Multi-cohort validation of Ascore: an anoikis-based prognostic signature for predicting disease progression and immunotherapy response in bladder cancer.

Bladder cancer ranks as the 10th most common cancer worldwide, with deteriorating prognosis as the disease advances. While immune checkpoint inhibitors (ICIs) have shown promise in clinical therapy in both operable and advanced bladder cancer, identifying patients who will respond is challenging. Anoikis, a specialized form of cell death that occurs when cells detach from the extracellular matrix, is closely linked to tumor progression. Here, we aimed to explore the anoikis-based biomarkers for bladder cancer prognosis and immunotherapeutic decisions. Through consensus clustering, we categorized patients from the TCGA-BLCA cohort into two clusters based on anoikis-related genes (ARGs). Significant differences in survival outcome, clinical features, tumor immune environment (TIME), and potential ICIs response were observed between clusters. We then formulated a four-gene signature, termed "Ascore", to encapsulate this gene expression pattern. The Ascore was found to be closely associated with survival outcome and served as an independent prognosticator in both the TCGA-BLCA cohort and the IMvigor210 cohort. It also demonstrated superior predictive capacity (AUC = 0.717) for bladder cancer immunotherapy response compared to biomarkers like TMB and PD-L1. Finally, we evaluated Ascore's independent prognostic performance as a non-invasive biomarker in our clinical cohort (Gulou-Cohort1) using circulating tumor cells detection, achieving an AUC of 0.803. Another clinical cohort (Gulou-Cohort2) consisted of 40 patients undergoing neoadjuvant anti-PD-1 treatment was also examined. Immunohistochemistry of Ascore in these patients revealed its correlation with the pathological response to bladder cancer immunotherapy (P = 0.004). Impressively, Ascore (AUC = 0.913) surpassed PD-L1 (AUC = 0.662) in forecasting immunotherapy response and indicated better net benefit. In conclusion, our study introduces Ascore as a novel, robust prognostic biomarker for bladder cancer, offering a new tool for enhancing immunotherapy decisions and contributing to the tailored treatment approaches in this field.

Impact of operator expertise on transperineal free-hand mpMRI-fusion-targeted biopsies under local anaesthesia for prostate cancer diagnosis: a multicenter prospective learning curve.

PURPOSE: Transperineal mpMRI-targeted fusion prostate biopsies (TPFBx) are recommended for prostate cancer diagnosis, but little is known about their learning curve (LC), especially when performed under local anaesthesia (LA). We investigated how operators' and institutions' experience might affect biopsy results. METHODS: Baseline, procedure and pathology data of consecutive TPFBx under LA were prospectively collected at two academic Institutions, from Sep 2016 to May 2019. Main inclusion criterion was a positive MRI. Endpoints were biopsy duration, clinically significant prostate cancer detection rate on targeted cores (csCDR-T), complications, pain and urinary function. Data were analysed per-centre and per-operator (with ≥ 50 procedures), comparing groups of consecutive patient, and subsequently through regression and CUSUM analyses. Learning curves were plotted using an adjusted lowess smoothing function. RESULTS: We included 1014 patients, with 27.3% csCDR-T and a median duration was 15 min (IQR 12-18). A LC for biopsy duration was detected, with the steeper phase ending after around 50 procedures, in most operators. No reproducible evidence in favour of an impact of experience on csPCa detection was found at operator's level, whilst a possible gentle LC of limited clinical relevance emerged at Institutional level; complications, pain and IPSS variations were not related to operator experience. CONCLUSION: The implementation of TPFBx under LA was feasible, safe and efficient since early phases with a relatively short learning curve for procedure time.

The Detection of Prostate Cancer with Magnetic Resonance Imaging-Targeted Prostate Biopsies is Superior with the Transperineal vs the Transrectal Approach. A European Association of Urology-Young Academic Urologists Prostate Cancer Working Group Multi-Institutional Study.

