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Simple Summary: In this review, we have summarized the crucial role of G9a in cellular biology and disease. By synthesizing recent research discoveries, we delve into the functions of G9a in gene expression regulation, cell proliferation, and biological development. Additionally, we explore its potential involvement in cancer and discuss its prospects as a therapeutic target specifically in prostate cancer. In summary, this review provides a comprehensive perspective on G9a, enhances understanding of the significance of G9a in biology and cancer, and offers insights into future research and drug development. G9a, also named EHMT2, is a histone 3 lysine 9 (H3K9) methyltransferase responsible for catalyzing H3K9 mono- and dimethylation (H3K9me1 and H3K9me2). G9a contributes to various aspects of embryonic development and tissue differentiation through epigenetic regulation. Furthermore, the aberrant expression of G9a is frequently observed in various tumors, particularly in prostate cancer, where it contributes to cancer pathogenesis and progression. This review highlights the critical role of G9a in multiple cancer-related processes, such as epigenetic dysregulation, tumor suppressor gene silencing, cancer lineage plasticity, hypoxia adaption, and cancer progression. Despite the increased research on G9a in prostate cancer, there are still significant gaps, particularly in understanding its interactions within the tumor microenvironment and its broader epigenetic effects. Furthermore, this review discusses the recent advancements in G9a inhibitors, including the development of dual-target inhibitors that target G9a along with other epigenetic factors such as EZH2 and HDAC. It aims to bring together the existing knowledge, identify gaps in the current research, and suggest future directions for research and treatment strategies. [ABSTRACT FROM AUTHOR]

Intraductal carcinoma of the prostate (IDC‐P) is an aggressive subtype of prostate cancer characterized by the growth of tumor cells within the prostate ducts. It is often found alongside invasive carcinoma and is associated with poor prognosis. Understanding the molecular mechanisms driving IDC‐P is crucial for improved diagnosis, prognosis, and treatment strategies. This review summarizes the molecular characteristics of IDC‐P and their prognostic indications, comparing them to conventional prostate acinar adenocarcinoma, to gain insights into its unique behavior and identify potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Thus, we aimed to develop the APGRC (Asian PCa Germline Risk Calculator), a risk assessment nomogram for predicting the probability of carrying germline PVs in 14 PCa predisposition DDR genes. Dear Editor, Prostate cancer (PCa) is a prominent global cancer among men, estimated at 1.3 million diagnoses and 359 thousand deaths in 2018,[1] with a strong hereditary component. [Extracted from the article]

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is overexpressed in a variety of malignancies including prostate cancer (PCa) and may play important roles in tumor progression. Gene copy number gains, enhanced transcription, and a few circRNAs have been reported to upregulate EZH2. It was not known whether EZH2 itself generates circRNAs that promote its own expression. We here report the identification of circEZH2E2/E3 that is derived from exons 2 and 3 of the EZH2 gene and overexpressed in PCa. We show that circEZH2E2/E3 functions as a dual inhibitor for both miR363 and miR708 that target the EZH2 3′UTR and CDS, respectively, resulting in the upregulation of EZH2 expression and hence the downregulation of EZH2‐repressed genes (e.g., CDH1 and DAB2IP), and enhancement of PCa cell proliferation, migration, invasion, and xenograft PCa growth. Overexpression of circEZH2E2/E3 is significantly correlated with higher tumor grade, tumor progression, and unfavorable progression‐free and disease‐specific survival in PCa patients. These findings show a novel autoenhancing EZH2–circEZH2E2/E3‐miR363/miR708–EZH2 regulatory loop, by which circEZH2E2/E3 plays important roles in PCa tumorigenesis and progression by upregulating EZH2, and may have potential diagnostic, prognostic, and therapeutic uses in PCa management. [ABSTRACT FROM AUTHOR]

Urological cancer is a collective term for cancers of the bladder, kidney, ureter, penis, prostate, and testicles. Last year, more than 444,000 people were diagnosed with urinary cancers in the United States. In this review, we talk about the complexity of prostate and kidney cancer. [ABSTRACT FROM AUTHOR]

