AEs were rash (12 [10.9%]) and hypertension (12 [10.9%]) for apalutamide. The efficacy and safety of apalutamide in the East Asian subgroup of the TITAN trial are consistent with the global results.

Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis.

BACKGROUND: Heterogeneous nuclear ribonucleoprotein K (HnRNPK) is a nucleic acid-binding protein that regulates diverse biological events. Pathologically, HnRNPK proteins are frequently overexpressed and clinically correlated with poor prognosis in various types of human cancers and are therefore pursued as attractive therapeutic targets for select patients. However, both the transcriptional regulation and degradation of HnRNPK in prostate cancer remain poorly understood. METHODS: qRT-PCR was used to detect the expression of HnRNPK mRNA and miRNA; Immunoblots and immunohistochemical assays were used to determine the levels of HnRNPK and other proteins. Flow cytometry was used to investigate cell cycle stage. MTS and clonogenic assays were used to investigate cell proliferation. Immunoprecipitation was used to analyse the interaction between SPOP and HnRNPK. A prostate carcinoma xenograft mouse model was used to detect the in vivo effects of HnRNPK and miRNA. RESULTS: In the present study, we noted that HnRNPK emerged as an important player in the carcinogenesis process of prostate cancer. miR-206 and miR-613 suppressed HnRNPK expression by targeting its 3'-UTR in PrCa cell lines in which HnRNPK is overexpressed. To explore the potential biological function, proliferation and colony formation of PrCa cells in vitro and tumor growth in vivo were also dramatically suppressed upon reintroduction of miR-206/miR-613. We have further provided evidence that Cullin 3 SPOP is a novel upstream E3 ubiquitin ligase complex that governs HnRNPK protein stability and oncogenic functions by promoting the degradation of HnRNPK in polyubiquitination-dependent proteolysis in the prostate cancer setting. Moreover, prostate cancer-associated SPOP mutants fail to interact with and promote the destruction of HnRNPK proteins. CONCLUSION: Our findings reveal new posttranscriptional and posttranslational modification mechanisms of HnRNPK regulation via miR-206/miR-613 and SPOP, respectively. More importantly, given the critical oncogenic role of HnRNPK and the high frequency of SPOP mutations in prostate cancer, our results provide a molecular rationale for the clinical investigation of novel strategies to combat prostate cancer based on SPOP genetic status.

Does Postoperative Rehabilitation for Radical Cystectomy Call for Enhanced Recovery after Surgery? A Systematic Review and Meta-analysis.

The aim of this review was to systematically compare the outcomes of enhanced recovery after surgery (ERAS) with standard care (SC) after radical cystectomy. We performed a systematic search of PubMed, Ovid, Web of Science, and the Cochrane Library to identify studies published until September 2017 which involved a comparison of ERAS and SC. A meta-analysis was performed to assess the outcomes of ERAS versus SC. Sixteen studies including 8 prospective and 8 retrospective trials met the eligibility criteria. A total of 2100 participants were assigned to ERAS (1258 cases) or SC (842 cases). The time to first flatus passage {WMD=-0.95 days, 95% CI (-1.50,-0.41), P=0.0006}, time until return to a regular diet {WMD=-2.15 days, 95% CI (-2.86,-1.45), P<0.00001} and the length of hospital stay {WMD=-3.75 days, 95% CI (-5.13,-2.36), P<0.00001} were significantly shorter, and the incidence of postoperative complications {OR=0.60, 95% CI (0.44, 0.83), P=0.002}, especially postoperative paralytic ileus {OR=0.43, 95% CI (0.30, 0.62), P<0.00001} and cardiovascular complications {OR=0.28, 95% CI (0.09, 0.90), P=0.03} was significantly lower in the ERAS group than those in the SC group. This meta-analysis demonstrated that ERAS was associated with a shorter time to first flatus passage, return of bowel function, and the length of hospital stay than SC in patients undergoing radical cystectomy, as well as a lower rate of postoperative complications, especially paralytic ileus and cardiovascular complications.

