Novel nomogram to predict biochemical recurrence-free survival after radical prostatectomy.

PURPOSE: Conditional survival represents the probability of subsequent survival given that patients have already survived a certain length of time. Several models predict biochemical recurrence (BCR) after radical prostatectomy. However, none of them include postoperative prostate-specific antigen (PSA). We aimed to analyze BCR-free survival evolution over time and develop a nomogram incorporating the postoperative PSA value to predict BCR-free survival. MATERIAL AND METHODS: We included patients treated with robot-assisted radical prostatectomy (RARP) for prostate cancer between 2009 and 2021 and calculated conditional survival. Cox proportional hazard regression analysis was used to assess the predictive variables of BCR. We developed a nomogram predicting BCR-free survival three and five years after RARP. We used c-index and decision curve analyses to compare the nomogram with the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score. RESULTS: We included 718 patients. The overall 3- and 5-year BCR-free survival rates were 85.1% and 75.7%, respectively. The 5-year BCR-free survival rates increased to 78.9%, 82.9%, 85.2%, and 84.7% for patients surviving 1, 2, 3, and 4 years without BCR, respectively. We developed a nomogram including the pathological Gleason score and T stage, positive surgical margin, PSA ≥ 0.05 ng/mL at one year, and lymph node involvement to predict BCR at 3 and 5 years postoperatively. Our nomogram presented a higher c-index (0.89) than the CAPRA-S score (0.78; p = 0.001) and a positive net benefit at 3 and 5 years postoperatively in the decision curve analyses. CONCLUSION: The 5-year conditional BCR-free survival increased with survival without BCR. The developed nomogram significantly improved the accuracy in predicting BCR-free survival after RARP.

Risk Factors Associated with Clinical Failure of Uterine Artery Embolization for Postpartum Hemorrhage.

PURPOSE: To identify risk factors for clinical failure of uterine artery embolization (UAE) for postpartum hemorrhage (PPH), with particular attention to the uterine artery diameter. MATERIALS AND METHODS: This retrospective study included 47 patients who underwent UAE for PPH between January 1, 2010, and January 31, 2021. Technical success was defined as the completion of embolization of the arteries thought to be the cause of the bleeding. Clinical success was defined as no recurrent bleeding or need for additional therapeutic interventions. Univariate and multivariate analyses were performed to examine the risk factors associated with clinical failure of UAE. RESULTS: Of the 47 patients, 6 had recurrent bleeding. Of the 6 patients, 4 underwent hysterectomy, and 2 underwent repeat embolization. The clinical success rate was 87.2% (41/47), with no major adverse events such as uterine infarction or death. In univariate analysis, there were slight differences in multiparity (P = .115) and placental abruption (P = .128) and a significant difference in the findings of a narrow uterine artery on digital subtraction angiography (DSA) (P = .005). In multivariate analysis, only a narrow uterine artery on DSA was a significant factor (odds ratio, 18.5; 95% confidence interval, 2.5-134.8; P = .004). CONCLUSIONS: A narrow uterine artery on DSA was a risk factor for clinically unsuccessful UAE for PPH. It may be prudent to conclude the procedure only after it is ensured that vasospasm has been relieved.

Fusion-targeted biopsy significantly improves prostate cancer detection in biopsy-naïve men.

