114 Background: Currently, the clinical outcomes of poly(ADP-ribose) polymerase (PARP) inhibitors varied widely in metastatic castration-resistant prostate cancer (mCRPC) patients with different HRR gene alterations (HRRalt). It is urgent and necessary to develop a novel biomarker for predicting the clinical efficiency of PARP inhibitors in the mCRPC patients. Tissue-based immunofluorescence (IF) assay for the functional RAD51 foci is emerging as a promising biomarker for assessing homologous recombination deficiency (HRD). However, the predictive value of the RAD51 foci using the IF assay for mCRPC patients following PARP inhibitors remains uncertain. This multicenter real-world study was to evaluate the predictive value of the RAD51 foci in the IF assay in mCRPC patients with HRRalt and not-altered HRR after the PARP inhibitor treatment. Methods: The multicenter real-world study involved 217 consecutive patients who had received the next-generation sequencing (NGS) and PARP inhibitor treatment from three tertiary referral hospitals. RAD51 foci were quantified in formalin-fixed, paraffin-bedded, untreated tumor specimens by IF. We assessed progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. Potential factors influencing PFS and OS were compared between the treatment arms using Cox proportional-hazards models. Prediction models were established to compare their predictive value in PFS and OS. The prostate-specific antigen (PSA) response and the treatment effect across subgroups were also evaluated. Results: RAD51 foci had significantly better predictive efficacy than the BRCA1/2alt and HRRalt, with a significantly higher predictive power in PFS and OS (RAD51: area under the curve [AUC]: PFS: 0.795; OS: 0.765, BRCA1/2alt: AUC: PFS: 0.669; OS: 0.628, HRRalt: AUC: PFS: 0.635; OS: 0.566). In the overall cohort, median PFS and OS were significantly longer in the RAD51-Low group than the RAD51-High group (PFS: 9.0 vs 2.0 mo; hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.18–0.35; p < 0.01; OS: 25.0 vs 11.0 mo; HR 0.34, 95% CI 0.22–0.43; p < 0.01). In the not-altered HRR cohort, the RAD51-Low group also had significantly longer survival than the RAD51-High group (PFS: 6.5 vs 1.0 mo; HR 0.21, 95% CI 0.11–0.40; p < 0.01; OS: 24.0 vs 8.0 mo; HR 0.32, 95% CI 0.17–0.56; p < 0.01). PSA responses were also significantly higher in the RAD51-Low group than the RAD51-High group. Limitations include its retrospective design and small sample size. Conclusions: In mCRPC patients treated with PARP inhibitors, RAD51 foci demonstrates a superior predictive value for clinical outcomes compared to HRRalt and BRCA1/2alt. RAD51 foci also serve as a pivotal biomarker for extending the PARP inhibitor efficacy to not-altered HRR patients. A large-scale prospective randomized controlled trial is needed to confirm these results.

Objective This study aims to develop and validate a comprehensive scoring system based on anatomical and clinical parameters to predict surgery duration, operative blood loss, and urinary control in patients undergoing laparoscopic radical prostatectomy (LRP). Methods This retrospective analysis included 361 patients with prostate cancer who underwent surgery performed by Xudong Yao. The study evaluated the correlation of variables such as height/weight ratio (HWR), prostate/pelvis ratio (PPR), retzius space (RS) size, intravesical prostatic protrusion (IPP), and prostate volume (PV). Based on these factors, the RRRIV scoring system was developed. The correlation between these variables and key outcomes (surgery duration, operative blood loss, and urinary function recovery) was then assessed in relation to the RRRIV score. Results Correlation analysis revealed significant positive associations between the RRRIV score and operative time (95% CI = 0.229(0.129-0.325), p < 0.001), operative blood loss (95% CI = 0.305(0.209-0.386), p < 0.001), and recovery of urinary function (95% CI = 0.381(0.289-0.466), p < 0.001). Furthermore, intergroup comparison showed that the medium and high-risk groups had significantly greater intraoperative blood loss, longer operative duration, and delayed recovery of urinary continence compared to the low-risk group. For the primary outcomes, the model demonstrated good discrimination, with an area under the curve ≥0.6. Conclusions The RRRIV scoring system provides a reliable method for predicting surgery duration, intraoperative blood loss, and recovery of urinary function in LRP, aiding surgeons in making more informed decisions during preoperative planning and patient discussions.