The putative tumour suppressor miR-1-3p modulates prostate cancer cell aggressiveness by repressing E2F5 and PFTK1.

BACKGROUND: Previous studies report that miR-1-3p, a member of the microRNA-1 family (miR-1), and functions as a tumor suppressor in several different cancers. However, little is known regarding the biological role and intrinsic regulatory mechanisms of miR-1-3p in prostate cancer (PCa). METHODS: In this study, the expression levels of miR-1-3p were first examined in PCa cell lines and tumor tissues by RT-qPCR and bioinformatics. The in vitro and in vivo functional effect of miR-1-3p was examined further. A luciferase reporter assay was conducted to confirm target associations. RESULTS: We found that miR-1-3p was significantly downregulated in advanced PCa tissues and cell lines. Low miR-1-3p levels were strongly associated with aggressive clinicopathological features and poor prognosis in PCa patients. Ectopic expression of miR-1-3p in 22RV1 and LncaP cells was sufficient to prevent tumor cell growth and cell cycle progression in vitro and in vivo. Further mechanistic studies revealed that miR-1-3p could directly target the mRNA 3'- untranslated region (3'- UTR) of two central cell cycle genes, E2F5 and PFTK1, and could suppress their mRNA and protein expression. In addition, knockdown of E2F5 and PFTK1 mimicked the tumor-suppressive effects of miR-1-3p overexpression on PCa progression. Conversely, concomitant knockdown of miR-1-3p and E2F5 and PFTK1 substantially reversed the inhibitory effects of either E2F5 or PFTK1 silencing alone. CONCLUSION: These data highlight an important role for miR-1-3p in the regulation of proliferation and cell cycle in the molecular etiology of PCa and indicate the potential for miR-1-3p in applications furthering PCa prognostics and therapeutics.

Audiovisual Sexual Stimulation and RigiScan Test for the Diagnosis of Erectile Dysfunction.

BACKGROUND: Currently available evaluation criteria for penile tumescence and rigidity have been fraught with controversy. In this study, we sought to establish normative Chinese evaluation criteria for penile tumescence and rigidity by utilizing audiovisual sexual stimulation and RigiScan™ test (AVSS-Rigiscan test) with the administration of phosphodiesterase-5 inhibitor. METHODS: A total of 1169 patients (aged 18-67 years) complained of erectile dysfunction (ED) underwent AVSS-RigiScan test with the administration of phosphodiesterase-5 inhibitor. A total of 1078 patients whose final etiological diagnosis was accurate by means of history, endocrine, vascular, and neurological diagnosis, International Index of Erectile Function 5 questionnaire, and erection hardness score were included in the research. Logistic regression model and receiver operating characteristic curve analysis were performed to determine the cutoff value of the RigiScan™ data. Then, the multivariable logistic analysis was used in the selected variables. RESULTS: A normal result is defined as one erection with basal rigidity over 60% sustained for at least 8.75 min, average event rigidity of tip at least 43.5% and base at least 50.5%, average maximum rigidity of tip at least 62.5% and base at least 67.5%, △tumescence (increase of tumescence or maximum-minimum tumescence) of tip at least 1.75 cm and base at least 1.95 cm, total tumescence time at least 29.75 min, and times of total tumescence at least once. Most importantly, basal rigidity over 60% sustained for at least 8.75 min, average event rigidity of tip at least 43.5%, and base at least 50.5% would be the new normative Chinese evaluation criteria for penile tumescence and rigidity. By multivariable logistic regression analysis, six significant RigiScan™ parameters including times of total tumescence, duration of erectile episodes over 60%, average event rigidity of tip, △tumescence of tip, average event rigidity of base, and △tumescence of base contribute to the risk model of ED. In logistic regression equation, predict value P < 0.303 was considered as psychogenic ED. The sensitivity and specificity of the AVSS-RigiScan test with the administration of phosphodiesterase-5 inhibitor in discriminating psychogenic from organic ED was 87.7% and 93.4%, respectively. CONCLUSIONS: This study suggests that AVSS-RigiScan test with oral phosphodiesterase-5 inhibitors can objectively assess penile tumescence and rigidity and seems to be a better modality in differentiating psychogenic from organic ED. However, due to the limited sample size, bias cannot be totally excluded.