PURPOSE: Our aim was to evaluate whether transperineal (TP) MRI-targeted prostate biopsy (TBx) may improve the detection of clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology ≥2, in comparison to transrectal (TR) TBx. MATERIALS AND METHODS: A multicenter retrospective cohort study comprising patients who underwent MRI-guided prostate biopsy was conducted. To address possible benefits of TP-TBx in the detection of prostate cancer (PCa) and csPCa, a cohort of patients undergoing TP-TBx were compared to patients undergoing TR-TBx. Multivariable logistic regression analyses were performed to assess predictors of PCa and csPCa detection. RESULTS: Overall, 1,936 and 3,305 patients who underwent TR-TBx vs TP-TBx at 10 referral centers were enrolled. The rate of PCa and csPCa diagnosed was higher for TP-TBx vs TR-TBx (64.0% vs 50%, p <0.01 and 49% vs 35%, p <0.01). At multivariable analysis adjusted for age, biopsy naïve/repeated biopsy, cT stage, Prostate Imaging-Reporting and Data System®, prostate volume, PSA, and number of biopsy cores targeted, TP-TBx was an independent predictor of PCa (odds ratio [OR] 1.37, 95% CI 1.08-1.72) and csPCa (1.19, 95% CI 1.12-1.50). When considering the approach according to the site of the index lesion, TP-TBx had a significantly higher likelihood than TR-TBx to detect csPCa in the apex (OR 4.81, 95% CI 1.03-6.27), transition/central zone (OR 2.67, 95% CI 1.42-5.00), and anterior zone (OR 5.62, 95% CI 1.74-8.13). CONCLUSIONS: The use of TP-TBx allows a better cancer grade definition and PCa risk assessment. This has important implication in the decision-making process and in patient counseling for further therapies.

[Accuracy of prostatic ultrasonography versus MRI in measuring prostate volume].

OBJECTIVE: To compare the accuracy of different methods of measuring the prostate volume (PV) based on the manifestations of prostatic ultrasonography and MRI. METHODS: Using the drainage method, we measured the volumes of 101 prostatic specimens collected from radical prostatectomy. And with the measures obtained as reference standards, we calculated the PV of the patients with the maximum width (W), height (H) and length (L) of the prostates obtained preoperatively by transabdominal ultrasonography (TAUS), transrectal ultrasonography (TRUS) and MRI using the ellipsoidal formula (PV = W × H × L × 0.52), bullet formula (PV = W × H × L × 0.65) and 3D reconstruction technology. We evaluated the accuracy of the above methods using the Mann-Whitney U test, intraclass correlation coefficient (ICC), and Bland-Altman scatterplot. RESULTS: No statistically significant differences were observed between the specimen and preoperative PVs. The ICCs of the specimen PVs obtained by MRI 3D reconstruction, TRUS bullet formula, MRI ellipsoidal formula and TAUS ellipsoidal formula were 0.978, 0.862, 0.857 and 0.745, respectively. The Bland-Altman scatterplot exhibited that the preoperative PV calculated by MRI 3D reconstruction had the highest consistency with that of the specimen PV, followed by that measured by TRUS bullet formula and that obtained by MRI ellipsoidal formula, while that determined by TAUS ellipsoidal formula had a low consistency. CONCLUSION: The MRI 3D reconstruction technology is the most reliable method for the measurement of PV, followed by TRUS bullet formula, but the latter is recommended for its high applicability in clinical practice.

[Trans-Douglas Retzius' space-sparing robot-assisted simple prostatectomy for large-volume benign prostate hyperplasia].

OBJECTIVE: To report the safety and efficacy of trans-Douglas Retzius' space-sparing robot-assisted simple prostatectomy (RSS-RASP) in the treatment of large-volume BPH. METHODS: This retrospective study included 24 cases of large-volume (>80 ml) BPH treated by trans-Douglas RSS-RASP from August 2019 to June 2021. The patients ranged in age from 55 to 80 (mean 68.5) years, with an average body mass index of 25.1 (20.5－34.9) kg/m2 , median prostate volume of 132.4 (85.6－235.7) ml, and preoperative tPSA of 10.8 (0.5－37.9) ng/ml, IPSS of 25 (3－35) and quality of life (QOL) score of 5 (3－8). Before surgery, 12 of the patients received catheterization for urinary retention, 1 underwent cystostomy, 2 were complicated with hydronephrosis, 1 had stones and diverticulum in the bladder, and 14 were excluded from the cases of PCa by prostatic biopsy. The operation time, intraoperative blood loss, hemoglobin level on the first day after surgery, blood transfusion, and intra- and postoperative complications were recorded. The patients were followed up for 3 to 21 months postoperatively. Comparisons were made before and after operation in the IPSS, maximum urinary flow rate (Qmax), postvoid residual volume (PVR), QOL score, IIEF score and Male Sexual Health Questionnaire (MSHQ) score. RESULTS: Trans-Douglas RSS-RASP was successfully completed in all the 24 cases, with a mean operation time of 175 (100－285) min, intraoperative blood loss of 200 (50－800) ml, hemoglobin decrease of 25 (4－57) g/L on the first day after surgery, postoperative drainage tube indwelling of 3 (2－7) d, and urinary catheterization of 12 (4－18) d. Six (25%) of the patients received intraoperative blood transfusion, 1 underwent transurethral electrocoagulation hemostasis 1 month after surgery because of postoperative bleeding, and 1 received transurethral resection of the cicatrical adhesive tissue of the bladder neck 12 months after surgery. No other complications occurred postoperatively. The IPSS (3 ［1－7］), Qmax (19.6 ［9.9－32.1］ ml/s), PVR (0 ［0－34.9］ ml) and QOL score (2 ［0－3］) of the patients were significantly improved after surgery (P < 0.05), but no statistically significant differences were observed in the IIEF (20 ［19－24］) and MSHQ scores (14 ［13－14］) as compared with the baseline (P > 0.05). CONCLUSION: Trans-Douglas RSS-RASP is a safe and effective minimally invasive method for the treatment of large-volume (>80 ml) BPH, which can improve the urinary function of the patient after operation.