OBJECTIVE: The precise diagnosis of prostate cancer (PC) is crucial to avoid underdiagnosis, overdiagnosis, and overtreatment. We aimed to compare clinically significant PC (csPC) detection between MRI/ultrasound fusion-targeted prostate (TBx) compared to systematic biopsy (SBx) in biopsy-naïve Japanese men. METHODS: We included patients with suspect PC due to elevated PSA level or abnormal digital rectal examination, or both. csPC was defined as International Society Urological Pathology (ISUP) grade group ≥2 (csPC-A) and ISUP grade group ≥3 (csPC-B). RESULTS: This study included 143 patients. Overall PC detection was 66.4% for SBx and 67.8% for MRI-TBx. MRI-TBx presented a significantly higher rate of csPC detection (csPC-A 67.1% vs. 58.7%, p = 0.04, and csPC-B 49.6% vs. 39.9%, p < 0.001) and significantly lower detection of non-csPC-A (0.6% vs. 6.7%). Importantly, MRI-TBx missed 4.9% (7/143) of csPC-A and only 0.7% (1/143) of csPC-B. On the other hand, SBx alone missed 13.3% (19/143) of csPC-A and 4.2% (6/143) of csPC-B. CONCLUSION: MRI-TBx significantly outperformed 12-cores SBx for csPC detection and decreased non-csPC detection in biopsy-naive men. Performing MRI-TBx without SBx would have missed some csPC, supporting that MRI-TBx synergizes with SBx to increase csPC detection.

Correlation between extended pelvic lymph node dissection and urinary incontinence at early phase after robot-assisted radical prostatectomy.

OBJECTIVES: To investigate the impact of extended pelvic lymph node dissection (ePLND) on urinary incontinence (UI) at early post-surgery robot-assisted radical prostatectomy (RARP). METHODS: Patients who underwent RARP without cavernous nerve sparing were included between 2014 and 2019. Patient data were obtained prospectively. The associations between ePLND and postoperative urinary continence were defined as a maximum of one daily pad use. International prostate symptom score (IPSS) was examined. Expression of synaptophysin and tyrosine hydroxylase (TH) in perilymph node adipose tissue (PLA) was evaluated by immunohistochemistry. RESULTS: In total, 186 and 163 patients underwent RARP with and without ePLND. Urinary continence rate at 1 month postoperatively among patients with ePLND was lower than those without ePLND (24.1% vs. 35.1%, p < 0.05), however, not significantly different at 3, 6, and 12 months after RARP (57.4 vs. 62.6%, 73.1 vs. 74.2%, and 83.0 vs. 81.2%, respectively). Total and voiding plus postvoiding IPSS scores at 1 month were higher in patients with ePLND than in those without ePLND (14.5 ± 0.5 vs. 13.6 ± 0.6, 7.0 ± 0.3 vs. 6.2 ± 0.4, respectively, p < 0.05). In univariate and multivariate analyses, larger prostate volume and ePLND were factors associated with an increased UI rate. Among patients who underwent ePLND, synaptophysin and TH-positive nerve fibers were detected in PLA. CONCLUSIONS: Detection of synaptophysin and TH-immunopositive nerves suggested denervation of sympathetic and peripheral nerves caused by ePLND might be associated with a higher UI rate and poor urinary symptoms at an early stage after RARP.

An oral first-in-class small molecule RSK inhibitor suppresses AR variants and tumor growth in prostate cancer.

Ribosomal S6 kinase has been shown to play a key role in cellular resistance to endocrine therapy in prostate cancer through its regulation of YB-1/androgen receptor (AR) signaling. PMD-026, an oral first-in-class small molecule kinase inhibitor, is the first identified ribosomal S6 kinase inhibitor. This study investigated the effect of PMD-026 on YB-1/AR signaling and its antitumor effect in prostate cancer in vitro and in vivo. Castration-resistant prostate cancer 22Rv1 cells that express high-level AR variants were used in this study. The effect of PMD-026 on YB-1/AR signaling was investigated by quantitative real-time PCR and western blot analysis. The effects of PMD-026 on prostate cancer cells were investigated by cytotoxicity analysis, apoptosis assay, and cell cycle assay in vitro and a mouse castration model in vivo. PMD-026 decreased YB-1 phosphorylation as well as AR V7 mRNA and AR variant expressions in 22Rv1 cells. PMD-026 suppressed cell proliferation alone and in combination with the second-generation antiandrogens enzalutamide and darolutamide by inducing cellular apoptosis and G2/M arrest. In a mouse xenograft model, PMD-026 suppressed tumor growth, and the combination of PMD-026 and enzalutamide inhibited tumor growth more prominently than single treatments. Our results demonstrate an excellent antitumor effect of the novel ribosomal S6 kinase inhibitor PMD-026 and the combination effect with the antiandrogen enzalutamide in castration-resistant prostate cancer. These findings warrant a clinical trial of PMD-026 in prostate cancer patients.

