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.

Bruton tyrosine kinase (BTK) may be a potential therapeutic target for interstitial cystitis/bladder pain syndrome.

AIMS: To determine the potential diagnostic and therapeutic targets of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). METHODS: We selected the GSE11783, GSE57560 and GSE621 datasets from the GEO database and merged them. R software was used to screen differentially expressed genes (DEGs) between IC/BPS and normal bladder tissues. The "String" online tool is used to analyze DEGs interaction and functional protein enrichment. CIBERSORT online tool was used to analyze the infiltration of immune cells. In addition, we verified the function of BTK in IC/BPS at the clinical samples and cells level. RESULTS: Bioinformatics analysis revealed that 5 genes were significantly overexpressed in IC/BPS, and the protein-protein interaction diagram showed that BTK was a critical link between these five proteins. At the same time, functional enrichment showed that they were significantly related to innate immunity. Immunoinfiltration showed that mast cell resting in IC/BPS was significantly higher. IHC staining of clinical samples showed that the mast cell markers Tryptase and BTK were highly expressed in IC/BPS tissues. At the cell level, knockdown of BTK inhibited proliferation, migration, invasion, and degranulation of mast cells. CONCLUSIONS: This study provides a new perspective for understanding the molecular mechanisms involved in IC/BPS and suggests that BTK may be a target for treating IC/BPS.

Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition).

Non-muscle invasive bladder cancer (NMIBC) is a major type of bladder cancer with a high incidence worldwide, resulting in a great disease burden. Treatment and surveillance are the most important part of NIMBC management. In 2018, we issued "Treatment and surveillance for non-muscle-invasive bladder cancer in China: an evidence-based clinical practice guideline". Since then, various studies on the treatment and surveillance of NMIBC have been published. There is a need to incorporate these materials and also to take into account the relatively limited medical resources in primary medical institutions in China. Developing a version of guideline which takes these two issues into account to promote the management of NMIBC is therefore indicated. We formed a working group of clinical experts and methodologists. Through questionnaire investigation of clinicians including primary medical institutions, 24 clinically concerned issues, involving transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy of NMIBC, and follow-up and surveillance of the NMIBC patients, were determined for this guideline. Researches and recommendations on the management of NMIBC in databases, guideline development professional societies and monographs were referred to, and the European Association of Urology was used to assess the certainty of generated recommendations. Finally, we issued 29 statements, among which 22 were strong recommendations, and 7 were weak recommendations. These recommendations cover the topics of TURBT, postoperative chemotherapy after TURBT, Bacillus Calmette-Guérin (BCG) immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ, radical cystectomy, treatment of NMIBC recurrence, and follow-up and surveillance. We hope these recommendations can help promote the treatment and surveillance of NMIBC in China, especially for the primary medical institutions.

Clinical practice guideline for transurethral plasmakinetic resection of prostate for benign prostatic hyperplasia (2021 Edition).

Benign prostatic hyperplasia (BPH) is highly prevalent among older men, impacting on their quality of life, sexual function, and genitourinary health, and has become an important global burden of disease. Transurethral plasmakinetic resection of prostate (TUPKP) is one of the foremost surgical procedures for the treatment of BPH. It has become well established in clinical practice with good efficacy and safety. In 2018, we issued the guideline "2018 Standard Edition". However much new direct evidence has now emerged and this may change some of previous recommendations. The time is ripe to develop new evidence-based guidelines, so we formed a working group of clinical experts and methodologists. The steering group members posed 31 questions relevant to the management of TUPKP for BPH covering the following areas: questions relevant to the perioperative period (preoperative, intraoperative, and postoperative) of TUPKP in the treatment of BPH, postoperative complications and the level of surgeons' surgical skill. We searched the literature for direct evidence on the management of TUPKP for BPH, and assessed its certainty generated recommendations using the grade criteria by the European Association of Urology. Recommendations were either strong or weak, or in the form of an ungraded consensus-based statement. Finally, we issued 36 statements. Among them, 23 carried strong recommendations, and 13 carried weak recommendations for the stated procedure. They covered questions relevant to the aforementioned three areas. The preoperative period for TUPKP in the treatment of BPH included indications and contraindications for TUPKP, precautions for preoperative preparation in patients with renal impairment and urinary tract infection due to urinary retention, and preoperative prophylactic use of antibiotics. Questions relevant to the intraoperative period incorporated surgical operation techniques and prevention and management of bladder explosion. The application to different populations incorporating the efficacy and safety of TUPKP in the treatment of normal volume (< 80 ml) and large-volume (≥ 80 ml) BPH compared with transurethral urethral resection prostate, transurethral plasmakinetic enucleation of prostate and open prostatectomy; the efficacy and safety of TUPKP in high-risk populations and among people taking anticoagulant (antithrombotic) drugs. Questions relevant to the postoperative period incorporated the time and speed of flushing, the time indwelling catheters are needed, principles of postoperative therapeutic use of antibiotics, follow-up time and follow-up content. Questions related to complications incorporated types of complications and their incidence, postoperative leukocyturia, the treatment measures for the perforation and extravasation of the capsule, transurethral resection syndrome, postoperative bleeding, urinary catheter blockage, bladder spasm, overactive bladder, urinary incontinence, urethral stricture, rectal injury during surgery, postoperative erectile dysfunction and retrograde ejaculation. Final questions were related to surgeons' skills when performing TUPKP for the treatment of BPH. We hope these recommendations can help support healthcare workers caring for patients having TUPKP for the treatment of BPH.