Can 68Ga-PSMA-11 Positron Emission Tomography/Computerized Tomography Predict Pathological Response of Primary Prostate Cancer to Neoadjuvant Androgen Deprivation Therapy? A Pilot Study.

PURPOSE: We explored the role of 68Ga-PSMA-11 positron emission/computerized tomography as a predictor of pathological response to neoadjuvant androgen deprivation therapy combined with abiraterone for high risk prostate cancer. MATERIALS AND METHODS: A total of 45 patients with localized high risk prostate cancer who had serial 68Ga-PSMA-11 positron emission tomography/computerized tomography scans before and after 6 months of androgen deprivation therapy plus abiraterone neoadjuvant treatment followed by radical prostatectomy were included in this study. Complete pathological response or minimal residual disease <5 mm on whole mount histopathology was defined as favorable pathological response. The diagnostic performance of prostate specific antigen response and positron emission tomography/computerized tomography response for favorable pathological response was calculated. Univariable and multivariable logistic regression analyses of clinical and imaging variables were also performed to identify favorable pathological response. RESULTS: Compared to the prostate specific antigen response, positron emission tomography/computerized tomography response had a significantly higher specificity in diagnosing favorable pathological response (89.7% vs 62.1%, p=0.043). Preoperative nadir prostate specific antigen (OR 0.121, 95% CI 0.028-0.529, p=0.005), posttreatment maximum standardized uptake value (OR 7.072, 95% CI 2.035-24.579, p=0.002) and posttreatment tumor volume (OR 7.896, 95% CI 1.415-44.054, p=0.018) measured on positron emission tomography/computerized tomography were significantly associated with favorable pathological response in univariable logistic regression analysis. On multivariable logistic regression analysis, only posttreatment maximum standardized uptake value was found to be an independent predictor of favorable pathological response (OR 9.69, 95% CI 1.439-65.242, p=0.020). CONCLUSIONS: 68Ga-PSMA positron emission tomography/computerized tomography has a better diagnostic performance of pathological response to neoadjuvant treatment compared with prostate specific antigen, with maximum standardized uptake value being an independent predictive factor. This pilot study suggests that prostate specific membrane antigen positron emission tomography/computerized tomography may serve as a potential predictor of pathological response to neoadjuvant treatment.

Transperineal freehand multiparametric MRI fusion targeted biopsies under local anaesthesia for prostate cancer diagnosis: a multicentre prospective study of 1014 cases.

OBJECTIVE: To assess the outcomes of multiparametric magnetic resonance imaging (mpMRI) transperineal targeted fusion biopsy (TPFBx) under local anaesthesia. PATIENTS AND METHODS: We prospectively screened 1327 patients with a positive mpMRI undergoing TPFBx (targeted cores and systematic cores) under local anaesthesia, at two tertiary referral institutions, between September 2016 and May 2019, for inclusion in the present study. Primary outcomes were detection of clinically significant prostate cancer (csPCa) defined as (1) International Society of Urological Pathologists (ISUP) grade >1 or ISUP grade 1 with >50% involvement of prostate cancer (PCa) in a single core or in >2 cores (D1) and (2) ISUP grade >1 PCa (D2). Secondary outcomes were: assessment of peri-procedural pain (numerical rating scale [NRS]) and procedure timings; erectile (International Index of Erectile Function) and urinary (International Prostate Symptom Score) function changes; and complications. We also investigated the value of systematic sampling and concordance with radical prostatectomy (RP). RESULTS: A total of 1014 patients were included, of whom csPCa was diagnosed in 39.4% (n = 400). The procedure was tolerable (NRS pain score 3.1 ± 2.3), with no impact on erectile (P = 0.45) or urinary (P = 0.58) function, and a low rate of complications (Clavien-Dindo grades 1 or 2, n = 8; grade >2, n = 0). No post-biopsy sepsis was recorded. Twenty-two men (95% confidence interval [CI] 17-29) needed to undergo additional systematic biopsy to diagnose one csPCa missed by targeted biopsies (D1). ISUP grade concordance of biopsies with RP was as follows: k = 0.40 (95% CI 0.31-0.49) for targeted cores alone and k = 0.65 (95% CI 0.57-0.72; P < 0.05) overall. CONCLUSIONS: The use of TPFBx under local anaesthesia yielded good csPCa detection and was feasible, quick, well tolerated and safe. Infectious risk was negligible. Addition of systematic to targeted cores may not be needed in all men, although it improves csPCa detection and concordance with RP.