Differential prognostic impact of complete blood count-related parameters by prior use of novel androgen receptor pathway inhibitors in docetaxel-treated castration-resistant prostate cancer patients.

There are multiple reports on the value of complete blood count (CBC)-related parameters on prognosis in docetaxel-treated castration-resistant prostate cancer (CRPC) patients before the emergence of androgen receptor pathway inhibitors (ARPIs). We investigated the prognostic significance of CBC-related parameters in docetaxel-treated CRPC patients. Patients treated with docetaxel chemotherapy for CRPC between 2008 and 2018 were included. We analyzed the relevance of CBC-related parameters to oncological prognosis in docetaxel chemotherapy, associated with prior use of novel ARPIs. Among 144 Japanese men treated with docetaxel, 49 men (34.0%) had already received ARPI therapy. A high neutrophil-lymphocyte ratio (NLR) was a prognostic factor for poor progression-free survival and overall survival (OS) in both univariate and multivariate analyses. In addition, a low hemoglobin (Hb) level and a high systemic immune-inflammation index (SII) were prognostic factors of poor OS in univariate analysis. Hb level was a prognostic factor of OS in both ARPI-naive and ARPI-treated patients. However, a high NLR and SII were only associated with a poor prognosis in ARPI-naive but not in ARPI-treated patients. Hb, NLR, and SII have been suggested to be prognosticators in docetaxel-treated CRPC patients. The differential prognostic value of NLR and SII between ARPI-naive and ARPI-treated patients may require caution when using these markers in docetaxel-treated CRPC patients.

Clinical impact of HSD3B1 polymorphism by metastatic volume and somatic HSD3B1 alterations in advanced prostate cancer.

This study aimed to investigate the significance of HSD3B1 gene status including germline polymorphism and somatic alterations in prostate cancer. Patients with prostate cancer treated with androgen-deprivation therapy, as well as tissues from metastatic prostate cancer, were included. Genomic DNA was extracted from cancer tissues and whole blood samples, and HSD3B1 (rs1047303, 1245C) was genotyped by Sanger sequencing. The association of HSD3B1 genotype with progression-free survival according to metastatic volume was examined. Copy number alteration and gene expression of HSD3B1 were examined in prostate cancer cells and public datasets. Among 194 patients, 121 and 73 patients were categorized into low- and high-volume diseases respectively. In multivariate analysis, the adrenal-permissive genotype (AC/CC) was significantly associated with increased risk of progression compared with the adrenal-restrictive genotype (AA) in low volume, but not high-volume diseases. Somatic mutation in HSD3B1 was detected at least in two cases of castration-resistant prostate cancer tissues. HSD3B1 amplification and overexpression were detected in castration-resistant prostate cancer cells and tissues. The current findings suggest that both germline and somatic alterations of HSD3B1 may cooperatively promote castration resistance in prostate cancer and HSD3B1 as a promising biomarker for precision medicine, warranting further investigations.

Testosterone level in seminal vesicle fluid is a better indicator of erectile function than serum testosterone in patients with prostate cancer.