Early studies indicated that the androgen-deprivation-therapy with antiandrogen Enzalutamide (Enz) could increase prostate cancer patients’ survival by an average of 4.8 months. Yet Enz might also have some adverse effects via increasing the prostate cancer (PCa) cell invasion. Here we found Enz treatment could increase SALL4 expression to increase the cancer stem cells-like (CSC-like) population that resulted in increasing the PCa cell invasion. Mechanism dissection revealed that Enz could function via androgen receptor (AR) to transcriptionally regulate the SALL4 expression via direct binding on the SALL4 5'-promoter. The consequences of such Enz/AR/SALL4 axis could upregulate the SOX2-OCT4 expression to increase the CSC-like population and the PCa cells invasion. Together, results from multiple in vitro and in vivo experiments all conclude that Enz may induce the adverse effect of increasing PCa cells invasion via altering the AR/SALL4/SOX2-OCT4 signaling to increase the CSC-like population, and targeting SALL4 may decrease this adverse effect for further suppress the PCa progression. AR represses SALL4 expression by targeting the SALL4 promoter and subsequently impacts tumor stemness. Inhibiting SALL4 may represent a potential therapeutic target for patients resistant to Enzalutamide.

Analysis for b.TRPC as an Independent Prognostic Factor

Multivariate Analysis of Prognostic Factors Based on Tumor Tissue

Prostate cancer (PCa) metastasis has emerged as a leading cause of mortality globally. Owing to the distinctive looping structure, circular RNA has become an ideal biological tumor marker. Here we investigate the mechanism and function of circular RNA, specifically circCNOT6L, on PCa metastasis. A loss-of-function assay was conducted in vitro to assess the impact of circCNOT6L on cancer cell proliferation, migration, invasion and ferroptosis. In addition, a xenograft mouse model was used to elucidate the influence of circCNOT6L on subcutaneous tumor xenograft and lung metastasis. Biochemical experiments elucidated the molecular mechanism by which circCNOT6L promotes malignant progression in PCa cells by modulating ferroptosis. Moreover, the combination of circCNOT6L-si and a ferroptosis activator was tested in organoids to evaluate their potential as suppressors of tumorigenesis. The novel circular RNA, circCNOT6L, was highly expressed in both PCa metastatic tissues and cells. circCNOT6L suppression resulted in a notable inhibition in PCa cell migration, invasion and ferroptosis in vitro. Furthermore, circCNOT6L inhibition hindered the growth and metastasis of mouse xenografts. Mechanistically, circCNOT6L, generated by the RNA-binding protein EIF4A3, competes with miR-143-5p for binding, thereby facilitating SRSF2-dependent splicing of SLC7A11 precursor RNA. This process inhibited ferroptosis in PCa cells and promoted PCa progression. Finally, inhibiting circCNOT6L overexpression in combination with the ferroptosis activator (erastin) significantly suppressed the viability of PCa-derived organoids. In conclusion, in the present study, we found that circCNOT6L induced by EIF4A3 through the SRSF2–SLC7A11 axis effectively inhibits ferroptosis, which in turn promotes malignant progression of PCa. Prostate cancer is the most common cancer in men worldwide. While treatments exist, the spread of cancer to other parts of the body makes it difficult to cure. This study explores how a molecule called circCNOT6L affects prostate cancer progression. Researchers collected tissue samples from patients and used advanced techniques to study circCNOT6L, a type of circular RNA. They found that circCNOT6L is abnormal in prostate cancer tissues and helps the cancer spread by interacting with other molecules such as SRSF2 and miR-143-5p. These interactions prevent a process called ferroptosis, which inhibits the metastasis of cancer cells. The study showed that reducing circCNOT6L levels, especially when combined with drugs that promote ferroptosis, could slow down cancer progression. This suggests that targeting circCNOT6L might be a promising new way to treat prostate cancer in the future.