Roles of the Exogenous H2S-Mediated SR-A Signaling Pathway in Renal Ischemia/ Reperfusion Injury in Regulating Endoplasmic Reticulum Stress-Induced Autophagy in a Rat Model.

OBJECTIVE: This study aims to explore the effects of the exogenous hydrogen sulfide (H2S)-mediated scavenger receptor A (SR-A) signaling pathway on renal ischemia/reperfusion injury (IRI) by regulating endoplasmic reticulum (ER) stress-induced autophagy in rats. METHODS: A total of 48 normal Sprague-Dawley (SD) rats and SR-A knockout rats were selected and divided into six groups (n = 8): wild-type (WT) + sham, WT + ischemia-reperfusion (I/R), WT + I/R + NaHS, SR-A-/- + sham, SR-A-/- + I/R and SR-A-/- + I/R + NaHS. The concentrations of urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), malondialdehyde (MDA) and H2S in renal tissue were detected. qRT-PCR and Western blotting were used to detect the mRNA and protein levels of IL-6, TGF-ß, SR-A, LC3I, LC3II, P62, PERK, ATF6 and IRE1 pathway-related genes. A TUNEL assay was used to detect cell apoptosis. Electron microscopy was applied to observe the structure of renal autophagosomes. RESULTS: Compared with the WT + sham group, in the rates of the WT + I/R group, the urine volume, urinary protein, BUN, SCR and MDA concentrations, the mRNA and protein expression of IL-6, TGF-ß, LC3II/I, and ER stress pathway-related genes, the cell apoptosis index, and the number of autophagosomes were significantly increased 24 h after I/R, while P62 and SR-A protein expression and SOD and H2S concentrations were significantly decreased (all P < 0.05). The levels of renal injury, autophagy and ER stress pathway-related genes were decreased in the WT + I/R + NaHS group but were increased in the SR-A-/- + I/R group relative to the WT + I/R group. No significant differences were observed in the urine volume; the concentrations of urinary protein, BUN, SCR and MDA; the SOD activity; the mRNA and protein expression of IL-6, TGF-ß, SR-A, GRP78, SR-A, GPR94, ATF4, IRE1, XBP1, ATF6, and eIF2α; the cell apoptosis index; or the number of autophagosomes in rats of the SR-A-/- + I/R and SR-A-/- + I/R + NaHS groups (all P > 0.05). CONCLUSION: These results demonstrate that the exogenous H2S-mediated SR-A signaling pathway reduces renal IRI injury by up-regulating ER stress-induced autophagy in rats.

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1.

Our previous studies have demonstrated that erectile function was preserved in aged transgenic rats (TGR) harboring the human tissue kallikrein 1 (hKLK1), while the molecular level of hKLK1 on corporal fibrosis to inhibit age-related erectile dysfunction (ED) is poorly understood. Male wild-type Sprague-Dawley rats (WTR) and TGR harboring the hKLK1 gene were fed to 4- or 18-month-old and divided into three groups: young WTR (yWTR) as the control, aged WTR (aWTR), and aged TGR (aTGR). Erectile function of all rats was assessed by cavernous nerve electrostimulation method. Masson's trichrome staining was used to evaluate corporal fibrosis in the corpus cavernosum. We found that the erectile function of rats in the aWTR group was significantly lower than that of other two groups. Masson's trichrome staining revealed that compared with those of the yWTR and aTGR groups, the ratio of smooth muscle cell (SMC)/collagen (C) was significantly lower in the aWTR group. Immunohistochemistry and Western blotting analysis were performed, and results demonstrated that expression of α-SMA was lower, while expressions of transforming growth factor-ß 1 (TGF-ß1), RhoA, ROCK1, p-MYPT1, p-LIMK2, and p-cofilin were higher in the aWTR group compared with those in other two groups. However, LIMK2 and cofilin expressions did not differ among three groups. Taken together, these results indicated that the RhoA/ROCK1/LIMK/cofilin pathway may be involved in the corporal fibrosis caused by advanced age, and hKLK1 may reduce this corporal fibrosis by inhibiting the activation of this pathway to ameliorate age-related ED.