OBJECTIVES: Semen comprises prostatic fluid and seminal vesicle fluid, and seminal vesicle fluid contains various factors such as prostaglandin E2 (PGE2), zinc, and testosterone, which play important roles in sperm motility. It is not known whether these factors affect erectile function. In this study, we investigated factors in seminal vesicle fluid that may affect erectile function. METHODS: After receiving institutional review board approval, we collected seminal vesicle fluid samples from 134 Japanese patients with localized prostate cancer who underwent robot-assisted radical prostatectomy. We examined the relationship between the results of the Sexual Health Inventory for Men (SHIM), erection hardness score, an original questionnaire on the presence or absence of sexual desire, and concentrations of several factors in seminal vesicle fluid (testosterone, PGE2, transforming growth factor ß1, and 8-hydroxy-2-deoxyguanosine), as well as the serum testosterone level. RESULTS: Median participant age was 67 (range 51-77) years. Median concentrations were as follows: seminal vesicle testosterone 1.85 (range 0.17-4.32) ng/ml and serum testosterone 4.60 (range 1.75-10.82) ng/ml. When the SHIM score was divided into two groups, seminal vesicle testosterone concentration was significantly increased (p = 0.002) in participants with a SHIM score ≥17, and no significant difference was observed in serum testosterone levels (p = 0.661). Multivariate analysis revealed that seminal vesicle testosterone was significantly correlated with the SHIM score (≥17 vs. <17; odds ratio 2.137, 95% confidence interval 1.148-3.978, p = 0.016). CONCLUSIONS: Testosterone levels in seminal vesicle fluid can reflect erectile function in patients with prostate cancer, suggesting that seminal vesicle testosterone is very important for male erectile function.

Validation of models predicting lymph node involvement probability in patients with prostate cancer.

OBJECTIVES: There are many models to predict lymph node involvement in patients with prostate cancer. We aimed to externally validate several models in a Japanese cohort. METHODS: We considered patients who were treated with robotic-assisted radical prostatectomy with extended pelvic lymph node dissection for prostate cancer. The risk of lymph node involvement was calculated for each patient in several models. Model performance was assessed by calculating the receiver operating characteristic curve and the area under the curve, calibration plots, and decision curve analyses. RESULTS: We identified lymph node involvement in 61 (18.4%) of the 331 considered patients. Patients with lymph node involvement had a higher prostate-specific antigen level, percentage of positive biopsy cores, primary Gleason grade, Gleason group grade, and clinical T-stage category. The Memorial Sloan Kettering Cancer Center web calculator presented the highest area under the curve (0.78) followed by the Yale formula area under the curve (0.77), the updated version of Briganti nomogram of 2017 area under the curve (0.76), and the updated version of the Partin table by Tosoian et al. had an area under the curve of 0.75. However, the 95% confidence interval for these models overlapped. The calibration plot showed that the Memorial Sloan Kettering Cancer Center web calculator and the updated version of the Briganti nomogram calibrated better. In the decision curve analyses, all models showed net benefit; however, it overlapped among them. However, the Memorial Sloan Kettering Cancer Center web calculator and the updated Briganti nomogram presented the highest net benefit for lymph node involvement risks <35%. CONCLUSION: Models predicting lymph node involvement were externally validated in Japanese men. The Memorial Sloan Kettering Cancer Center web calculator and the updated Briganti nomogram of 2017 were the most accurate performing models.

Impact of nerve sparing in robot-assisted radical prostatectomy on the risk of positive surgical margin and biochemical recurrence.

OBJECTIVES: Nerve sparing may increase positive surgical margin rate during radical prostatectomy. Our objective was to analyze the positive surgical margin rate and location as well as its impact on biochemical recurrence according to nerve sparing procedure in robot-assisted radical prostatectomy. METHODS: We included 814 patients treated with robot-assisted radical prostatectomy between 2009 and 2021, and evaluated the impact of nerve sparing on positive surgical margin and biochemical recurrence using logistic regression and Cox models. RESULTS: Unilateral nerve sparing and bilateral nerve sparing were performed in 152 (18.6%) cases and 118 (14.5%) cases, respectively. On multivariable analysis, in addition to nerve sparing, bilateral nerve sparing, but not unilateral nerve sparing was associated with an increased risk of positive surgical margin compared with non-nerve sparing. Positive surgical margin at any location increased the risk of biochemical recurrence. During unilateral nerve sparing, positive surgical margin in nerve sparing side, but not in non-nerve sparing side was associated with increased risk of biochemical recurrence on multivariate analysis. CONCLUSIONS: Taken together, surgeons need to notice an increased risk of biochemical recurrence associated with positive surgical margin when performing nerve sparing in robot-assisted radical prostatectomy, and then need to choose the patients suitable for nerve sparing.