[Modified Vattikuti Institute prostatectomy for the treatment of localized prostate cancer].

OBJECTIVE: To investigate the effect of modified Vattikuti Institute prostatectomy (mVIP) in the treatment of localized PCa. METHODS: This retrospective study included 50 cases of localized PCa treated by mVIP and another 50 by robot-assisted radical prostatectomy (RARP) from March 2018 to April 2019. We analyzed the baseline data, the surgical techniques used and the results of short-term follow-up. RESULTS: All the operations were completed successfully without conversion to open surgery. The mVIP group, compared with the RARP, showed longer operation time (ï¼»90.35 ± 24.22ï¼½ vs ï¼»84.46 ± 19.18ï¼½ min, P > 0.05), more intraoperative blood loss (ï¼»220.00 ± 15.10ï¼½ vs ï¼»215.00 ± 15.10ï¼½ ml, P > 0.05), shorter postoperative hospital stay (ï¼»5.75 ± 1.45ï¼½ vs ï¼»6.20 ± 1.50ï¼½ d, P > 0.05), and higher rates of positive surgical margins (22.00% vs 14.00%, P > 0.05) and urinary continence at 1 month (76%vs 22%,P < 0.05), 6 months (84% vs 79%, P > 0.05) and 12 months after surgery (96% vs 94%, P > 0.05). CONCLUSIONS: Modified VIP can better preserve the lateral and posterolateral prostatic fascial tissue in the treatment of localized PCa and therefore significantly promote the recovery of urinary continence after surgery.

Pain in Men Undergoing Transperineal Free-Hand Multiparametric Magnetic Resonance Imaging Fusion Targeted Biopsies under Local Anesthesia: Outcomes and Predictors from a Multicenter Study of 1,008 Patients.

PURPOSE: Several transperineal biopsy series have proven feasibility under local anesthesia. However, there is a lack of large analyses detailing pain outcomes and factors influencing pain. MATERIALS AND METHODS: From 2016 to 2019 we performed a multicenter prospective study in men undergoing multiparametric magnetic resonance imaging-transperineal fusion biopsies (target+systematic cores) under local anesthesia. Primary outcomes were 1) pain scores (assessed through a 0 to 10-point numeric rating scale) and 2) identification of factors associated with severe pain. The secondary outcome was to evaluate pain influence on clinically significant prostate cancer target cores detection. RESULTS: We included 1,008 men undergoing transperineal fusion biopsies under local anesthesia. Mean±SD numeric rating scale pain scores were 3.9±2.1 at local anesthesia administration and 3.1±2.3 when performing biopsies. Pain was not associated with lower clinically significant prostate cancer detection on targeted cores (p=0.23 and p=0.47 depending on clinically significant prostate cancer definition). On multivariate analysis age (OR 0.96, 95% CI 0.94-0.99) and severe anxiety (OR 2.99, 95% CI 1.83-4.89) were a protective and risk factor, respectively, for severe biopsy pain. Procedural time was also associated with an increased risk of experiencing severe biopsy pain (OR 1.04, 95% CI 1.00-1.08). If aiming to test the possible effects of anxiety preventive measures on pain, an anxiety cutoff greater than 6 on a numeric rating scale would decrease to 13% the number of patients being treated while identifying 56% of those experiencing severe pain. CONCLUSIONS: Transperineal fusion biopsies under local anesthesia result in moderate pain. Pain does not influence clinically significant prostate cancer target detection. Patient anxiety predicts pain. A numeric rating scale based anxiety assessment may be used to identify those at higher risk for experiencing severe pain in men undergoing transperineal fusion biopsies.

Clinico-radiological characteristic-based machine learning in reducing unnecessary prostate biopsies of PI-RADS 3 lesions with dual validation.