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.

Global, regional, and national burden of kidney, bladder, and prostate cancers and their attributable risk factors, 1990-2019.

BACKGROUND: The burden of kidney, bladder, and prostate cancers has changed in recent decades. This study aims to investigate the global and regional burden of, and attributable risk factors for genitourinary cancers during the past 30 years. METHODS: We extracted data of kidney, bladder, and prostate cancers from the Global Burden of Disease 2019 database, including incidence, mortality, disability-adjusted life-years (DALYs), and attributable risk factors from 1990 to 2019. Estimated annual percentage changes (EAPC) were calculated to assess the changes in age-standardized incidence rate, age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR). The associations between cancers burden and socio-demographic index (SDI) were also analyzed. RESULTS: Compared with 1990, the global incident cases in 2019 were higher by 154.78%, 123.34%, and 169.11% for kidney, bladder, and prostate cancers, respectively. During the 30-year study period, there was a downward trend in ASMR and ASDR for bladder cancer (EAPC = - 0.68 and - 0.83, respectively) and prostate cancer (EAPC = - 0.75 and - 0.71, respectively), but an upward trend for kidney cancer (EAPC = 0.35 and 0.12, respectively). Regions and countries with higher SDI had higher incidence, mortality, and DALYs for all three types of cancers. The burden of bladder and prostate cancers was mainly distributed among older men, whereas the burden of kidney cancer increased among middle-aged men. Smoking related mortality and DALYs decreased, but high body mass index (BMI) and high fasting plasma glucose (FPG) related mortality and DALYs increased among kidney, bladder, and prostate cancers during the study period. CONCLUSIONS: Kidney, bladder, and prostate cancers remain major global public health challenges, but with distinct trend for different disease entity across different regions and socioeconomic status. More proactive intervention strategies, at both the administrative and academic levels, based on the dynamic changes, are needed.

The expression of Beclin-1 in testicular tissues of non-obstructive azoospermia patients and its predictive value in sperm retrieval rate.

BACKGROUND: Beclin-1 is an autophagy gene and higher levels suggest mammalian testicular damage. Our study aims at exploring the role of Beclin-1 in non-obstructive azoospermia (NOA) patients and clarifying the predictive value of Beclin-1for sperm retrieval in microdissection testicular sperm extraction (micro-TESE). METHODS: In the present study, 62 NOA patients were finally recruited. Serum hormone including luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol II (E2), testosterone (T) and prolactin (PRL), as well as testicular volume were measured. Testicular histopathology was diagnosed by two independent pathologists. The expression of Beclin-1 was detected by real-time PCR in testicular tissue. RESULTS: Our study illustrated that Beclin-1 was differently expressed in three pathological types of NOA. Compared with hypospermatogenesis (HS, P=0.002) or maturation arrest (MA, P=0.049), Beclin-1 showed significantly up-regulated in Sertoli cell-only syndrome (SCOS) group. Moreover, Beclin-1 expression was obviously positive related with serum LH (rho =0.269, P=0.036), meanwhile significantly negative correlation with testicular volume (rho =-0.370, P=0.003), serum T (rho =-0.326, P=0.010), Johnsen score (rho =-0.318, P=0.012), and pathologic type (rho =-0.452, P<0.001). Furthermore, a logistic regression model demonstrated that Beclin-1 is an important predictor of failed sperm retrieval (OR =0.001, P=0.007), which exhibited a pretty AUC =78.6 (P=0.001). CONCLUSIONS: Beclin-1 may play a critical role in spermatogenesis. Elevated Beclin-1 may be obviously associated with lower chances of positive sperm retrieval.

