Zhenhua Liu

The presence and clinical implication of intraductal carcinoma of prostate in metastatic castration resistant prostate cancer

Intraductal carcinoma of prostate (IDC‐P) is always underestimated pathological pattern in prostate cancer and its role is still unclear in castration resistant prostate cancer (CRPC). This study was conducted to investigate the presence and the roles of IDC‐P in patients with metastatic CRPC.

The prognostic implication of intraductal carcinoma of the prostate in metastatic castration-resistant prostate cancer and its potential predictive value in those treated with docetaxel or abiraterone as first-line therapy

Intraductal carcinoma of the prostate (IDC-P) is recognized as a newly pathological entity in 2016 WHO classification. Its role in metastatic castration-resistant prostate cancer (CRPC) remains obscure. We aimed to explore the association of IDC-P with clinical outcome and to further identify its potential predictive role in making first-line treatment decisions for mCRPC. We retrospectively analyzed data of 131 mCRPC patients. IDC-P was diagnosed by re-biopsy at the time of mCRPC. Among total patients, 45 and 41 received abiraterone or docetaxel as first-line therapies, respectively. PSA response, PSA progression-free survival (PSA-PFS) and overall survival (OS) from mCRPC to death were analyzed using Kaplan-Meier curves, Log-rank test, Cox regression models and Harrells C-index. The incidence of IDC-P in mCRPC reached 47.3%. IDC-P was not only related to rapid PSA progression, but also associated with a 20-month decrease in OS. Among IDC-P(-) patients, PSA response, PSA-PFS and OS were comparable in abiraterone-treated and docetaxel-treated groups. In contrast, among IDC-P(+) patients, PSA response rate is higher in abiraterone-treated group vs. docetaxel-treated group (52.4% vs. 21.7%; p = 0.035). Also, PSA-PFS and OS were much longer in the IDC-P(+) abiraterone-treated group vs. the docetaxel-treated group (PSA-PFS: 13.5 vs.6.0 months, p = 0.012; OS: not reach vs.14.7 months, p = 0.128). Overall, IDC-P in mCRPC from re-biopsy was an independent prognosticator for clinical outcome. Abiraterone was observed having a better therapeutic efficacy than docetaxel as the first-line therapy in IDC-P(+) mCRPC patients. Thus, we suggest IDC-P should be considered as a novel predictive marker helping physicians making treatment decisions for mCRPC.Intraductal carcinoma of the prostate (IDC-P) is recognized as a newly pathological entity in 2016 WHO classification. Its role in metastatic castration-resistant prostate cancer (CRPC) remains obscure. We aimed to explore the association of IDC-P with clinical outcome and to further identify its potential predictive role in making first-line treatment decisions for mCRPC. We retrospectively analyzed data of 131 mCRPC patients. IDC-P was diagnosed by re-biopsy at the time of mCRPC. Among total patients, 45 and 41 received abiraterone or docetaxel as first-line therapies, respectively. PSA response, PSA progression-free survival (PSA-PFS) and overall survival (OS) from mCRPC to death were analyzed using Kaplan-Meier curves, Log-rank test, Cox regression models and Harrells C-index. The incidence of IDC-P in mCRPC reached 47.3%. IDC-P was not only related to rapid PSA progression, but also associated with a 20-month decrease in OS. Among IDC-P(-) patients, PSA response, PSA-PFS and OS were comparable in abiraterone-treated and docetaxel-treated groups. In contrast, among IDC-P(+) patients, PSA response rate is higher in abiraterone-treated group vs. docetaxel-treated group (52.4% vs. 21.7%; p = 0.035). Also, PSA-PFS and OS were much longer in the IDC-P(+) abiraterone-treated group vs. the docetaxel-treated group (PSA-PFS: 13.5 vs.6.0 months, p = 0.012; OS: not reach vs.14.7 months, p = 0.128). Overall, IDC-P in mCRPC from re-biopsy was an independent prognosticator for clinical outcome. Abiraterone was observed having a better therapeutic efficacy than docetaxel as the first-line therapy in IDC-P(+) mCRPC patients. Thus, we suggest IDC-P should be considered as a novel predictive marker helping physicians making treatment decisions for mCRPC.