OBJECTIVE: To evaluate machine learning-based classifiers in detecting clinically significant prostate cancer (PCa) with Prostate Imaging Reporting and Data System (PI-RADS) score 3 lesions. METHODS: We retrospectively enrolled 346 patients with PI-RADS 3 lesions at two institutions. All patients underwent prostate multiparameter MRI (mpMRI) and transperineal MRI-ultrasonography (MRI-US)-targeted biopsy. We collected data on age, pre-biopsy serum prostate-specific antigen (PSA) level, prostate volume (PV), PSA density (PSAD), the location of suspicious PI-RADS 3 lesions, and histopathology results. Four machine learning-based classifiers-logistic regression, support vector machine, eXtreme Gradient Boosting (XGBoost), and random forest-were trained using datasets from Nanjing Drum Tower Hospital. External validation was carried out using datasets from Molinette Hospital. RESULTS: Among 287 PI-RADS 3 patients, prostate cancer was proven pathologically in 59 (20.6%), and 228 (79.4%) had benign lesions. For 380 PI-RADS 3 lesions, 81 (21.3%) were proven to be PCa and 299 (78.7%) benign. Among four classifiers, the random forest classifier had the best performance in both patient-based and lesion-based datasets, with overall accuracy of 0.713 and 0.860, sensitivity of 0.857 and 0.613, and area under curve (AUC) of 0.771 and 0.832, respectively. In external validation, our best classifiers had an AUC of 0.688 with the best sensitivity (0.870) and specificity (0.500) in the 59 PI-RADS 3 patients in Molinette Hospital dataset. CONCLUSIONS: The machine learning-based random forest classifier provided a reliable probability if a PI-RADS 3 patient was benign. KEY POINTS: • Machine learning-based classifiers could combine the clinical characteristics with accessible information on image report of PI-RADS 3 patient to generate a probability of malignancy. • This probability could assist surgeons to make diagnostic decisions with more confidence and higher efficiency.

Wnt7a activates canonical Wnt signaling, promotes bladder cancer cell invasion, and is suppressed by miR-370-3p.

Once urinary bladder cancer (UBC) develops into muscle-invasive bladder cancer, its mortality rate increases dramatically. However, the molecular mechanisms of UBC invasion and metastasis remain largely unknown. Herein, using 5637 UBC cells, we generated two sublines with low (5637 NMI) and high (5637 HMI) invasive capabilities. Mass spectrum analyses revealed that the Wnt family protein Wnt7a is more highly expressed in 5637 HMI cells than in 5637 NMI cells. We also found that increased Wnt7a expression is associated with UBC metastasis and predicted worse clinical outcome in UBC patients. Wnt7a depletion in 5637 HMI and T24 cells reduced UBC cell invasion and decreased levels of active ß-catenin and its downstream target genes involved in the epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM) degradation. Consistently, treating 5637 NMI and J82 cells with recombinant Wnt7a induced cell invasion, EMT, and expression of ECM degradation-associated genes. Moreover, TOP/FOPflash luciferase assays indicated that Wnt7a activated canonical ß-catenin signaling in UBC cells, and increased Wnt7a expression was associated with nuclear ß-catenin in UBC samples. Wnt7a ablation suppressed matrix metalloproteinase 10 (MMP10) expression, and Wnt7a overexpression increased MMP10 promoter activity through two TCF/LEF promoter sites, confirming that Wnt7a-mediated MMP10 activation is mediated by the canonical Wnt/ß-catenin pathway. Of note, the microRNA miR-370-3p directly repressed Wnt7a expression and thereby suppressed UBC cell invasion, which was partially restored by Wnt7a overexpression. Our results have identified an miR-370-3p/Wnt7a axis that controls UBC invasion through canonical Wnt/ß-catenin signaling, which may offer prognostic and therapeutic opportunities.

[Combination of serum PSA assay, multi-parametric MRI and targeted prostate biopsy for prostate cancer screening in Nanjing].

OBJECTIVE: To investigate the exact prevalence of PCa among males in Nanjing and search for a mode of PCa screening suitable for the specific conditions. METHODS: From January to December 2018, we collected serum samples and clinical information from 6 903 men aged ≥50 years taking physical examination in 16 community health service centers in Nanjing. We proposed multi-parametric MRI (mpMRI) for those with serum PSA ≥4 µg/L, transperineal systematic biopsy and MRI/ultrasound fusion targeted prostate biopsy for those who scored ≥3 points on the Prostate Imaging-Reporting and Data System Version 2 (PI-RADS v2), transperineal systematic biopsy only for those with a PI-RADS v2 score of <3 and serum PSA ≥10 µg/L, and follow-up examinations every 6 months for those with a PI-RADS v2 score of <3 and serum PSA <4 µg/L. RESULTS: Among the 6 903 male subjects, 835 (12.1%) were found with serum PSA≥4 µg/L; 229 (77.4%) of the 296 men that received mpMRI scored ≥3 points on PI-RADS v2; and 79 (53.4%) of the 148 males that underwent prostate biopsy were diagnosed with PCa, with a total detection rate of 1.14% in all the subjects. Of the 77 patients with complete pathological data, 73 (94.8%) were found with clinically significant PCa, 30 (39.0%) with localized, 41 (53.2%) with locally advanced and 6 (7.8%) with metastatic malignancy, 6 (7.8%) in stage Ⅰ, 21 (27.3%) in stage Ⅱ, 34 (44.2%) in stage Ⅲ and 16 (20.8%) in stage Ⅳ. There were 47 (66.2%) high-risk, 18 (25.4%) moderate-risk and 6 (8.5%) low-risk cases among those with localized or locally advanced PCa. CONCLUSIONS: The prevalence of PCa in Nanjing deserves considerable attention, and PCa screening is highly necessary in the high-risk population, for which the combination of serum PSA assay, mpMRI and targeted prostate biopsy may be an ideal method.