Global, Regional, and National Incidence and Year Lived with Disability for Benign Prostatic Hyperplasia from 1990 to 2019.

The objective of this study is to provide comprehensive and up-to-date estimates on the disease burden of BPH in 204 countries and territories between 1990 and 2019. Data about incidence, year lived with disability (YLD), and their age-standardized rates (ASRs) for 21 regions, 5 Socio-demographic Index (SDI) quintiles, 204 countries and territories, and 12 age categories from 1990 to 2019 were obtained from the Global Burden of Disease 2019 study. Estimated annual percentage changes (EAPCs) of the ASRs and the associations between SDI and the ASRs were estimated. The effects of population growth, population aging, and age-specific rate on the changes in the absolute numbers of incidence and YLD were quantified. Globally, there were 11.26 million (95% uncertainty interval [UI]: 8.79, 14.46) new cases and 1.86 million (95%UI: 1.13, 2.78) YLD due to BPH in 2019. The global ASRs of incidence (EAPC: -0.031, 95% CI: -0.050, -0.012) and YLD (EAPC: -0.058, 95% CI: -0.084, -0.031) decreased slightly from 1990 to 2019, whereas the absolute numbers increased dramatically from 1990 (incidence by 105.7% and YLD by 110.6%), mainly driven by the population growth (53.5% for incidence and 54.4% for YLD) and population aging (55.7% for incidence and 63.2% for YLD). The burden of BPH varied markedly among different regions, socioeconomic status, and countries. As the population is growing and aging, great efforts are required to develop effective prevention, treatment and management strategies to meet the high and increasing burden of BPH worldwide.

The BPSC: A prospective study investigating the clinical effect of interventional therapy and the risk factors for bladder cancer and benign prostatic hyperplasia in Chinese population.

Bladder cancer and benign prostatic hyperplasia have been two very common diseases among the elderly men, especially with the aging of the population in the world. We have designed a study to investigate the clinical effect of interventional therapy for plasmakinetic resection of the prostate and plasmakinetic resection of the bladder, which is called "BPSC" (The bladder cancer and benign prostatic hyperplasia study in Chinese population). The BPSC is not only a specific study, it is made up of many studies. In this article, we introduced the research background, source, name, study framework, study management and further direction of BPSC project. We hope this process will contribute to the growth of the database through sharing data and enriching the evidence of bladder cancer and benign prostatic hyperplasia in the Chinese population, thereby finally improving the accessibility of these important findings for doctors, researchers, and patients.

PrLZ increases prostate cancer docetaxel resistance by inhibiting LKB1/AMPK-mediated autophagy.

Rationale: Docetaxel-mediated chemotherapy is the first-line standard approach and has been determined to show a survival advantage for metastatic castration-resistant prostate cancer (mCRPC) patients. However, a substantial proportion of patients eventually becomes refractory due to drug resistance. The detailed mechanisms remain unclear. We have previously reported that Prostate Leucine Zipper (PrLZ), a specific oncogene of prostate cancer (PCa), promotes PCa cell growth at the castration-resistant stage, thus suggesting a vital role of PrLZ in the progression of CRPC. In this study, we aimed to investigate the role of PrLZ in docetaxel resistance in PCa, focusing on PrLZ-regulating autophagy pathway. Methods: Human PCa PC3, LNCaP and C4-2 cell lines were used as the model system in vitro and PCa xenografts and PrLZ-knockout mice were used as the model system in vivo. Docetaxel-induced cell death and apoptosis in PCa were determined by MTT and flow cytometry assay. The role of PrLZ on the regulation of autophagy and liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway was analyzed using immunoblotting, immunoprecipitation, siRNA silencing and plasmid overexpression. Results: PrLZ increased docetaxel-mediated drug resistance both in vitro and in vivo. Mechanistic dissection revealed that PrLZ interacted with LKB1 and further inhibited the activation of LKB1/AMPK signals, which negatively contributed to the induction of autophagy. Moreover, PrLZ/LKB1-mediated autophagy conferred resistance to docetaxel-induced cell death and apoptosis both in vitro and in vivo. Conclusion: These findings identify a novel role of PrLZ in autophagy manipulation and provide new insight into docetaxel chemoresistance in PCa, suggesting a new strategy for treating mCRPC by targeting this newly identified signaling pathway.

PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: evidence from patients in Northwestern China.

Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA) level ≥50% during the treatment and investigated the potential role of time to nadir (TTN) of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS). In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN <17 weeks (42.83 vs 21.50 weeks, P < 0.001). The time to PSA progression in patients with TTN ≥17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was <17 weeks. We found several factors to be associated with OS, including TTN (hazard ratio [HR]: 3.937, 95% confidence interval [CI]: 1.502-10.309, P = 0.005), PSA level at the diagnosis of cancer (HR: 4.337, 95% CI: 1.616-11.645, P = 0.004), duration of initial androgen deprivation therapy (HR: 2.982, 95% CI: 1.104-8.045, P = 0.031), neutrophil-to-lymphocyte ratio (HR: 3.963, 95% CI: 1.380-11.384, P = 0.011), and total PSA response (Class 1 [<0 response] compared to Class 2 [0-50% response], HR: 3.978, 95% CI: 1.278-12.387, P = 0.017). In conclusion, TTN of PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have >50% PSA remission.

Andrographolide sensitizes prostate cancer cells to TRAIL-induced apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for anticancer therapy. The identification of small molecules that can establish the sensitivity of prostate cancer (PCa) cells to TRAIL-induced apoptosis is crucial for the targeted treatment of PCa. PC3, DU145, JAC-1, TsuPr1, and LNCaP cells were treated with Andrographolide (Andro) and TRAIL, and the apoptosis was measured using the Annexin V/PI double staining method. Real time-polymerase chain reaction (PCR) and Western blot analysis were performed to measure the expression levels of target molecules. RNA interference technique was used to down-regulate the expression of the target protein. We established a nude mouse xenograft model of PCa, which was used to measure the caspase-3 activity in the tumor cells using flow cytometry. In this research study, our results demonstrated that Andro preferentially increased the sensitivity of PCa cells to TRAIL-induced apoptosis at subtoxic concentrations, and the regulation mechanism was related to the up-regulation of DR4. In addition, it also increased the p53 expression and led to the generation of reactive oxygen species (ROS) in the cells. Further research revealed that the DR4 inhibition, p53 expression, and ROS generation can significantly reduce the apoptosis induced by the combination of TRAIL and Andro in PCa cells. In conclusion, Andro increases the sensitivity of PCa cells to TRAIL-induced apoptosis through the generation of ROS and up-regulation of p53 and then promotes PCa cell apoptosis associated with the activation of DR4.

Genetic Association between Matrix Metalloproteinases Gene Polymorphisms and Risk of Prostate Cancer: A Meta-Analysis.

Background and Objective: Studies suggests that matrix metalloproteinase (MMP)-2-1306 C/T and MMP-1-1607 1G/2G polymorphisms affect the risk of prostate cancer. However, the conclusions remain controversial and no pooled evidence of this topic has been published. Therefore, we aimed to perform a meta-analysis to shed some light on the controversial conclusion pertaining to the associations of MMP-2-1306 C/T and MMP-1-1607 1G/2G polymorphisms with prostate cancer susceptibility. Methods: A thorough literature search was performed up to August, 2016 with the PubMed, EMBASE, CBM, CNKI, and Wanfang databases. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were calculated to address the correlations between these polymorphisms and risk of prostate cancer. Results: The meta-analysis included six studies (1,921 patients and 1,988 controls) on MMP-2-1306 C/T polymorphism and three studies on MMP-1-1607 1G/2G polymorphism (438 patients and 394 controls), respectively. The overall results of meta-analysis showed that an elevated risk of the disease was implicated in MMP-2-1306 C/T polymorphism under two genetic models (CT vs. CC: OR = 1.78, 95% CI = 1.33-2.38; TT+CT vs. CC: OR = 1.62, 95% CI = 1.24-2.12) and no significant association was observed between MMP-1-1607 1G/2G polymorphism and the risk of prostate cancer. The subgroup analysis results of MMP-2-1306 C/T polymorphism were similar to the overall results. However, decreased risk of prostate cancer was observed in the Caucasians for MMP-1-1607 1G/2G polymorphism. Conclusions: Current meta-analysis indicates that MMP-2-1306 C/T polymorphism is associated with elevated risk of prostate cancer, but MMP-1-1607 1G/2G polymorphism may inhibit the occurrence of prostate cancer in Caucasians. Further studies are warranted to verify the conclusions.