UC-VEGF-SMC Three Dimensional (3D) Nano Scaffolds Exhibits Good Repair Function in Bladder Damage.

We constructed a UC-VEGF-SMC three dimensional (3D) scaffold to explore its effect on blood vessel regeneration and bladder repair function in a rabbit model with bladder injury. Rabbit adipose tissue-derived stem cells (ADSCs) were cultured to construct pluripotent stem cell systems that can be induced to differentiate into urothelial cells (UCs) and smooth muscle cells (SMCs). Reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, MTT assay and HE staining were used in our study. Rabbit models were divided into an experimental group, control group and sham group. The bladder histology, urodynamics, smooth muscle function, stent degradation rate, urothelial permeability and biomechanical determination of rabbits were detected after grafting the scaffold. Correct stem cells based on the ADSC surface marker and found that CD90 and CD105 were positive and that CD34 and CD45 were negative. RT-PCR showed that ADSC-iPS cells expressed the marker gene of embryonic stem cells (ESCs), which indicated that Sox2, Klf4, Oct4 and c-Myc were inserted into the iPS nucleus and that the ADSC-iPS system was constructed successfully. Immunofluorescence and MTT assays indicated that iPS differentiated into mature SMCs and UCs. ELISA and HEMC culturing methods revealed that vascular endothelia growth factor (VEGF) could promote the growth of HMECs. Rabbit bladder repair function (urodynamics, smooth muscle function, urothelial permeability and biomechanical determination) was stronger in the experimental group than in the control group. UC-VEGF-SMC 3D nano scaffold exhibits good repair function for bladder damage, which may helpful for treatment of damaged bladders.

miR-206 inhibits renal cell cancer growth by targeting GAK.

Renal cell cancer (RCC) remains one of the most lethal types of cancer in adults. MicroRNAs (miRNAs) play key roles in the pathogenesis of RCC. The role of miR-206 in RCC has not been fully understood. The purpose of this study was to examine the role of miR-206 in the regulation of proliferation and metastasis of RCC and the possible mechanism. miR-206 expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in RCC cell lines (786-O and OS-RC-2 cells) and clinical samples. MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] method, colony formation and transwell assay were used to detect the tumor-suppressing ability of miR-206 in RCC. Luciferase assay was performed to verify the precise target of miR-206. The results showed that the expression of miR-206 was significantly down-regulated in RCC tissues and cells. The expression level of cyclin G-associated kinase (GAK), a master regulator of tumor proliferation and metastasis, was up-regulated with the decrease in miR-206 in RCC tissues as well as RCC cell lines. In addition, the miR-206 inhibitor promoted the proliferation, migration and invasion of 786-O and OS-RC-2 cells. Bioinformatics combined with luciferase and Western blot assays revealed that miR-206 inhibited the expression of GAK. Moreover, miR-206 regulates RCC cell growth partly through targeting GAK. Our study indicated that miR-206 functions as a tumor suppressor in regulating the proliferation, migration and invasion of RCC by directly targeting GAK, and it holds promises as a potential therapeutic target for RCC.

Demystifying the mechanistic and functional aspects of p21 gene activation with double-stranded RNAs in human cancer cells.