Background: MRI‐targeted biopsy (MRTB) improves the clinically significant prostate cancer (csPCa) detection rate with fewer biopsy cores in men with suspected PCa. However, whether concurrent systematic biopsy (SB) can be avoided in patients undergoing MRTB remains unclear. Purpose: To evaluate the potential value of MRI‐based radiomics models in avoiding unnecessary SB in biopsy‐naïve patients. Study type: Retrospective. Population: A total of 226 patients (mean age 66.6 ± 9.02 years) with suspicion of PCa (PI‐RADS score ≥ 3) and received combined cognitive MRTB with SB were retrospectively recruited and randomly divided into training (N = 180) and test (N = 46) cohorts at an 8:2 ratio. Field Strength/Sequence: A 3.0 T, biparametric MRI (bpMRI) including T2‐weighted imaging (T2WI) and apparent diffusion coefficient (ADC) map. Assessment: The whole prostate gland (PG) and the index lesion (IL) were delineated. Three radiomics models of bpMRIPG, bpMRIIL, and bpMRIPG+IL were constructed, respectively, and the performance of each radiomics model was compared with that of PI‐RADS assessment. Statistical Tests: The least absolute shrinkage and selection operator (LASSO) regression method was used to select texture features. The area under the curve (AUC) and decision curve analysis were used to estimate the models. Results: The bpMRIPG+IL radiomics model exhibited good discrimination, calibration, and net benefits, which would reduce the SB biopsy in 71.2% and 71.4% of men with PI‐RADS ≥ 5 lesions in the training and test cohorts, respectively. Data Conclusion: A bpMRIPG+IL radiomics model may outperform PI‐RADS category in help reducing unnecessary SB in biopsy‐naïve patients. Evidence Level: 3 Technical Efficacy: Stage 6 [ABSTRACT FROM AUTHOR]

Purpose Aldo-keto reductase family 1 member C3 (AKR1C3) is important in prostate cancer progression, being a potential biomarker in metastatic castration-resistant prostate cancer (mCRPC). Previous explorations of AKR1C3 are mainly based on tissue samples. This study investigates using plasma-based liquid biopsy to validate the prognostic and predictive value of AKR1C3 in patients with mCRPC. Materials and Methods We prospectively recruited 62 patients with mCRPC. All patients received repeated prostate biopsies at the time of mCRPC diagnosis, and immunohistochemistry (IHC) staining was used to detect protein expression of AKR1C3 in the tissues. We took their blood simultaneously and performed digital droplet polymerase chain reaction (ddPCR) to measure expression levels of AKR1C3 in the exosomes. The detected plasma and tissue AKR1C3 expression levels were analyzed for patients' overall survival (OS) and progression-free survival under first-line abiraterone use (ABI-PFS). Results All other baseline characteristics were balanced between the 2 groups. 15/62 (24.2%) and 25/62 (40.3%) patients showed AKR1C3-EXO positive (≥20 copies/20 μL) and AKR1C3-IHC positive, respectively. Positive AKR1C3-EXO expression was associated with decreased patients' survival [ABI-PFS: 3.9 vs 10.1 months, P <.001; OS: 16.2 vs 32.5 months, P <.001]. AKR1C3-IHC positivity was also correlated with ABI-PFS and OS (P =.010, P =.016). In patients with worse baseline blood tests (including higher alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) level and lower hemoglobin (HB) level), and lower ISUP/WHO group (<4), their OS was significantly worse when showing AKR1C3-EXO positive. Conclusion AKR1C3-EXO is associated with patient prognosis regarding OS and ABI-PFS and can be used as a biomarker in mCRPC. [ABSTRACT FROM AUTHOR]

CDK12 (Cyclin-Dependent Kinase 12)-mutated prostate cancer patients often respond badly to current therapies. Immunotherapy and platinum-based chemotherapy are recommended based on the molecular features of CDK12-mutated tumors, but the reported patient outcomes are still unsatisfying. Here we report a prostate cancer patient with CDK12 somatic mutation who received multiple therapy options, including platinum-based chemotherapy and immunotherapy. His sequential circulating tumor DNA (ctDNA) -based liquid biopsy tests showed that his original CDK12 mutation fell undetectable twice. This phenomenon was observed only when he was responding well to platinum-based chemotherapy. His responses to immunotherapy were not satisfying. This case indicates that platinum-based chemotherapy can be a good option for treating patients with CDK12 mutation. More importantly, dynamic ctDNA-based liquid biopsies to monitor patients' CDK12 mutation status are critical in evaluating patients' response and tolerance during platinum-based chemotherapy, therefore may lead to a better overall prognosis. In conclusion, CDK12-mutated prostate cancer patients are likely to benefit from platinum-based chemotherapy, especially with the help of dynamic ctDNA-based liquid biopsies to monitor their CDK12 mutation status. [ABSTRACT FROM AUTHOR]