Prospective evaluation of fluorescence in situ hybridization for diagnosing urothelial carcinoma

Urothelial carcinoma (UC) is the most common type of cancer of the bladder and upper urinary tract, and is characterized by a high risk of recurrence and progression. Urine fluorescence in situ hybridization (FISH) is a technique that detects genetic aberrations in exfoliated cells in the urine, with specific probes for chromosomes 3, 7 and 17 and the p16 gene. To evaluate the diagnostic value of FISH in UC, 119 patients from November 2010 to June 2012 with suspected UC were recruited into a prospective, cross-sectional study and were followed up for 12-30 months. These patients received voided urine cytology and FISH tests, and underwent cystoscopy and/or ureteroscopy as a reference standard. The final diagnoses confirmed 73 patients with UC, located in the bladder, upper urinary tracts or the two. The sensitivity of FISH for detecting UC was superior to cytology, irrespective of tumor grade and stage: Overall, 80.8 vs. 32.9% (P<0.001); low grade, 75.8 vs. 12.1% (P<0.001); high grade, 85 vs. 50% (P<0.005); non-muscle-invasive, 81.1 vs. 28.3% (P<0.001) and muscle-invasive, 80 vs. 45% (P<0.05), respectively. The specificities of the two tests were similar; overall, the specificity was 89.1% for cytology vs. 100% for FISH, and no significant difference was observed between the methods. Notably, FISH exhibited 100% sensitivity for cytologically non-diagnostic UC, but 33.3% specificity. In conclusion, FISH is a reliable and non-invasive diagnostic tool for bladder and upper urinary tract UC, particularly in patients with low-grade or early stage tumors.

The characteristics of circular disposable devices and in situ devices for optimizing male circumcision: a network meta-analysis

In situ device (ISD) and circular disposable device (CDD) are used for optimizing male circumcision (MC), but evidence to explore the characteristics of these two devices is insufficient. In order to explore this issue systematically and provide reliable evidence, ten published randomized controlled trials (RCTs) exploring the safety and efficacy of ISDs and CDDs were included (involving 4649 men). Moderate quality of the RCTs included was found after assessment. Pairwise meta-analyses and network meta-analyses were processed in stata 13.0 and AIDDS v1.16.6 respectively. According to the outcomes that were statistically significant in both pairwise and network meta-analyses, ISD was found to have less intraoperative blood loss (IB), less operative time (OT) and less incidence of wound bleeding (WB) than conventional circumcision (CC); ISD was found to have less WB but more wound healing time (WHT) than CDD; CDD was found to have less IB and less OT than CC. CDD tended to have the best wound healing condition and least pain experience; ISD tended to have the least IB, least OT, least WB, and highest satisfaction rate. With their own superiorities in many aspects, CDD and ISD are both safe and effective devices for optimizing MC.

What kind of patients with castration-naïve prostate cancer can benefit from upfront docetaxel and abiraterone: A systematic review and a network meta-analysis

We conducted a systematic network meta-analysis to review the relevant literature evaluating the therapeutic efficacy of upfront docetaxel (Doc) or abiraterone (Abi) plus androgen deprivation therapy (ADT) on oncological outcome in patients with castration-naïve prostate cancer (CNPC). An attempt to identify subgroups of patients who would benefit most either from Doc or Abi plus ADT and further compare the efficacy and safety between these two combination therapies was made. A comprehensive search of the PubMed/Medline, Embase databases, International Clinical Trial Registration Platform (ICTRP), Clinical Trial, and Cochrane Central Register of Controlled Trials to December 2017 was performed. Six studies, involving 6480 patients, were included in this meta-analysis, consisting of over 60% (4462/6480) of patients with metastatic CNPC (mCNPC, M1), and 31.1% (2018/6480) of patients with non-metastatic CNPC (M0). In total, combination therapies (ADT plus Doc or Abi) significantly improved overall survival (OS) and failure-free survival (FFS) for all CNPC patients. For M1 patients, combination therapies were dramatically associated with improved OS and FFS, but for M0 patients, only with moderate improvement in FFS. M1 patients < 70 years old, Eastern Cooperative Oncology Group (ECOG) performance status (ECOG PS) 0-1, Gleason score (< 8), or visceral metastases could realize better survival benefit from either combination therapy. In indirect comparisons among M1 patients with younger age (< 70 years), ECOG PS 0-1 or aggressive Gleason score (GS ≥ 8), upfront Abi showed superiority to Doc in prolonging FFS. The incidence of severe adverse events (AEs ≥ 3) was comparable between these two therapeutic regimens. In conclusion, upfront Doc or Abi plus ADT should be considered a standard of care in selected patients with mCNPC. For a subset of populations, Abi may be the first choice for men who start treatment for the first time.

