Background: Accumulating evidence points to epigenetic mechanisms as essential in tumorigenesis. Treatment that targets epigenetic regulators is becoming an attractive strategy for cancer therapy. The role of epigenetic therapy in prostate cancer (PCa) remains elusive. Previously we demonstrated a correlation of levels of histone lysine demethylase KDM4B with the appearance of castration resistant prostate cancer (CRPC) and identified a small molecular inhibitor of KDM4B, B3. In this study, we aim to define the role of KDM4B in promoting PCa progression and test the efficacy of B3 using clinically relevant PCa models. Methods: KDM4B was overexpressed in LNCaP cells or knocked down (KD) in 22Rv1 cells. The specificity of B3 was determined in vitro using recombinant KDM proteins and in vivo using 22Rv1 cell lysates. The efficacy of B3 monotherapy or in combination with androgen receptor (AR) antagonist enzalutamide or the mTOR inhibitor rapamycin was tested using xenograft models in castrated mice. Comparative transcriptomic analysis was performed on KDM4B KD and B3-treated 22Rv1 cells to determine the on-target (KDM4B-dependent) and off-target (non-KDM4B-associated) effects of B3.Results: Overexpression of KDM4B in LNCaP cells enhanced its tumorigenicity whereas knockdown of KDM4B in 22Rv1 cells reduced tumor growth in castrated mice. B3 suppressed the growth of both 22Rv1 and VCaP xenografts and sensitized 22Rv1 cells to enzalutamide inhibition. B3 also inhibited 22Rv1 tumor growth synergistically with rapamycin that resulted in cell apoptosis. Mechanistically, B3 inhibited expression of AR-V7 and genes involved in epithelial-to-mesenchymal transition. DNA replication stress marker γH2A.X was upregulated by B3, which is further increased when combined with rapamycin. Based on transcriptomic and biochemical analyses, B3 inhibits both H3K9me3 and H3K27me3 demethylase activity, which is believed to underlie its anti-tumor action.Conclusions: Our studies establish KDM4B as a potent target for CRPC and B3 as a potential therapeutic agent. B3 as monotherapy or in combination with other anti-PCa therapeutics offers proof of principle for the clinical translation of epigenetic therapy targeting KDMSs for CRPC patients.

Objectives To describe a technique to improve exposure of prostate during extraperitoneal robot-assisted radical prostatectomy (EP-RARP). Material and methods From March 2020 to June 2022, a total of 41 patients with prior intra-abdominal surgery underwent EP-RARP. 23 patients improved exposure by traction of prostate through urinary catheter. The catheter traction technology (CTT) group was compared with the standard prostatectomy (SP) group (18 patients) in terms of estimated blood loss (EBL), operative time, positive surgical margin rate, the recovery rate of urinary continence, Gleason score and postoperative hospital stays. Differences were considered significant when P < 0.05. Results The operative time was lower in the CTT group (109.63 min vs. 143.20 min; P < 0.001). EBL in the CTT group was 178.26 ± 30.70 mL, and in the standard prostatectomy group, it was 347.78 ± 53.53 mL (P < 0.001). No significant differences with regard to postoperative hospital stay, recovery rate of urinary continence, catheterization time and positive surgical margin were observed between both groups. No intraoperative complications occurred in all the patients. After 6 months of follow-up, the Post-op Detectable prostate specific antigen was similar between the two groups. Conclusion CTT is a feasible, safe, and valid procedure in EP-RARP. Application of CTT improved the exposure of prostate, reduced operative time and blood loss in comparison with the conventional procedure.