Assessment of free-hand transperineal targeted prostate biopsy using multiparametric magnetic resonance imaging-transrectal ultrasound fusion in Chinese men with prior negative biopsy and elevated prostate-specific antigen.

BACKGROUND: To evaluate the role of free-hand transperineal targeted prostate biopsy using multiparametric magnetic resonance imaging-transrectal ultrasound (mpMRI-TRUS) fusion in Chinese men with repeated biopsy. METHODS: A total of 101 consecutive patients suspicious of prostate cancer (PCa) at the mpMRI scan and with prior negative biopsy and elevated PSA values were prospectively recruited at two urological centers. Suspicious areas on mpMRI were defined and graded using PI-RADS score. Targeted biopsies (TB) were performed for each suspicious lesion and followed a 12-core systematic biopsy (SB). Results of biopsy pathology and whole-gland pathology at prostatectomy were analyzed and compared between TB and SB. The risk for biopsy positivity was assessed by univariate and multivariate logistic regression analysis. RESULTS: Fusion biopsy revealed PCa in 41 of 101 men (40.6%) and 25 (24.8%) were clinically significant. There was exact agreement between TB and SB in 74 (73.3%) men. TB diagnosed 36% more significant cancer than SB (22 vs 13 cases, P = 0.012). When TB were combined with SB, an additional 14 cases (34.1%) of mostly significant PCa (71.4%) were diagnosed (P = 0.036). TB had greater sensitivity and accuracy for significant cancer than SB in 26 men with whole-gland pathology after prostatectomy. PI-RADS score on mpMRI was the most powerful predictor of PCa and significant cancer. CONCLUSIONS: Free-hand transperineal TB guided with MRI-TRUS fusion imaging improves detection of clinical significant PCa in Chinese men with previously negative biopsy. PI-RADS score is a reliable predictor of PCa and significant cancer.

Membrane-associated RING-CH 7 inhibits stem-like capacities of bladder cancer cells by interacting with nucleotide-binding oligomerization domain containing 1.

BACKGROUND: Cancer stem-like capacities are major factors contributing to unfavorable prognosis. However, the associated molecular mechanisms underlying cancer stem-like cells (CSCs) maintain remain unclear. This study aimed to investigate the role of the ubiquitin E3 ligase membrane-associated RING-CH 7 (MARCH7) in bladder cancer cell CSCs. METHODS: Male BALB/c nude mice aged 4-5 weeks were utilized to generate bladder xenograft model. The expression levels of MARCHs were checked in online databases and our collected bladder tumors by quantitative real-time PCR (q-PCR) and immunohistochemistry (IHC). Next, we evaluated the stem-like capacities of bladder cancer cells with knockdown or overexpression of MARCH7 by assessing their spheroid-forming ability and spheroid size. Additionally, we conducted proliferation, colony formation, and transwell assays to validate the effects of MARCH7 on bladder cancer CSCs. The detailed molecular mechanism of MARCH7/NOD1 was validated by immunoprecipitation, dual luciferase, and in vitro ubiquitination assays. Co-immunoprecipitation experiments revealed that nucleotide-binding oligomerization domain-containing 1 (NOD1) is a substrate of MARCH7. RESULTS: We found that MARCH7 interacts with NOD1, leading to the ubiquitin-proteasome degradation of NOD1. Furthermore, our data suggest that NOD1 significantly enhances stem-like capacities such as proliferation and invasion abilities. The overexpressed MARCH7 counteracts the effects of NOD1 on bladder cancer CSCs in both in vivo and in vitro models. CONCLUSION: Our findings indicate that MARCH7 functions as a tumor suppressor and inhibits the stem-like capacities of bladder tumor cells by promoting the ubiquitin-proteasome degradation of NOD1. Targeting the MARCH7/NOD1 pathway could be a promising therapeutic strategy for bladder cancer patients.

External validation of an algorithm to personalize nerve sparing approaches during robot-assisted radical prostatectomy in men with unilateral high-risk prostate cancer.