The prognostic value of the proportion/architectural patterns of intraductal carcinoma of the prostate (IDC-P) in patients with de novo metastatic prostate cancer

Purpose: Intraductal carcinoma of the prostate is an adverse prognosticator of prostate cancer. However, the roles of proportion and architectural patterns of intraductal prostate carcinoma in patient outcomes remain unclear. Materials and Methods: We retrospectively analyzed data on 644 patients with de novo metastatic prostate cancer between 2010 and 2017. Intraductal carcinoma of the prostate was identified from 12-core prostate biopsy. We calculated the proportion of intraductal prostate carcinoma and identified patterns according to the 2016 WHO classification. Propensity score matching was performed to balance baseline characteristics between patients with and without intraductal prostate carcinoma. Kaplan-Meier curves and Cox regression were used for survival analyses. The end points were castration resistant prostate cancer-free survival and overall survival. Results: Of the 644 patients 180 (28.0%) harbored intraductal carcinoma of the prostate. A 10% or greater incidence of the carcinoma was independently associated with worse prognosis (castration resistant prostate cancer-free survival HR 2.06, 95% CI 1.51–2.81, p <0.001, and overall survival HR 2.52, 95% CI 1.52–4.16, p <0.001), as was pattern 2 intraductal carcinoma of the prostate (HR 1.86, 95% CI 1.40–2.49, p <0.001, and HR 2.12, 95% CI 1.29–3.46, p = 0.003, respectively). Based on these 2 risk factors all men were classified into 5 groups. Patients in group 0 (no intraductal carcinoma of the prostate) and prostate intraductal carcinoma group 1 (less than 10% intraductal carcinoma, pattern 1) had favorable median castration resistant prostate cancer-free survival (18.0 vs 16.9 months, p = 0.871) and median overall survival (neither reached, p = 0.698). Men in intraductal carcinoma of the prostate group 4 (10% or greater intraductal carcinoma, pattern 2) harbored the worst outcomes (median castration resistant prostate cancer-free and overall survival 8.4 and 29.9 months, respectively). Group 2 (less than 10% intraductal carcinoma, pattern 2, with median castration resistant prostate cancer-free and overall survival 14.2 and 45.9 months) and group 3 (10% or less prostate intraductal carcinoma, pattern 1, with median castration resistant prostate cancer-free and overall survival 11.9 and 39.7 months, respectively) had an intermediate prognosis. Conclusions: A 10% or greater proportion of intraductal carcinoma of the prostate and pattern 2 were 2 unfavorable prognosticators of metastatic prostate cancer. Pathological reporting criteria based on intraductal carcinoma of the prostate could improve the prediction of patient outcomes and optimize treatment decisions.

Expression and epigenetic regulatory mechanism of BNIP3 in clear cell renal cell carcinoma

The majority of clear cell renal cell carcinomas (ccRCCs) are caused by an accumulation of hypoxia-inducible factor (HIF) and the overexpression of downstream genes in response to the von Hippel-Lindau (VHL) gene becoming inactivated. In the present study, our hypothesis was that BNIP3, a gene positioned downstream of HIF, would be expressed at a higher level in ccRCC; however, instead, lower levels of BNIP3 expression were identified in RCC tumor tissues compared with adjacent non-tumor tissues. These changes were associated with lower levels of VHL, and higher levels of HIF and vascular endothelial growth factor. BNIP3 was also undetectable in three investigated RCC cell lines (786-O, ACHN, A498) and GRC-1-1 cells. Methylation of the BNIP3 promoter was not detected, and neither did treatment with a methylation inhibitor cause cell proliferation. However, treatment with a histone deacetylation inhibitor, trichostatin A (TSA), inhibited cultured RCC cell proliferation, promoted apoptosis and restored BNIP3 expression. Furthermore, histone deacetylation of the BNIP3 promoter was identified in ACHN and 786-O cells, and the acetylation status was restored following TSA treatment. Taken together, the results of the present study suggest that histone deacetylation, but not methylation, is most likely to cause BNIP3 inactivation in RCC. The data also indicated that restoration of BNIP3 expression by a histone deacetylation inhibitor led to growth inhibition and apoptotic promotion in RCC.

The Efficiency and Safety of Intrarectal Topical Anesthesia for Transrectal Ultrasound-Guided Prostate Biopsy: A Systematic Review and Meta-Analysis

Objective: The study aims to review the current evidence to determine the efficiency and safety of intrarectal topical anesthesia (ITA) for transrectal ultrasound-guided prostate biopsy. Materials and Methods: A comprehensive search of the literature was performed using Medline, Embase and Cochrane central register of controlled trials. All randomized controlled trials (RCTs) comparing the efficacy and safety of periprostatic nerve block (PNB), ITA, and PNB combined with ITA were included. The mean pain scores after the biopsy procedure, the mean pain scores after the probe insertion and adverse events were evaluated. Results: Thirty-2 RCTs were identified in the meta-analysis. ITA could significantly reduce pain during probe insertion compared to control and placebo. The PNB group had less pain after the prostate biopsy than the ITA group. PNB combined with ITA could significantly reduce pain during the biopsy procedure compared to ITA alone. No significant differences were found in adverse events in ITA versus control, ITA versus placebo, and ITA versus PNB. Conclusions: ITA could reduce pain after probe insertion and pain after biopsy although it was inferior to PNB in reducing pain during prostate biopsy. ITA combined with PNB was more effective than ITA alone. In addition, it was safe to perform ITA for prostate biopsy.