Intrafascial versus interfascial nerve sparing in radical prostatectomy for localized prostate cancer: a systematic review and meta-analysis.

The present study aimed to systematically evaluate the effectiveness and safety of the intrafascial and interfascial nerve sparing (ITR-NS and ITE-NS) radical prostatectomy. PubMed, Embase, and Cochrane Library databases were searched for eligible studies. Meta-analysis with random-effects model was performed. Six comparative trials were selected and embraced in this research, including one randomized controlled trial, three prospective comparative trials, and two retrospective comparative trials. With regard to perioperative parameters, no significant association of operative time, blood loss, transfusion rates, duration of catheterization, and hospital stay existed between ITR-NS and ITE-NS. With respect to the functional results, ITR-NS had advantages in terms of both continence and potency recovery compared with ITE-NS. In reference to the oncologic results, the ITR-NS showed lower overall positive surgical margin (PSM) compared with ITE-NS but pT2 PSM and biochemical recurrence free rates were similar to the two surgical types. This study demonstrates that ITR-NS has better continence at 6 mo and 36 mo and better potency recovery at 6 mo and 12 mo postoperatively, regardless of the surgical technique. The cancer control of ITR-NS was also better than that of ITE-NS. This may be explained by the fact that patients in ITE-NS group present higher risk cancer than patients in ITR-NS group.

Prognostic factors of first-line docetaxel treatment in castration-resistant prostate cancer: roles of neutrophil-to-lymphocyte ratio in patients from Northwestern China.

OBJECTIVE: To evaluate the potential role of neutrophil-to-lymphocyte ratio (NLR) with therapeutic response in patients who were treated with docetaxel for mCRPC. MATERIALS AND METHODS: We retrospectively analyzed the clinical data from 111 consecutive patients who were treated with docetaxel for mCRPC from 2009 to 2016 in a single center from Northwestern China. Pretreatment baseline and follow-up data including age, PSA response, Gleason score, and cycle number were reviewed, and multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS) and progression-free survival (PFS). RESULTS: In Kaplan-Meier analyses, the NLR (optimal threshold 3.3), total PSA response, number of chemotherapy cycles, stage T, baseline of PSA, albumin, presence of visceral metastases, and PSA level at the diagnosis of cancer were significantly associated with OS, respectively. In multivariable analyses, higher NLR (>3.3), PSA level at the diagnosis of cancer (≥162 ng/ml), number of chemotherapy cycles, and albumin (<40.5 g/l) were associated with increased risk of death, respectively. Meanwhile, young age, higher NLR, number of chemotherapy cycles, presence of visceral metastases, and poor PSA response were associated with shorter PFS. CONCLUSION: NLR combined with PSA level at the diagnosis of cancer remains an important prognostic marker in predicting therapeutic outcome in Chinese men who receive chemotherapy for mCRPC.

Validation of DAB2IP methylation and its relative significance in predicting outcome in renal cell carcinoma.

We have recently reported tumor suppressive role of DAB2IP in RCC development. In this study, We identified one CpG methylation biomarker (DAB2IP CpG1) located UTSS of DAB2IP that was associated with poor overall survival in a cohort of 318 ccRCC patients from the Cancer Genome Atlas (TCGA). We further validated the prognostic accuracy of DAB2IP CpG methylation by pyrosequencing quantitative methylation assay in 224 ccRCC patients from multiple Chinese centers (MCHC set), and 239 patients from University of Texas Southwestern Medical Center at Dallas (UTSW set) by using FFPE samples. DAB2IP CpG1 can predict the overall survival of patients in TCGA, MCHC, and UTSW sets independent of patient age, Fuhrman grade and TNM stage (all p<0.05). DAB2IP CpG1 successfully categorized patients into high-risk and low-risk groups with significant differences of clinical outcome in respective clinical subsets, regardless of age, sex, grade, stage, or race (HR: 1.63-7.83; all p<0.05). The detection of DAB2IP CpG1 methylation was minimally affected by ITH in ccRCC. DAB2IP mRNA expression was regulated by DNA methylation in vitro. DAB2IP CpG1 methylation is a practical and repeatable biomarker for ccRCC, which can provide prognostic value that complements the current staging system.

[Efficacy and tolerability of dapoxetine in the treatment of premature ejaculation].