Background: The prognostic risk of non-metastatic clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is variable among individual patients following radical nephrectomy and thrombectomy. However, the prognostic potential of multiple pathological features of VTT are unexploited, and risk stratification models specific for these patients are lacking.Patients and methods: This retrospective, nationwide cohort comprised 1263 non-metastatic ccRCC patients with VTT from multicentre, including Training (n=664), China-validation (n=517) and Poland-Validation cohorts (n=82). In addition to the collection of traditional clinicopathologic features, the pathologic characteristics of VTT were centrally reviewed. Independent predictors from multivariable Cox regression analysis were developed into a prognostic model. Harrell's concordance index (c-index), area under the receiver operating characteristic curve (AUC) and decision curve analysis were used to evaluate the association of the variables and prognostic models with overall survival (OS) and disease-free survival (DFS).Results: Using a multi-cohort of 1263 patients, we identified that VTT grading represents an unheeded and powerful independent prognostic factor of adverse outcomes across all cohorts in multivariate analysis for OS and DFS (P < .001; P < .001; P = 0.014 in Training, China-Validation, and Poland-Validation cohorts, respectively). Moreover, VTT grading showed superiority in predicting survival risk compared with the PT grading and other indicators. A risk positioning model, named the TT-GPS score, was constructed based on four independent predictors: VTT height, VTT Grading, Perinephric fat invasion, and Sarcomatoid differentiation in primary tumor. The TT-GPS score displayed better discriminatory ability than available models in risk assessment (OS, c-index: 0.736 and 0.746, AUC: 0.828 and 0.815; DFS, c-index: 0.705 and 0.710, AUC: 0.797 and 0.787 in Training and China-Validation cohorts, respectively). Poland-Validation cohort validated the superiority of the TT-GPS score (OS, c-index: 0.840, AUC: 0.874). Conclusions: VTT grading displayed superior accuracy in prediction of survival risk. By incorporating VTT grading, the TT-GPS score is a powerful predictor of adverse outcomes in non-metastatic ccRCC patients with VTT.

Background: To investigate the value of contrast-enhanced transrectal ultrasound (CETRUS) in reducing unnecessary biopsy during prostate cancer screening and predicting biochemical recurrence in patients with localized prostate cancer. Methods:This was a prospective study of patients suspected of prostate cancer who were evaluated with CETRUS followed by prostate biopsy. Prostate blood flow on CETRUS was graded using a 5-point scale. The relationship between CETRUS score and biopsy outcomes was analyzed; Univariate and multi-variate analyses were used to determine the probable prognostic factors with biochemical recurrence in patients with localized prostate cancer underwent radical prostatectomy. Results:A total of 347 patients were enrolled. Prostate cancer was found in 164 patients. A significant positive correlation (r = 0.69, p < 0.001) was found between CETRUS scores and prostate cancer. Using CETRUS score ≥ 2 as the threshold for biopsy could have reduced the number of biopsies by 12.1% (42/347) without missing cancer and spared 23.0% (42/183) of patients from unnecessary biopsy. 77 patients with localized prostate cancer underwent radical prostatectomy and followed up. 17 of 77 patients exhibited biochemical recurrence. The 3-year biochemical recurrence-free survival rates were 86% for patients with CETRUS low scores (≤ 3) and 59% for patients with high scores (> 3; p = 0.015). Multivariate Cox regression analysis showed that CETRUS score was an independent predictor of biochemical recurrence (HR: 7.02; 95% CI: 2.00-24.69; p = 0.002). Conclusions:CETRUS score may be a useful tool to reduce unnecessary biopsy during prostate cancer screening and predict biochemical recurrence of localized prostate cancer after radical prostatectomy. BackgroundProstate cancer is the most common solid neoplasm and the second leading cause of cancer death in men in the U.S. [1]. With increasing incidence and mortality, an estimated 60,300 new cases were diagnosed and 26,600 deaths were attributed to this disease in China in 2015 [2]. Approximately one million prostate biopsies are conducted per year in the U.S.. However, prostate-specific antigen (PSA) testing, the most widely used screening tests for prostate cancer, leads to 750,000 unnecessary biopsies-and attendant pain, inconvenience, financial burden, and risk of infection [3]. Therefore, Hong-wei Zhao and Yong Fang: Project development, Data Collection, Study design, Manuscript editing; Jian Li, Jia-Zheng Cao and Juan Lin: Manuscript writing, Study design, Data Collection, Statistical analysis; Zhu Wang, Jian-yao Lv,and Jin-huan We:Manuscript editing, Data Collection; Jinhuan Wei and Zhen-hua Chen: Data Collection,Statistical analysis; Hao-hua Yao, Yi-hui Pan, Zhen-li Gao, Jun-hang Luo, Wei Chen,and Lei Shi: Data Collection, Datainterpretation. All authors read and approved the final manuscript.

No abstract