Establishment and Validation of a Novel Prediction Model for Early Natural Biochemical Recurrence After Radical Prostatectomy Based on Post-Operative PSA at Sixth Week.

Objective: Based on post-operative PSA at 6th week (PSA6w) after radical prostatectomy to establish an optimal model for predicting natural biochemical recurrence (BCR). Methods: A total of 742 patients with post-operative PSA6w from PC-follow database, between January 2003 and October 2022, were included. All the patients had not received any hormone therapy and radiotherapy before operation and BCR. Of these patients, 588 cases operated by one surgeon were enrolled for modelling and another 154 cases operated by other surgeons were for external validation. After screened by Cox regression, the post-operative PSA6w, pathological stage, Gleason Grade and positive surgical margins were adopted for modelling. The R software was used to plot the nomogram of the prediction model for BCR. C-index and calibration curve were calculated to evaluate the new model. Finally, integrated discrimination improvement was adopted to evaluate the prediction performances of the new nomogram model and the classical Kattan nomogram. Results: The C-index of the new model was 0.871 (95% CI: 0.830-0.912). The calibration curve of the new model demonstrated superior consistency between the predicted and actual value. The C-index of the external validation group was 0.850 (95% CI: 0.742-0.958), which demonstrated perfect universality. The integrated discrimination improvement showed a 12.61% improvement in prediction performance over that of the classical Kattan nomogram (P < 0.01). Based on the new nomogram, patients were divided to high and low BCR group with a 3 year BCR-free cutoff probability as 74.72%. Low-risk patients, accounting for 77.89% of the patients, have no need to follow up frequently with a false-negative rate only 5.24%, which will save medical resources to a large extent. Conclusion: Post-operative PSA6w is a sensitive risk biomarker for early natural BCR. The new nomogram model could predict BCR probability with a higher accuracy and will further simplify the clinical follow-up strategies.

Adjuvant radiotherapy in patients with node-positive prostate cancer after radical prostatectomy.

PURPOSE: Our study was to determine whether immediate androgen deprivation therapy (ADT) plus radiotherapy (RT) extends survival in men with node-positive prostate cancer (PCa) after radical prostatectomy (RP) compared with those who received ADT alone. METHODS: A total of 99 consecutive patients with pathological positive lymph nodes (pN1) PCa were included in this study to receive immediate ADT plus RT (n = 70) or to receive immediate ADT alone (n = 29). The primary endpoint was castration-resistant prostate cancer (CRPC) free survival; the secondary endpoints were distant metastasis-free survival. Cox regression was used to assess the independent risk factors for CRPC. RESULTS: The median follow-up time was 34.0 (24.8, 47.8) months and 34.25 (23.0, 49.0) months, respectively, in the ADT + RT group and ADT-alone group. The 5-year CRPC-free survival rate was 79.5% and 58.3%, respectively, in the ADT + RT group and ADT-alone group (p = 0.308). The 5-year distant metastasis-free survival rate was 71.4% and 38.8, respectively, in the ADT + RT group and ADT-alone group (p = 0.478). Compared with ADT-alone group, we saw a modest, but no significant improvement in CRPC-free survival and distant metastasis-free survival in ADT + RT group. The results of Cox regression showed that positive lymph nodes ≥ 4 was an independent risk factor for CRPC (p = 0.041). CONCLUSIONS: We found that immediate ADT plus RT compared to ADT alone did not improve CRPC-free and metastasis-free survival. Multivariate Cox regression analyses also indicated that patients with positive lymph nodes < 4 may benefits from ADT plus RT.

TAGLN Is Downregulated by TRAF6-Mediated Proteasomal Degradation in Prostate Cancer Cells.

Transgelin (TAGLN, also named SM22) is an actin-associated protein and affects dynamics of actin filaments. Deregulation of TAGLN contributes to the development of different cancers, and it is commonly considered to be a tumor suppressor. TAGLN is usually downregulated in prostate cancer; however, the detailed functions of TAGLN in prostate cancer and how TAGLN is regulated remains unclear. In this study, we confirmed that TAGLN is downregulated in prostate cancer tissues and demonstrated that the downregulation of TAGLN occurs through proteasomal degradation. Next, we found that the expression level of TAGLN is inversely correlated with TRAF6. We screened more than 20 E2-E3 pairs by in vitro ubiquitination assay and found that the E2A-TRAF6 pair catalyzed mono ubiquitination of TAGLN. We then identified the ubiquitination sites of TAGLN to be on K89 or K108 residues and demonstrated that ubiquitination of TAGLN on K89/K108 are important for TRAF6-mediated proteasomal degradation. Furthermore, we investigated the function of TAGLN in prostate cancer cells. We found that ablation of TAGLN promoted prostate cancer cell proliferation and suppressed their migration via activation of NF-κB and Myc signaling pathways. Overall, our study provided new insights into the mechanisms underlying TAGLN expression and activity in prostate cancer. IMPLICATIONS: E3 ligase TRAF6 mediate mono-ubiquitination and degradation of TAGLN, which leads to activation of NF-κB and Myc signaling pathways in prostate cancer cells.