The purpose of our study was to investigate the safety, pharmacokinetics (PK), and initial antitumor efficacy of HC‐1119 in patients with metastatic castration‐resistant prostate cancer (mCRPC). Eligible mCRPC patients were included in our study (NCT 03774056) with two parts. Part A was a dose escalation study in which patients received a dose escalation of HC‐1119 (40, 80, 160 and 200 mg/day). Part B was a dose expansion study in which patients received HC‐1119 at the dose of 80 and 160 mg. Safety assessment and pharmacokinetic samplings were performed for all patients at the given time points; preliminary tumor response was also assessed. Twenty‐four patients were enrolled in part A and 19 patients in part B, respectively. HC‐1119 was safe, well tolerated and no dose‐limiting toxicity was observed. Fatigue was the most common treatment‐related adverse event and no seizures were observed. At the dose levels of 40, 80 and 160 mg, the AUC and Cmax of HC‐1119 in plasma increased almost dose‐proportionally at the steady state in mCRPC patients. Maximum prostate‐specific antigen (PSA) response rates (≥50% reduction from the baseline) in dose escalation and dose expansion cohorts were 77% and 75%, respectively; the overall disease control rate (22 patients available for imaging analysis) was 72.7%, with PR in 4 patients, SD in 12 patients and PD in 6 patients; the 2‐year overall survival rate in patients from Part B was 56.8%. HC‐1119 was safe, well tolerated and efficacious and HC‐1119 at 80 mg/day is recommended for further studies. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether additional systematic biopsy is necessary in all biopsy naïve patients with MRI visible lesions by taking PI-RADS score and prostate volume into consideration. Materials and Methods: Patients who underwent combined systematic biopsy (SB) and cognitive MRI-targeted biopsy (TB) in our hospital between May 2018 and June 2020 were retrospectively reviewed. The detection rate of clinical significant prostate cancer (csPCa), biopsy grade group (GG) concordance, and disease upgrading rate on radical prostatectomy were compared between SB and TB and further stratified by PI-RADS v2.0 category and prostate volume. Results: A total of 234 patients were analyzed in this study. TB alone detected more csPCa and less clinically insignificant prostate cancer (cisPCa) than SB alone in the whole cohort (57.3 vs 53%, P = 0.041; 3.8 vs 7.7%, P = 0.049 respectively). The additional SB indicated only a marginal increase of csPCa detection but a remarkable increase of cisPCa detection compared with targeted biopsy (59.4 vs 57.3%, P = 0.064; 3.8 vs 7.7%, P = 0.012). As stratified by PI-RADS category, the difference of csPCa detection rate between TB and SB was not significant either in PI-RADS 5 subgroup (83.8 vs 76.3%, P = 0.07) or in PI-RADS 3–4 subgroup (43.5 vs 40.9%, P = 1.0). Additional SB decreased the rate of disease upgrading on radical prostatectomy (RP) than TB alone in PI-RADS 3–4 subgroup (14.5 vs 25.5%, P = 0.031) other than PI-RADS 5 subgroup (6 vs 6%, P = 1.0). When stratified by prostate volume (PV), TB alone detected more csPCa than SB in small prostate (PV < 30 ml) group (81.0 vs 71.0%, P = 0.021) but not in large prostate (PV ≥ 30 ml) group (44.0 vs 42.7%, P = 0.754). The additional SB did not significantly decrease the rate of disease upgrading on RP than TB alone in either small or large prostate (6.4 vs 8.5%, P = 1.0; 13.8 vs 22.4%, P = 0.063). Conclusion: The combination biopsy method was no superior than targeted biopsy alone in PI-RADS 5 or in small volume prostate subgroup. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to compare the efficacy of radical prostatectomy (RP) + extended pelvic lymph node dissection (ePLND) and radiotherapy (RT) in localized prostate cancer (PCa) patients with a risk of lymph node invasion (LNI) over 5%. Methods: The Surveillance, Epidemiology, and End Results (SEER) databases were used to identify patients with PCa from 2010 to 2014. Propensity score matching (PSM) was performed to balance baseline characteristics between patients in different treatment groups. Kaplan-Meier curves and Cox regression were used to assess the effects of treatments on cancer-specific survival (CSS) and overall survival (OS). Results: Overall 20584 patients were included in this study, with 4,057 and 16,527 patients receiving RP + ePLND and RT, respectively. After PSM, patients with RP + ePLND had similar CSS (5-year CSS rate: 97.8% vs. 97.2%, P=0.310) but longer OS (5-year OS rate: 96.0% vs. 90.8%, P<0.001) compared to those receiving RT. When separating RT cohort into external beam radiotherapy (EBRT) group and EBRT+ brachytherapy (BT) group, treatments with RP + ePLND and EBRT+ BT achieved equivalent OS and were both superior to EBRT alone (5-year OS rate: 96.0% vs. 94.4% vs. 90.0%, P<0.001). Subgroup analyses and multivariate analyses further confirmed the superiority of RP + ePLND and EBRT+ BT. Conclusion: RP + ePLND and EBRT + BT were associated with better survival outcomes compared to EBRT alone in PCa patients with a probability of LNI over 5%. However, no survival difference was observed between RP + ePLND and EBRT + BT. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy and safety of current systemic combination therapies for patients with mHSPC and help select candidates for optimal treatment. Methods: Databases of MEDLINE and EMBASE, Cochrane Central Register of Controlled Trials, and Clinical Trial.gov were searched for eligible studies. Direct and network meta-analysis were conducted to compare various systemic combination therapies and the surface under the cumulative ranking curve (SUCRA) was generated for treatment ranking. Subgroup analyses were performed according to the extent of metastasis. Adverse events (AEs) were compared among the effective treatments. Results: Ten trials with 16 publications were included in this network meta-analysis. Direct and network meta-analysis consistently suggested that androgen-deprivation therapy (ADT) combined with docetaxel, abiraterone, enzalutamide, or apalutamide could significantly improve overall survival (OS) and failure-free survival (FFS) compared to ADT alone in men with mHSPC. SUCRA analysis demonstrated the superiority of ADT plus abiraterone or enzalutamide over other therapies. Subgroup analyses indicated that additional abiraterone to ADT had the highest ranking in patients with high-volume diseases or visceral metastases and enzalutamide plus ADT outperformed other treatments in patients with low-volume diseases or without visceral metastases. Different combination therapies had variable AE profiles and ADT in addition with docetaxel or abiraterone had the highest risk of AEs. Conclusion: ADT plus docetaxel, abiraterone, enzalutamide, or apalutamide were associated with significantly improved survival in patients with mHSPC. ADT plus abiraterone or enzalutamide appeared to be the most effective treatments. Clinicians should balance the efficacy, potential AEs, and disease status to select the optimal treatment. [ABSTRACT FROM AUTHOR]