Limited evidence exists about preserving neurovascular bundles during radical prostatectomy (RP) for high-risk prostate cancer (HRPCa) patients. Hence, we validated an existing algorithm predicting contralateral extraprostatic extension (cEPE) risk in unilateral high-risk cases. This algorithm aims to assist in determining the suitability of unilateral nerve-sparing RP. Among 264 patients, 48 (18%) had cEPE. The risk of cECE varied: 8%, 17.2%, and 30.8% for the low, intermediate, and high-risk groups, respectively. Despite a higher risk of cECE among individuals classified as low-risk in the development group compared to the validation group, our algorithm's superiority over always/never nerve-sparing RP was reaffirmed by decision curve analysis. Therefore, we conclude that bilateral excision may not always be justified in men with unilateral HRPCa. Instead, decisions can be based on our suggested nomogram.

The presence of intraductal carcinoma of prostate is a risk factor for poor pathologic response in men with high-risk prostate cancer receiving neoadjuvant therapy.

OBJECTIVE: To explore the potential association between the presence of intraductal carcinoma of the prostate (IDC-P) on biopsy and pathologic response of primary tumor to neoadjuvant therapy in patients with high-risk prostate cancer. METHODS: Eighty-five patients with high-risk localized/locally advanced prostate cancer (CaP) who were given 6-month neoadjuvant therapies of androgen deprivation therapy plus docetaxel or abiraterone prior to radical prostatectomy in 2 prospective trials were included in this study. The presence of IDC-P in biopsy pathology was rereviewed by 2 experienced pathologists. Favorable pathologic response was defined as pathologic complete response or minimal residual disease <5 mm on whole-mount histopathology. Characteristics of clinical and biopsy pathology variables were included in univariate and multivariate logistic regression analyses to identify risk factors for the prediction of favorable pathologic response on final pathology. RESULTS: IDC-P was identified to be present on biopsy pathology of 35 patients (41.2%) while favorable pathologic responses were confirmed in 25 patients (29.4%). Initial prostate-specific antigen (PSA) (OR 3.592, 95% CI 1.176-10.971, P = 0.025) and the presence of IDC-P on biopsy pathology (OR 3.837, 95% CI 1.234-11.930, P = 0.020) were found to be significantly associated with favorable pathologic response in multivariate logistic regression analysis. CONCLUSION: IDC-P on biopsy pathology was found to be an independent risk factor to predict a poor pathology response of primary CaP to neoadjuvant therapies.

Which Patients with Prostate Cancer and Lymph Node Uptake at Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography/Computerized Tomography Scan Are at a Higher Risk of Prostate-specific Antigen Persistence After Radical Prostatectomy? Identifying Indicators of Systemic Disease by Integrating Clinical, Magnetic Resonance Imaging, and Functional Imaging Parameters.

BACKGROUND: The role of local therapies including radical prostatectomy (RP) in prostate cancer (PCa) patients with clinical lymphadenopathies on prostate-specific membrane antigen (PSMA) positron emission tomography/computerized tomography (PET/CT) has scarcely been explored. Limited data are available to identify men who would benefit from RP; on the contrary, those more likely to benefit already have systemic disease. OBJECTIVE: We aimed to assess the predictors of prostate-specific antigen (PSA) persistence in surgically managed PCa patients with lymphadenopathies on a PSMA PET/CT scan by integrating clinical, magnetic resonance imaging (MRI), and PSMA PET/CT parameters. DESIGN, SETTING, AND PARTICIPANTS: We identified 519 patients treated with RP and extended lymph node dissection, and who received preoperative PSMA PET between 2017 and 2022 in nine referral centers. Among them, we selected 88 patients with nodal uptake at preoperative PSMA PET (miTxN1M0). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PSA persistence, defined as a PSA value of ≥0.1 ng/ml at the first measurement after surgery. Multivariable logistic regression models tested the predictors of PSA persistence. Covariates consisted of biopsy International Society of Urological Pathology (ISUP) grade group, clinical stage at MRI, and number of positive spots at a PET/CT scan. A regression tree analysis stratified patients into risk groups based on preoperative characteristics. RESULTS AND LIMITATIONS: Overall, lymph node invasion (LNI) was detected in 63 patients (72%) and 32 (36%) experienced PSA persistence after RP. At multivariable analyses, having more than two lymph nodal positive findings at PSMA PET, seminal vesicle invasion (SVI) at MRI, and ISUP grade group >3 at biopsy were independent predictors of PSA persistence (all p < 0.05). At the regression tree analysis, patients were stratified in four risk groups according to biopsy ISUP grade, number of positive findings at PET/CT, and clinical stage at MRI. The model depicted good discrimination at internal validation (area under the curve 78%). CONCLUSIONS: One out of three miN1M0 patients showed PSA persistence after surgery. Patients with ISUP grade 2-3, as well as patients with organ-confined disease at MRI and a single or two positive nodal findings at PET are those in whom RP may achieve the best oncological outcomes in the context of a multimodal approach. Conversely, patients with a high ISUP grade and extracapsular extension or SVI or more than two spots at PSMA PET should be considered as potentially affected by systemic disease upfront. PATIENT SUMMARY: Our novel and straightforward risk classification integrates currently available preoperative risk tools and should, therefore, assist physician in preoperative counseling of men candidates for radical treatment for prostate cancer with positive lymph node uptake at prostate-specific membrane antigen positron emission tomography.