BACKGROUND: The recently identified phenomenon of double-stranded RNA (dsRNA)-mediated gene activation (RNAa) has been studied extensively, as it is present in humans, mice, and Caenorhabditis elegans, suggesting that dsRNA-mediated RNAa is an evolutionarily conserved mechanism. Previous studies have shown that dsP21-322 can induce tumor suppressor gene p21 expression in several human cancer cells. Nonetheless, the role of dsRNAs in the activation of gene expression, including their target molecules and associated key factors, remains poorly understood. METHODS: Oligonucleotides were used to overexpress dsRNAs and dsControl. Real-time PCR and Western blotting were used to detect corresponding mRNA and protein expression, respectively. Fluorescence microscopy was used to examine the kinetics of dsRNA subcellular distribution. Luciferase reporter assays were performed to verify dsRNA target molecules. Chromatin immunoprecipitation (ChIP) assays were carried out to determine whether histone modification and other associated key factors are involved in saRNA-mediated p21 expression. RESULTS: We demonstrated that dsRNA-mediated p21 induction in human cell lines is a common phenomenon. This process occurs at the transcriptional level, and the complementary p21 promoter is the intended dsRNA target. Additionally, ChIP assays indicated that p21 activation was accompanied by an increased enrichment of AGO1 and the trimethylation of histone H3K4 at dsRNA-targeted genomic sites. CONCLUSION: These data systematically reveal the mechanistic and functional aspects of ncRNA-mediated p21 activation in human cancer cells, which may be a useful tool to analyze gene function and aid in the development of novel drug targets for cancer therapeutics.

Urodynamic characteristics of awake rats under retrained versus freely moving condition: Using a novel model.

Urodynamic investigation in conscious rats is widely employed to explore functional bladder disorders of various etiologies and pathogeneses. Rats can be placed in restraining cages or wide cabinets where they are allowed to move freely during cystometry. However, the requirements of special devices hampered the application of urodynamic test in freely moving rats, and whether the restraint has any effects on urodynamic parameters in conscious rats remains obscure. In the present study, we described a novel approach for urodynamic investigation in both restrained and freely moving conscious rats. In addition, we for the first time systematically compared the urodynamic parameters of rats in the two conditions. With the current method, we successfully recorded stable and repeatable intravesical pressure traces and collected expected reliable data, which supported the idea that the restraint does not affect the activity of the micturition reflex in rats, provided sufficient and appropriate measures could be applied during cystometry. Fewer technique problems were encountered during urodynamic examination in restrained rats than in freely moving ones. Taken together, conscious cystometry in rats placed in restraining cages with proper managements is a reliable and practical approach for evaluating the detrusor activity and bladder function.

Decreased Endogenous Hydrogen Sulfide Generation in Penile Tissues of Diabetic Rats with Erectile Dysfunction.

INTRODUCTION: Hydrogen sulfide (H2S) is an endogenous gasotransmitter. The levels of H2S-generating enzyme expression and endogenous H2S production in diabetic rats with erectile dysfunction (ED) remain unknown. The aim of this study was to investigate the expression of the H2S-generating enzymes and endogenous production of H2S in penile tissues of diabetic ED rats. METHODS: Experimental rats were randomly divided into normal control group, apomorphine (APO)-positive group and APO-negative group. Primary rat corpus cavernosum smooth muscle cells (CCSMCs) and aortic endothelial cells (AECs) were isolated and cultured in vitro under 3 different conditions: normal glucose (NG) condition, high glucose (HG) condition, and osmotic control (OC) condition. MAIN OUTCOME MEASURES: Erectile function; H2S concentrations in plasma or penile tissues; expression of H2S-generating enzymes and endogenous H2S production in penile tissues, CCSMCs, and AECs. RESULTS: Erectile function was significantly decreasedin the APO-negative group. In addition to significantly decreased expression of cysteine aminotransferase (CAT), d-amino acid oxidase (DAO), and 3-mercaptopyruvate sulfurtransferase (3-MST), the H2S concentrations in plasma and penile tissues and endogenous H2S production were significantly decreased in the APO-negative group. Endogenous H2S production by cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE) decreased to the same levels in the APO-negative and APO-positive groups as that in the normal control group. However, CBS and CSE expression remained unchanged in the 3 groups. Under HG conditions, H2S-generating enzyme expression in AECs did not change, while CAT, DAO, and 3-MST expression in CCSMCs was significantly decreased. In both cell types, H2S production by these enzymes was decreased in the HG group. CONCLUSION: Endogenous H2S production was significantly decreased in the diabetic ED rats' penile tissues due to downregulated expression of the CAT/3-MST and DAO/3-MST pathways and low activities of CBS and CSE.