Experience of one single surgeon with the first 500 robot-assisted laparoscopic prostatectomy cases in mainland China.

OBJECTIVES: To summarize the experience of the first 500 robot-assisted laparoscopic radical prostatectomy (RALP) cases by one surgeon and analyze the influencing factors of functional and oncological outcomes. METHODS: Between April 2012 and October 2017, 500 patients who underwent RALP were included and divided sequentially into five equal groups. Patients' preoperative, perioperative and postoperative outcomes were analyzed and evaluated, and the Kruskal-Wallis test was used to analyze and compare the effect of surgeon experience by case. RESULTS: There is a statistically significant reduction in operative time, intraoperative estimated blood loss and postoperative hospital stay time (all p<0.001) with the increased experience. The results show that experience was the most important influencing factor in both operative time and blood loss. Pelvic lymph node dissection (PLND) might increase the operative time. The total positive surgical margin (PSM) rate was 21.8%. The PSM rate in pT3 tumors was significantly higher than that in pT2 tumors (12.0% vs. 37.1%, p<0.001). The 5-year biochemical recurrence (BCR)-free rate was 70.8%. The results of Cox regression showed that preoperative prostate-specific antigen (PSA), postoperative Gleason score (GS), and pathologic T stage were independent risk factors for BCR. CONCLUSION: After approximately 200 cases, the surgeon reached a plateau for RALP, but the outcomes could still improve after more cases. The surgeon's experience was the most important influencing factor for both operative time and blood loss. PSM rate was mainly determined by tumor stage rather than by operation experience.

Transrectal Ultrasound-Guided Transperineal Puncture: A Viable Alternative for Difficult Removal of an Indwelling Catheter in a Postrobot-Assisted Laparoscopic Radical Prostatectomy Patient.

Background: The inability to remove an indwelling urethral catheter in a postrobot-assisted laparoscopic radical prostatectomy (RALP) patient constitutes a serious problem to the urologist. If the proper deflation of the catheter balloon is not observed, forcible extraction can lead to devastating consequences such as urethral disruption and subsequent stricture formation. Case Presentation: A 60-year-old male patient developed lower urinary-tract symptoms 20 months after robotic prostatectomy for early prostate cancer. Cystourethroscopy revealed a migrated Hemo-lok clip that was extracted near the anastomotic site, followed by insertion of an indwelling Foley catheter. Two weeks later, the patient accidentally pulled the catheter into the urethra. Several attempts were done to deflate the catheter, which failed. Subsequently, a transrectal ultrasound (TRUS)-guided transperineal puncture was done to deflate the catheter balloon followed by effective catheter removal. Conclusion: TRUS-guided transperineal puncture (under local anesthesia) of an indwelling catheter balloon is a viable alternative for patients who have a history of RALP.

Short-term therapeutic outcomes of robotic-assisted laparoscopic radical prostatectomy for oligometastatic prostate cancer: a propensity score matching study.

BACKGROUND: The role of local treatment in oligometastatic prostate cancer (PCa) is gaining interest with the oligometastases hypothesis proposed and the improvement of various surgical methods and techniques. This study aimed to compare the short-term therapeutic outcomes of robotic-assisted laparoscopic radical prostatectomy (RALP) for oligometastatic prostate cancer (OPC) vs. localized PCa using propensity score matching. METHODS: Totally 508 consecutive patients underwent RALP as a first-line treatment. The patients were divided into two groups according to oligometastatic state: the OPC group (n = 41) or the localized PCa group (n = 467). Oligometastatic disease was defined as the presence of two or fewer suspicious lesions. The association between the oligometastatic state and therapeutic outcomes of RALP was evaluated, including biochemical recurrence (BCR) and overall survival (OS). A Cox proportional hazards model was used to assess the possible risk factors for BCR. RESULTS: Totally 41 pairs of patients were matched. The median operative time, the median blood loss, the overall positive surgical margin rate, the median post-operative hospital stays, and the post-operative urinary continence recovery rate between the two groups showed no statistical significance. The 4-year BCR survival rates of the OPC group and localized PCa group were 56.7% and 60.8%, respectively, without a significant difference (P = 0.804). The 5-year OS rates were 96.3% and 100%, respectively (P = 0.326). Additionally, the results of Cox regression showed that oligometastatic state was not an independent risk factor for BCR (P = 0.682). CONCLUSIONS: Our findings supported the safety and effectiveness of RALP in OPC. Additionally, oligometastatic state and sites did not have an adverse effect on BCR independently.

PARP Inhibition Suppresses GR-MYCN-CDK5-RB1-E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer.