Objectives: To document the management of advanced prostate cancer including diagnosis, prognosis, treatment, and care, in real‐world practice in Asia using the United in Fight against prOstate cancer (UFO) registry. Patients and Methods: We established a multi‐national, longitudinal, observational registry of patients with prostate cancer presenting to participating tertiary care hospitals in eight Asian countries. A total of 3636 eligible patients with existing or newly diagnosed high‐risk localised prostate cancer (HRL), non‐metastatic biochemically recurrent prostate cancer (M0), or metastatic prostate cancer (M1), were consecutively enrolled and are being followed‐up for 5 years. Patient history, demographic and disease characteristics, treatment and treatment decisions, were collected at first prostate cancer diagnosis and at enrolment. Patient‐reported quality of life was prospectively assessed using the European Quality of Life‐five Dimensions, five Levels (EQ‐5D‐5L) and Functional Assessment of Cancer Therapy for Prostate Cancer questionnaires. In the present study, we report the first interim analysis of 2063 patients enrolled from study start (15 September 2015) until 18 May 2017. Results: Of the 2063 enrolled patients, 357 (17%), 378 (19%), and 1328 (64%) had HRL, M0 or M1 prostate cancer, respectively. The mean age at first diagnosis was similar in each group, 56% of all patients had extracapsular extension of their tumour, 28% had regional lymph node metastasis, and 53% had distant metastases. At enrolment, 62% of patients had at least one co‐morbidity (mainly cardiovascular disease or diabetes), 91.8% of M1 patients had an Eastern Cooperative Oncology Group performance score of <2 and the mean EQ‐5D‐5L visual analogue score was 74.6–79.6 across cohorts. Treatment of M1 patients was primarily with combined androgen blockade (58%) or androgen‐deprivation therapy (either orchidectomy or luteinising hormone‐releasing hormone analogues) (32%). Decisions to start therapy were mainly driven by treatment guidelines and disease progression. Decision to discontinue therapy was most often due to disease progression (hormonal drug therapy) or completion of therapy (chemotherapy). Conclusion: In the UFO registry of advanced prostate cancer in Asia, regional differences exist in prostate cancer treatment patterns that will be explored more deeply during the follow‐up period; prospective follow‐up is ongoing. The UFO registry will provide valuable descriptive data on current disease characteristics and treatment landscape amongst patients with prostate cancer in Asia. [ABSTRACT FROM AUTHOR]