Abiraterone acetate for metastatic castration-resistant prostate cancer after docetaxel failure: A randomized, double-blind, placebo-controlled phase 3 bridging study.

OBJECTIVES: To evaluate the efficacy and safety of abiraterone acetate-prednisone versus placebo-prednisone in Asian metastatic castration-resistant prostate cancer patients who have failed docetaxel-based chemotherapy. METHODS: In this double-blind, phase 3 study from China, 214 patients were randomized (2:1) to abiraterone acetate 1000 mg once daily plus prednisone 5 mg twice daily and placebo plus prednisone 5 mg twice daily in 28-day treatment cycles. RESULTS: Abiraterone acetate-prednisone treatment significantly decreased prostate-specific antigen progression risk by 49%, with longer median time to prostate-specific antigen progression of 5.55 months versus 2.76 months in the placebo-prednisone group (hazard ratio 0.506, P = 0.0001, primary end-point). There was a strong trend for improved overall survival in the abiraterone acetate-prednisone group, with a 40% decrease in the risk of death (hazard ratio 0.604, P = 0.0597); however, median survival was not reached in either group because of the short follow-up period (12.9 months) and limited number of observed death events. The prostate-specific antigen response rate was higher in the abiraterone-prednisone group (49.7%) than in the placebo-prednisone group (14.1%). A total of 37.1% patients in this group had pain progression events compared with 50.7% in the placebo-prednisone group. Abiraterone-prednisone significantly decreased the risk of pain progression by 50% (hazard ratio 0.496, P = 0.0014). The incidence of adverse events was similar between the two groups; the most common adverse events being anemia (25.9% for abiraterone-prednisone vs 22.5% for placebo-prednisone), hypokalemia (25.9% and 11.3%), bone pain (23.8% and 21.1%), hypertension (16.1% and 12.7%) and increased aspartate aminotransferase (14.7% and 15.5%), respectively. CONCLUSIONS: Abiraterone-prednisone significantly delays disease and pain progression, and prostate-specific antigen, with a favorable benefit-risk ratio in Asian metastatic castration-resistant prostate cancer patients in the post-docetaxel setting.

Prognostic significance of lymphovascular invasion in bladder cancer after surgical resection: A meta-analysis.

Bladder cancer remains a commonly diagnosed malignancy worldwide, bringing huge economic burden and high morbidity for patients. Assessment of prognostic significance of lymphovascular invasion (LVI) is a critical issue in the surgical management of bladder cancer after transurethral resection or radical cystectomy. A systematic search of PubMed, Embase and Cochrane Library was performed up to Oct 10, 2014 to identify eligible studies. Outcomes of interest were collected from studies comparing overall survival (OS), cancer specific survival (CSS) and recurrence free survival (RFS) in patients with the LVI. Results of studies were pooled, and combined hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for survival were used as the effect size estimation. Funnel plots were done to show the publication bias, while the forest plots and subgroup analyses were used to limit the heterogeneity. A total of 20 studies (10 663 patients) met the eligibility criteria and were included for this meta-analysis. Our pooled results showed that there were significant differences in OS (pooled HR, 1.71; 95%CI, 1.52-1.92; P<0.00001), CSS (pooled HR, 2.25; 95% CI, 1.80-2.81; P<0.00001) and RFS (pooled HR, 1.91; 95% CI, 1.57-2.32; P<0.00001) between the patients with LVI and the patients without LVI. There were significant heterogeneities observed in the studies concerning the relationship between LVI and CSS, RFS. There was no clear evidence of publication bias. When tumor stage was beyond T3, LVI lost its predictive value for CSS and RFS. For the patients who had negative lymph nodes, LVI was still an adverse predictor. Our pooled results demonstrate that LVI indicates poor prognosis of patients with bladder cancer after surgical procedures, and it can be of particular importance in clinical practice. However, these results need to be further confirmed by more adequately designed prospective studies.