PURPOSE: In this study, we addressed the underlying mechanisms for the association between enzalutamide (ENZ) treatment and neuroendocrine prostate cancer (NEPC), and the critical involvement of MYCN, and loss of RB1 function in neuroendocrine differentiation (NED) of prostatic epithelial cells, and the development of NEPC. We further sought to determine whether PARP inhibition could suppress NEPC, and to identify molecular determinants of this therapeutic activity. EXPERIMENTAL DESIGN: We used a novel prostate cancer patient-derived xenograft (PDX) treatment model, prostatic adenocarcinoma and NEPC cell lines, an NEPC organoid line, and NEPC xenograft models to address the mechanistic basis of ENZ-induced NED, and to analyze suppression of NED and NEPC growth by PARP inhibition. RESULTS: We identified an ENZ treatment-associated glucocorticoid receptor (GR)-MYCN-CDK5-RB1-E2F1 signaling pathway that drives NED in prostatic adenocarcinoma PDX and cell line models. Mechanistically, long-term ENZ treatment transcriptionally upregulates signaling of the GR-MYCN axis, leading to CDK5R1 and CDK5R2 upregulation, Rb1 phosphorylation, and N-Myc-mediated and E2F1-mediated NED gene expression. Importantly, olaparib (OLA) or talazoparib (TALA) suppressed these activities, and the combination of OLA and dinaciclib (DINA), an inhibitor of CDK2 and CDK5, which also inhibits Rb1 phosphorylation, suppressed NED and significantly improved therapeutic efficiency in NEPC cells in vitro and in NEPC tumors in vivo. CONCLUSIONS: The results of our study indicate an important role of GR-MYCN-CDK5R1/2-RB1-NED signaling in ENZ-induced and PARP inhibitor-suppressed NEPC. We also demonstrated efficacy for OLA+DINA combination therapy in NEPC xenograft models.

Alterations in expressed prostate secretion-urine PSA N-glycosylation discriminate prostate cancer from benign prostate hyperplasia.

The prostate specific antigen (PSA) test is widely used for early diagnosis of prostate cancer (PCa). However, its limited sensitivity has led to over-diagnosis and over-treatment of PCa. Glycosylation alteration is a common phenomenon in cancer development. Different PSA glycan subforms have been proposed as diagnostic markers to better differentiate PCa from benign prostate hyperplasia (BPH). In this study, we purified PSA from expressed prostate secretions (EPS)-urine samples from 32 BPH and 30 PCa patients and provided detailed PSA glycan profiles in Chinese population. We found that most of the PSA glycans from EPS-urine were complex type biantennary glycans. We observed two major patterns in PSA glycan profiles. Overall there was no distinct separation of PSA glycan profiles between BPH and PCa patients. However, we detected a significant increase of glycan FA2 and FM5A2G2S1 in PCa when compared with BPH patients. Furthermore, we observed that the composition of FA2 glycan increased significantly in advanced PCa with Gleason score ≥8, which potentially could be translated to clinic as a marker for aggressive PCa.

PAQR3 suppresses the proliferation, migration and tumorigenicity of human prostate cancer cells.

As a newly discovered tumor suppressor, the potential function of PAQR3 in human prostate cancer has not been demonstrated. In this study, we report that PAQR3 is able to inhibit the growth and migration of human prostate cancer cells both in vitro and in vivo. Overexpression of PAQR3 inhibits the proliferation of PC3 and DU145 cells by both MTT and colony formation assays. Consistently, knockdown of PAQR3 enhances the proliferation of these cells. In wound-healing and transwell assays, overexpression of PAQR3 reduces the migration of PC3 and DU145 cells, while PAQR3 knockdown increases it. In a tumor xenograft model, overexpression of PAQR3 suppresses tumor growth of PC3 cells in vivo, while PAQR3 knockdown promotes the tumor growth. PAQR3 is also able to inhibit serum-induced phosphorylation of AKT and ERK in both PC3 and DU145 cells. In addition, PAQR3 suppresses the expression of epithelial-mesenchymal transition (EMT) markers in PC3 cells. Collectively, these data indicate that PAQR3 has a tumor suppressive activity in human prostate cancer cells and may stand out as a potential therapeutic target for prostate cancers.

Robotic-assisted Laparoscopic Radical Prostatectomy From a Single Chinese Center: A Learning Curve Analysis.

OBJECTIVE: To investigate the learning curve of robotic-assisted laparoscopic radical prostatectomy (RALP) and analyze whether a surgeon's prior surgical experience has effects on the surgery. PATIENTS AND METHODS: From April 2012 to August 2015, 3 surgeons performed RALP on 355 consecutive patients with prostate cancer. Among these cases, 184 were by surgeon A with prior open experiences, 92 by surgeon B with both open and laparoscopic experiences, and 79 by surgeon C with laparoscopic experiences only. Perioperative, oncological, and functional outcomes were evaluated and compared between surgeons. Learning curve patterns were evaluated to determine the number of cases to reach plateau. RESULTS: Marked difference was observed in operative time among the 3 groups (all P <.05). Length of hospital stay was also statistically significant (all P <.001), except for that between Group B and Group C (P = .739). Continence at 1-year and 6-month postoperatively was better in Groups B and C compared with Group A (P <.001). Intraoperative blood loss, pathologic stage, positive surgical margin, biochemical recurrence-free rate, and other pathological findings showed no statistical significance between the groups. The number of cases required to reach plateau may vary for surgeons with different surgical experiences. CONCLUSION: Different early surgical background may affect the perioperative parameters of novice RALP surgeons. Previous laparoscopic experiences may provide additional advantage in learning curve parameters compared with surgeons with open experiences only. A better overall continence for laparoscopic surgeons requires further validation.