Comparative diagnostic efficacy of biopsy strategies for prostate cancer detection: a Bayesian network meta-analysis of 24 randomised controlled trials

Abstract Background The introduction of three kinds of MRI-guided prostate biopsies (MRI-PB) has changed the model of practice regarding prostate biopsies. The most appropriate strategy is still unknown, we therefore aimed to compare and rank prostate biopsies strategies. Methods We did a network meta-analysis to incorporate both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library Central Register of Controlled Trials, Scopus, Embase, and the reference lists of relevant articles for randomised controlled trials published up to Sept 1, 2016, of different strategies for prostate biopsy. Involved studies were full text reports of randomised trials that compared different biopsy strategies, and reported efficacy endpoints. The primary outcome was overall prostate cancer detection rate. We did pairwise meta-analyses by random effects model and network meta-analysis by Bayesian random effects model. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42016044011. Findings From a total of 3616 citations, 24 randomised trials with a total of 6497 participants were included in this network meta-analysis. We considered 11 strategies of prostate biopsy published between 2000 and 2016. Cognitive MRI prostate biopsy was significantly better (relative risk [RR] 2·66, 95% credible interval [CrI] 1·44–4·72) than TRUS (10-12; PCa detection from 10–12 needle core transrectal ultrasound prostate biopsy) prostate biopsy considering overall prostate cancer detection rate. Detection rates of clinically significant and insignificant prostate cancers suggested no significant difference between any group of all biopsy techniques. Interpretation Although cognitive MRI prostate biopsy obtained better detection rates of overall prostate cancer than did TRUS (10-12) prostate biopsy, it had no remarkable advantages in detection of clinically significant and insignificant prostate cancers. Nevertheless, these results should be considered together with all known safety and economy information when selecting the strategy for individual patients. Funding This study was supported by the Prostate Cancer Foundation Young Investigator Award 2013, the National Natural Science Foundation of China (81300627, 81370855) and Programs from Science and Technology Department of Sichuan Province (2013SZ0006, 2014JY0219).

Efficacy and safety of medical expulsion therapy for ureteral calculi: a systematic review and network meta-analysis

Abstract Background The effectiveness of medical expulsive therapy for the non-invasive management of patients with ureteral calculi has been called into question. We aimed to evaluate the benefits and harms of various medical expulsive therapies using a systematic review and network meta-analysis. Methods We incorporated both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library Central Register of Controlled Trials, Scopus, Embase, and the reference lists of relevant articles for randomised controlled trials published up to Oct 1, 2016, of medical expulsive therapy. The primary outcome was the proportion of participants who did not need further intervention for stone clearance within 4 weeks of randomisation, stone expulsion rate, stone expulsion time, and adverse events. We did pairwise meta-analyses by random effects model and network meta-analysis by Bayesian random effects model. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number 42016051277. Findings From a total of 1873 citations, 65 randomised trials with a total of 10 493 participants were included in this network meta-analysis. 14 strategies for medical expulsive therapy published between 2000 and 2016 were considered. Tamsulosin plus tadalafil (relative risk [RR] 7·31, 95% credible interval [CrI] 1·83–14·37), surface under the cumulative ranking curve [SUCRA], 0·90) was ranked the best, followed by alfuzosin (6·50, 3·50–12·2, SUCRA 0·81), tadalafil (6·39, 2·15–10·02, SUCRA 0·77), doxazosin (6·13, 3·50–11·5, SUCRA 0·75), and tamsulosin (5·89, 1·50–9·42, SUCRA 0·69) considering stone expulsion rate. Alfuzosin showed significant superiority over nifedipine (RR 6·19, 95% CrI 2·72–13·57) and ramsulosin (2·19, 1·18–4·04) in terms of stone expulsion rate. Tamsulosin plus tadalafil was significantly more effective than nifedipine (standardised mean difference [SMD] −0·89, 95 % CI −1·19 to −0·60), Tamsulosin (−2·36, −4·61 to −0·81), and placebo (SMD −3·20, −5·19 to −2·21) in terms of stone expulsion time. No significant difference between any group of medical expulsive therapy was found in terms of further intervention need for stone clearance and adverse events. Out results showed the same significance in the subgroup analysis of stone size ( vs >5 mm) and stone location (upper and lower ureteral). Interpretation In adults with ureteral stones smaller than 10 mm in size, tamsulosin plus tadalafil and alfuzosin are safe and effective for expulsive therapy. Nevertheless, these results should be considered together with all known safety and economic information when selecting the strategy for individual patients. Head-to-head comparisons of medical expulsive therapy are limited, but still needed to confirm the findings. Funding Prostate Cancer Foundation Young Investigator Award 2013, National Natural Science Foundation of China (81300627 and 81370855), and Programs from Science and Technology Department of Sichuan Province (2013SZ0006 and 2014JY0219).