[Concentration of basic fibroblast growth factor in plasma and cavernous corpus of aged rat].

OBJECTIVE: To investigate the concentration of basic fibroblast growth factor (bFGF) in aged rat plasma and penile tissues. METHODS: Twelve 24-month-old rats and ten 12-week-old rats were selected. We assessed the erectile responses of rats to cavernous nerve electrostimulation. Then the concentrations of bFGF in the rats' plasma and penile tissues were detected by ELISA kit and smooth muscle contents in the rats' cavernous corpus were evaluated by masson trichrome staining. RESULTS: Compared with the young rats, we found that the erectile function of the aged rats were significantly attenuated (The Max ICP/MAP in the aged rats were 0.41±0.05, 0.44±0.04 and 0.51±0.06 at 2.5 volts, 5.0 volts and 7.5 volts respectively while the Max ICP/MAP in the normal controls were 0.70±0.06, 0.75±0.07 and 0.81±0.04 at 2.5 volts, 5 volts and 7.5 volts respectively, P<0.05). The concentrations of bFGF [The bFGF levels in plasma and penile tissues in the aged rat were (6.43±0.51) µg/L and (598.6±51.7) pg/mg protein respectively while the bFGF levels in the normal control were (10.53±0.42) µg/L and (985.8±76.8) pg/mg protein] were significantly reduced (P<0.05). Furthermore, the smooth muscle contents in the aged rats' penile tissues (0.038±0.005) were dramatically decreased compared with the normal control (0.075±0.006, P<0.05). CONCLUSION: The reduced levels of bFGF may be related to the decreased smooth muscle contents in the penile tissues of the aged rats.

OK-432 Suppresses Proliferation and Metastasis by Tumor Associated Macrophages in Bladder Cancer.

OK-432, a Streptococcus-derived anticancer immunotherapeutic agent, has been applied in clinic for many years and achieved great progress in various cancers. In the present study, we investigated its anticancer effect on bladder cancer through tumor associated macrophages (TAMs). MTS assay validated OK-432 could inhibit proliferation in both T24 and EJ bladder cell lines. OK-432 also induced apoptosis of bladder cancer cells in vitro. Consequently, we demonstrated that OK-432 could suppress the bladder cancer cells migration and invasion by altering the EMT-related factors. Furthermore, using SD rat model, we revealed that OK-432 inhibited tumor growth, suppressed PCNA expression and inhibited metastasis in vivo. Taken together, these findings strongly suggest that OK-432 inhibits cell proliferation and metastasis through inducing macrophages to secret cytokines in bladder cancer.

Percent free prostate-specific antigen is effective to predict prostate biopsy outcome in Chinese men with prostate-specific antigen between 10.1 and 20.0 ng ml(-1).

Percent free prostatic-specific antigen (%fPSA) has been introduced as a tool to avoid unnecessary biopsies in patients with a serum PSA level of 4.0-10.0 ng ml-1 , however, it remains controversial whether %fPSA is effective in PSA range of 10.1-20.0 ng ml-1 in both Chinese and Western population. In this study, the diagnostic performance of %fPSA and serum PSA in predicting prostate cancer (PCa) and high-grade PCa (HGPCa) was analyzed in a multi-center biopsy cohort of 5915 consecutive Chinese patients who underwent prostate biopsy in 22 hospitals across China from January 1, 2010 to December 31, 2013. The indication for biopsy was PSA>4.0 ng ml-1 or/and suspicious digital rectal examination. Total and free serum PSA determinations were performed by three types of electrochemiluminescence immunoassays with recalibration to the World Health Organization standards. The diagnostics accuracy of PSA, %fPSA and %fPSA in combination with PSA (%fPSA + PSA) was determined by the area under the receivers operating characteristic curve (AUC). %fPSA was more effective than PSA in men aged ≥60 years old. The AUC was 0.584 and 0.635 in men aged ≥60 years old with a PSA of 4.0-10.0 ng ml-1 and 10.1-20.0 ng ml-1 , respectively. The AUC of %fPSA was superior to that of PSA in predicting HGPCa in patients ≥60 years old in these two PSA range. Our results indicated that %fPSA is both statistically effective and clinical applicable to predict prostate biopsy outcome in Chinese patients aged ≥60 years old with a PSA of 4.0-10.0 ng ml-1 and 10.1-20.0 ng ml-1 .