Nomogram for predicting PFS based on b.TRPC score.

External validation of the b.TRPC model in an independent dataset. A and B, ROC curves assessing the predictive performance of b.TRPC for 0.5-, 1-, and 2-year CRPC-free survival in the external validation cohort. C and D, Calibration plots confirming the reliability of the b.TRPC model across all time points. E, Comparison of C-index values for b.TRPC and ctDNA% in the external dataset. F–H, DCA demonstrating the clinical utility of b.TRPC for risk stratification in an independent patient cohort. FPR, false positive rate; TPR, true positive rate.

Clinical Data Correlated with Genomic Alterations

Study design and patient cohort selection.

Figure S1. Construction of the alternative genes signature for prognostic risk prediction.

Figure S4. External validation and clinical applicability of the t.TRPC-based prognostic model in the validation cohort.

Epidemiological studies indicate that prostate cancer (PCa) is the second prevalent malignant tumor affecting men globally. Environmental pollution such as cigarette smoke is one of the important risk factors for the development of prostate cancer. However, as one of the main carcinogens in cigarette smoke, the role of benzo[a]pyrene (BaP) in prostate cancer is still unclear. The current study aimed to investgate the impacts of BaP exposure on the progression of PCa toward malignancy and the regulation of the immune microenvironment. We verified that BaP exposure can promote the proliferation, migration, and apoptosis of prostate cancer cells through in vitro experiments. We constructed a subcutaneous xenograft tumor model of BaP exposure mouse and found that can promote the proliferation of tumors in vivo. Organoids-driven by PCa patients showed higher growth rate under BaP exposure. Flow cytometric analysis demonstrated a remarkable decrease in CD4+ T and CD8+ T cell infiltration levels. Moreover, we identified four genes (Mdm2, Ar, Foxo1, Crebbp) were strongly associated with BaP exposure by combining mouse tumor RNA-seq and CTD database. Additionally, a nomogram integrating clinicopathological features was constructed to assess the prognosis of prostate cancer patients under BaP exposure. This study systematically proved that BaP exposure promotes malignant progression of PCa and suppresses the immune microenvironment, in which Mdm2, Ar, Foxo1, Crebbp may play a crucial role in inhibiting apoptosis. These findings offer novel insights into the mechanisms via which BaP exposure contributes to PCa development.

BACKGROUND:This study aims to compare the combined MRI-TRUS fusion targeted biopsy (TB) and systematic biopsy (SB) vs SB for the detection of prostate cancer in Chinese biopsy-naïve patients suspected of prostate cancer. METHODS:This prospective study enrolled biopsy-naïve patients presenting from October 2020 to July 2024. Patients with PI-RADS scores ≥ 3 who met the inclusion criteria underwent transperineal TB combined with SB. Postoperative pathological data were collected from patients opting for radical prostatectomy at our institution. The primary outcome was the detection rate of clinically significant prostate cancer (csPCa) between combined biopsy and SB. RESULTS:A total of 644 biopsy-naïve patients participated, with 375 diagnosed with prostate cancer. Combined biopsy detected more csPCa cases compared to SB (316(49.1%) vs 277(43.0%), Absolute Risk Difference (ARD) 6.1% (95% CI: 4.2- 7.9), p<0.001). Exploratory subgroup analyses demonstrated that combined biopsy yielded significant benefits across most subgroups, particularly in patients with PSA density >0.15 ng/mL and those with PI-RADS scores of 4-5. Among the 268 patients who underwent radical prostatectomy, the combined biopsy approach resulted in the lowest rate of postoperative pathological upgrading. CONCLUSIONS:The combination of TB and SB demonstrates superior performance compared to SB alone in detecting csPCa in Chinese patients, with marked advantages observed in specific subgroups and a significant reduction in pathological upgrading following radical prostatectomy.

Figure S3. Internal validation and clinical utility of the t.TRPC-based prognostic model.

Clinical characteristics at diagnosis with mHSPC.

Multivariate Analysis of Prognostic Factors Based on ctDNA

Figure S2. Nomogram for predicting progression-free survival (PFS) based on t.TRPC and disease volume score.