Second generation androgen receptor antagonist, TQB3720 abrogates prostate cancer growth via AR/GPX4 axis activated ferroptosis.

Purpose: Prostate cancer (PCa) poses a great threat to humans. The study aimed to evaluate the potential of TQB3720 in promoting ferroptosis to suppress prostate cancer, providing a theoretical basis for PCa therapy. Methods: PCa cells and nude mice models were divided into TQB3720, enzalutamide (ENZ), and control groups. Sulforhodamine B assay, colony formation assessment, organoids culture system, and the CCK8 assay were used for detecting proliferation. Western blot assay was processed to detect the expression of androgen receptor (AR), ferroptosis, and apoptosis-related genes. Flow cytometry was applied to measure the intracellular ROS levels. ELISA was performed to determine the cellular oxidized glutathione (GSSG) and malondialdehyde (MDA) levels. RT-qPCR was conducted to detect the mRNA expression of genes in AR signaling. BODIPYTM™ 581/591 was processed for detection of intracellular lipid peroxidation levels. The interaction of AR with other translational factor complex proteins was explored using Co-immunoprecipitation (Co-IP), and the chromatin immunoprecipitation (ChIP) assay was performed to detect the binding of AR-involved translational complex to downstream genes promoter. Luciferase reporter assay was conducted to examine the translation activity of GPX4 promoter, and immunohistochemistry (IHC) was conducted to analyze the levels of c-MYC, Ki-67 and AR in TQB3720-treated cancer tissues. Results: Here, we found TQB3720 inhibits the growth of prostate cancer in vitro and in vivo. TQB3720 treatment induced intracellular levels of GSSG and MDA significantly, by which hints AR antagonist caused ferroptosis-related cell death. Moreover, molecular evidence shown TQB3720 regulates downstream of AR signaling by binding AR resulting in inhibition of AR entry into the nucleus. Additional, we also proved that TQB3720 abrogates the interaction between AR and SP1 and leads to decrease GPX4 transcription. Conclusion: TQB3720 promotes ferroptosis in prostate cancer cells by reducing the AR/SP1 transcriptional complex binding to GPX4 promoter. As a result, it is suggested to be a potential drug for clinic prostate cancer treatment.

Androgen deprivation therapy plus abiraterone or docetaxel as neoadjuvant therapy for very-high-risk prostate cancer: a pooled analysis of two phase II trials.

Objective: The study aimed to compare the efficacy and safety of androgen deprivation therapy (ADT) with abiraterone or docetaxel versus ADT alone as neoadjuvant therapy in patients with very-high-risk localized prostate cancer. Methods: This was a pooled analysis of two single-center, randomized, controlled, phase II clinical trials (ClinicalTrials.gov: NCT04356430 and NCT04869371) conducted from December 2018 to March 2021. Eligible participants were randomly assigned to the intervention (ADT plus abiraterone or docetaxel) and control (ADT alone) groups at a 2:1 ratio. Efficacy was evaluated by pathological complete response (pCR), minimal residual disease (MRD), and 3-year biochemical progression-free survival (bPFS). Safety was also analyzed. Results: The study included 42 participants in the ADT group, 47 in the ADT plus docetaxel group, and 48 in the ADT plus abiraterone group. A total of 132 (96.4%) participants had very-high-risk prostate cancer, and 108 (78.8%) had locally advanced disease. The ADT plus docetaxel group (28%) and ADT plus abiraterone group (31%) had higher rates of pCR or MRD (p = 0.001 and p < 0.001) compared with the ADT group (2%). The 3-year bPFS was 41.9% (95% CI: 26.6-57.2), 51.1% (95% CI: 36.8-65.4), and 61.2% (95% CI: 45.5-76.9), respectively. Significant difference was found among groups in terms of bPFS (p = 0.037). Conclusion: Compared with ADT alone, neoadjuvant therapy with ADT plus docetaxel or abiraterone could achieve better pathological outcomes (pCR or MRD) for very-high-risk localized prostate cancer. The ADT plus abiraterone group showed longer bPFS than ADT alone. The combination regimens were tolerable.