A multicenter, randomized clinical trial comparing the three-weekly docetaxel regimen plus prednisone versus mitoxantone plus prednisone for Chinese patients with metastatic castration refractory prostate cancer.

PURPOSE: To explore the feasibility and efficacy of docetaxel plus prednisone for Chinese population with metastatic castration refractory prostate cancer (mCRPC). PATIENTS AND METHODS: A total of 228 patients recruited from 15 centers were randomized to receive 10 cycles of D3P arm (docetaxel: 75 mg/m2, intravenous infusion, every three weeks; Prednisone 10mg orally given daily) or M3P arm (mitoxantrone: 12 mg/m2, intravenous infusion, every three weeks; Prednisone 10mg orally given daily). Primary end point was overall survival, and secondary end points were events progression-free survival (PFS), response rate, response duration. Quality of life (QoL) was also assessed in both treatment groups. RESULTS: The median overall survival was 21.88 months in D3P arm and 13.67 months in M3P arm (P = 0.0011, hazard ratio = 0.63, 95% confidence interval, 0.46-0.86). Subgroup analysis was consistent with the results of overall analysis. Events progression-free survival (pain, PSA, tumor and disease) were significantly improved in D3P arm compared with M3P arm. PSA response rate was 35.11% for patients treated by D3P arm and 19.39% for M3P arm (P = 0.0155). Pain response rate was higher in D3P arm (61.11%, P = 0.0011) than in M3P (23.08%) arm. No statistical differences were found between D3P arm and M3P arm for QoL, tumor response rate and response duration of PSA and pain. The tolerability and overall safety of D3P arm were generally comparable to that of M3P arm. CONCLUSIONS: Compared with M3P arm, D3P arm significantly prolonged overall survival for the Chinese patients with mCRPC and improved the response rate for PSA and pain. TRIAL REGISTRATION: clinicaltrials.gov NCT00436839.

Efficacy and safety of solifenacin plus tamsulosin oral controlled absorption system in men with lower urinary tract symptoms: a meta-analysis.

We performed a meta-analysis to compare treatment with a combination of solifenacin plus tamsulosin oral controlled absorption system (TOCAS) with placebo or TOCAS monotherapy. The aim of the meta-analysis was to clarify the efficacy and safety of the combination treatments method for lower urinary tract symptoms (LUTS). We searched for trials of men with LUTS that were randomized to combination treatment compared with TOCAS monotherapy or placebo. We pooled data from three placebo-controlled trials meeting inclusion criteria. Primary outcomes of interest included changes in International Prostate Symptom Score (IPSS) and urinary frequency. We also assessed postvoid residual, maximum urinary flow rate, incidence of urinary retention (UR), adverse events. Data were pooled using random or fixed effect models for continuous outcomes and the Mantel-Haenszel method to generate risk ratio. Reductions in IPSS storage subscore and total urgency and frequency score (TUFS) were observed with solifenacin 6 mg plus TOCAS compared with placebo (P< 0.0001 and P< 0.0001, respectively). Reductions in IPSS storage subscore and TUFS were observed with solifenacin 9 mg plus TOCAS compared with placebo (P = 0.003 and P= 0.0006, respectively). Reductions in TUFS was observed with solifenacin 6 mg plus TOCAS compared with TOCAS (P = 0.01). Both combination treatments were well tolerated, with low incidence of UR. Solifenacin 6 mg plus TOCAS significantly improved total IPSS, storage and voiding symptoms compared with placebo. Solifenacin 6 mg plus TOCAS also improved storage symptoms compared with TOCAS alone. There was no additional benefit of solifenacin 9 mg compared with 6 mg when used in combination with TOCAS.