Background: The optimal treatment for patients with high-risk prostate cancer (PCa) remains a debate and selection of patients to receive proper therapy is still an unsettled question. This systematic review was conducted to compare the effectiveness of prostatectomy (RP) and radiotherapy (RT) in patients with high-risk PCa and to select candidates for optimal treatment. Methods: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were searched for eligible studies. We extracted hazard ratios (HRs) and 95% confidence interval (CI) of all included studies. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS); the secondary outcomes were biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS) and clinical recurrence-free survival (CRFS). The meta-analysis was performed using Review Manager 5.3. Subgroup analyses were conducted according to Gleason score (GS), T stage and RT types. Quality of life (QoL) was compared with these two treatments. Results: A total of 25 studies were included in this meta-analysis. Overall, RP showed more survival benefits than RT on CSS (P = 0.003) and OS (P = 0.002); while RT was associated with better BRFS (P = 0.002) and MFS (P = 0.004). Subgroup analyses showed RT was associated with similar or even better survival outcomes compared to RP in patients with high GS, high T stage or received external beam radiotherapy plus brachytherapy (EBRT + BT). As for QoL, RP was associated with poorer urinary and sexual function but better performance in the bowel domain. Conclusion: RP could prolong the survival time of patients with high-risk PCa; however, RT could delay the disease progression, and combined RT (EBRT + BT) even brought preferable CSS and similar OS compared to RP. RT might be the prior choice for patients with high T stage or high GS. RP could lead to poorer urinary and sexual function, while bringing better performance in the bowel domain. [ABSTRACT FROM AUTHOR]

Introduction: Since the new 2014 grading system was recommended by the International Society of Urological Pathology (ISUP), it has been validated in patients with localized prostate cancer (PCa) and it has shown excellent prognostic value. However, its predictive power in high-risk PCa remains unclear. Methods: A total of 420 patients with high-risk PCa who underwent radical prostatectomy (RP) were included in this study. Biochemical recurrence-free survival (BRFS) was set as the endpoint. Results: Biochemical recurrence occurred in 84/420 (20.0%) patients at the end of follow-up. Compared to the three-tier grouping system, the five-tier grouping system could more effectively distinguish the BRFS of patients with higher predictive accuracy (C-index: 0.599 vs 0.646). The BRFS of patients with grade group (GG) 1 and GG 2 was similar (P=0.593). Also, the prognosis between those with GG 2 and GG 3 could be clearly distinguished (P=0.001). However, the discrimination capacity between patients with GG 3 and GG 4 was limited (P=0.681). When tertiary Gleason pattern (TGP5) and intraductal carcinoma of the prostate (IDC-P) were excluded, the HR value of the GG 4 group vs the GG 3 group increased from 1.15 (95% CI: 0.59–2.22) to 1.49 (95% CI: 0.72–3.10) and 1.36 (95% CI:0.65–2.83), respectively. Conclusions: This study is the first to validate the new 2014 ISUP grading system in patients with high-risk PCa who underwent RP. The 2014 system could effectively classify patients into five groups with high predictive accuracy. Notably, the existence of TGP5 and IDC-P needs to be routinely reported in clinical practice, which could help to support the predictive value of the new grading system. [ABSTRACT FROM AUTHOR]

Objective: The role of additional chemotherapy in the treatment of high-risk prostate cancer (PCa) remains a controversy. This meta-analysis aimed to investigate the effect of additional chemotherapy on high-risk PCa. Methods: Randomized controlled trials (RCTs) about additional chemotherapy for high-risk PCa were searched in PubMed, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We extracted HRs of overall survival (OS) and progression-free survival (PFS) for each trial and performed the meta-analysis using Review Manager 5.3.Results: Eight RCTs involving 4,007 patients were included. Data from four trials, which could collect OS, showed that additional chemotherapy could not significantly improve the OS in patients with high-risk PCa (HR: 0.93; 95% CI: 0.79–1.09; P=0.37). However, the pooled analysis suggested significantly longer PFS in high-risk PCa patients treated with additional chemotherapy (HR: 0.81; 95% CI: 0.74–0.90; P,0.0001). The meta-analysis showed additional chemotherapy to androgen-deprivation therapy improved PFS (HR: 0.82; 95% CI: 0.74–0.91; P=0.0002). Greater improvement in PFS was found in high-risk PCa patients treated with additional docetaxel-based chemotherapy (HR: 0.73; 95% CI: 0.64–0.83; P,0.00001). No pro-longed PFS was observed in high-risk PCa patients with non-docetaxel-based chemotherapy (HR: 0.97; 95% CI: 0.83–1.14; P=0.74).Conclusion: Additional chemotherapy, especially docetaxel-based chemotherapy, could significantly improve the PFS in high-risk PCa patients. More evidence about the effect of additional chemotherapy on OS is needed. Further investigations in PCa should also focus on the suitable population for chemotherapy as well as optimal use of chemotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]