OBJECTIVE: To investigate the efficacy and adverse effects of dapoxetine in the treatment of premature ejaculation. METHODS: We randomly assigned outpatients with premature ejaculation in the proportion of 2:1 to receive 30 mg dapoxetine on demand (n =78) or 50 mg sertraline qd for one month (n = 39). Follow-up was accomplished in 95 cases, 63 in the dapoxetine group and 32 in the sertraline group. We recorded the intravaginal ejaculatory latency time (IELT), clinical global impression of change (CGIC) score, and adverse reactions of the patients and compared them between the two groups. RESULTS: IELT was significantly increased in both the dapoxetine (from [0.87 ± 0.31] to [2.84 ± 0.68] min, P < 0.05) and the sertraline group (from [0.84 ± 0.28] to [2.71 ± 0.92] min, P < 0.05) after medication. Based on the CGIC scores in premature ejaculation, the rate of excellence or effectiveness was 36.5% in the dapoxetine and 37. 5% in the sertraline group, and the rate of improvement was 63.5% in the former and 71.9% in the latter. The incidence rates of dizziness, nausea, headache, and diarrhea were slightly higher (P > 0.05) while those of fatigue, somnolence, and dry mouth significantly higher (P < 0.05) in the sertraline than in the dapoxetine group. CONCLUSION: On-demand oral medication of dapoxetine is effective and well-tolerated for the treatment of premature ejaculation.

A CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma.

Clear cell renal cell carcinomas (ccRCCs) display divergent clinical behaviours. Molecular markers might improve risk stratification of ccRCC. Here we use, based on genome-wide CpG methylation profiling, a LASSO model to develop a five-CpG-based assay for ccRCC prognosis that can be used with formalin-fixed paraffin-embedded specimens. The five-CpG-based classifier was validated in three independent sets from China, United States and the Cancer Genome Atlas data set. The classifier predicts the overall survival of ccRCC patients (hazard ratio=2.96-4.82; P=3.9 × 10(-6)-2.2 × 10(-9)), independent of standard clinical prognostic factors. The five-CpG-based classifier successfully categorizes patients into high-risk and low-risk groups, with significant differences of clinical outcome in respective clinical stages and individual 'stage, size, grade and necrosis' scores. Moreover, methylation at the five CpGs correlates with expression of five genes: PITX1, FOXE3, TWF2, EHBP1L1 and RIN1. Our five-CpG-based classifier is a practical and reliable prognostic tool for ccRCC that can add prognostic value to the staging system.

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 .

miR-124 represses FZD5 to attenuate P-glycoprotein-mediated chemo-resistance in renal cell carcinoma.

Renal cell carcinoma (RCC) is one of most malignant neoplasms, exhibiting poor responsiveness to the conventional chemo-regime. Abnormal expression of P-glycoprotein (P-gp) has been implicated in the emergence of multiple-drug resistance (MDR) by reducing the accumulation of intracellular chemotherapy drugs. Wnt signaling plays critical roles in renal cancer and is triggered by binding of Wnt ligands to Frizzled (FZD) receptor proteins. miR-124 is a tumor suppressor associated with cancer relapse and MDR, whereas its role in P-gp-mediated MDR in refractory RCC is as yet unrevealed. Our study aimed to investigate the roles of miR-124 in chemo-resistant RCC cells and the potential targeted signaling paths in inducing P-gp expression. Doxorubicin (DOX)- and vinblastine (VBL)-resistant Caki-2 cells were developed by exposure of parental Caki-2 cells to the agents over a long period of time. In comparison with their parental cells, miR-124 was downregulated in Caki-2/DOX and Caki-2/VBL cells, accompanied by increased FZD5 and P-gp. IC50 values were reduced significantly after miR-124 mimics were introduced into Caki-2/DOX cells. In addition, miR-124 mimics significantly promoted apoptosis of Caki-2/DOX cells. miR-124 targeted to FZD5 and miR-124 mimics as well as FZD5 siRNA showed significant inhibitory effects on P-gp expression in Caki-2/DOX cells. Furthermore, Wnt-5a dose-dependently stimulated the presentation of p-PKCα/ßII and p-CamKII via activating FZD5, which was reversed by FZD5 silencing. Moreover, FZD5/protein kinase C (PKC) signaling is responsible for the elevation of P-gp and cancer cell survival. In conclusion, restoring miR-124 may function as a promising strategy to overcome P-gp-mediated MDR by inhibiting FZD5/PKC signaling.