Predictive factors of survival outcomes in first-line therapy for metastatic castration-resistant prostate cancer.

OBJECTIVES: To investigate predictive factors of survival of metastatic castration-resistant prostate cancer patients undergoing first-line treatment with androgen receptor pathway inhibitors or docetaxel. METHODS: Japanese patients with metastatic castration-resistant prostate cancer treated with androgen receptor pathway inhibitor or docetaxel between 2008 and 2018 were included. The differential impact of various clinicopathological factors on the outcome, including progression-free survival and overall survival, was compared between treatment with androgen receptor pathway inhibitor and docetaxel. RESULTS: Of 254 patients with metastatic castration-resistant prostate cancer, 119 (46.9%) and 135 (53.2%) were treated with androgen receptor pathway inhibitor and docetaxel, respectively. The multivariate analysis showed that androgen receptor pathway inhibitor was an independent prognostic factor for better progression-free survival (hazard ratio 0.62, 95% confidence interval 0.42-0.92, P = 0.016) and overall survival (hazard ratio 0.61, 95% confidence interval 0.41-0.93, P = 0.021), compared with docetaxel. Pretreatment prostate-specific antigen levels and time to castration-resistant prostate cancer were differentially associated with progression-free survival and overall survival between androgen receptor pathway inhibitor or docetaxel. In patients who presented <6 months to castration-resistant prostate cancer, progression-free survival was shorter in those treated with androgen receptor pathway inhibitor (median 1.1 months, 95% confidence interval 0.2-2.8 months) compared with those who received docetaxel (median 5.0 months, 95% confidence interval 1.8-6.7 months; P = 0.014). CONCLUSIONS: First-line therapy with androgen receptor pathway inhibitor is associated with a better prognosis when compared with docetaxel, even after adjustment for prognostic factors. However, a shorter time to castration-resistant prostate cancer is associated with better progression-free survival for patients receiving docetaxel, suggesting that docetaxel is the preferred option for patients with a shorter time to castration-resistant prostate cancer.

Gene amplification of YB-1 in castration-resistant prostate cancer in association with aberrant androgen receptor expression.

Although Y-box binding protein-1 (YB-1) is known to be overexpressed in prostate cancer, especially castration-resistant prostate cancer (CRPC), the mechanism of its overexpression remains unclear. We aimed to elucidate the mechanism of YB-1 overexpression in CRPC. Gene amplification in CRPC cells and tissues was examined by public database analysis, and digital PCR. The significance of YB-1 amplification for the YB-1/androgen receptor (AR) axis and prognosis was examined by public database analysis and immunohistochemistry. YB-1 amplification was mainly observed in CRPC tissues by public database analysis and confirmed in CRPC cells and tissues by digital PCR. Expression of YB-1 was increased in CRPC tissues compared with treatment-naïve tissues. Furthermore, YB-1 and phosphorylated YB-1 levels were associated with AR and AR V7 expression levels. Finally, YB-1 amplification was associated with poor outcomes in CRPC. Taken together, the present findings suggest that YB-1 amplification contributes to progression to CRPC through regulation of AR and AR V7 expressions, and that YB-1 is a promising therapeutic target in CRPC.

Efficacy and Safety of 4-Weekly Docetaxel for Castration-Resistant Prostate Cancer.

We investigated the efficacy and safety profiles of 4-weekly docetaxel for castration-resistant prostate cancer. Patients treated with ≥2 courses of docetaxel chemotherapy (median, 70 mg/m2) between 2008 and 2018 were included. Among 125 Japanese men, 40 (32.0%) and 85 (68.0%) were treated with 3-weekly and 4-weekly regimens, respectively. In the 4-weekly regimen, the risks of progression, treatment failure, and any-cause mortality were comparable to those in the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. These data suggest that the 4-weekly regimen may be an acceptable option for selected patients.

Venous Sac and Feeding Artery Embolization versus Feeding Artery Embolization Alone for Treating Pulmonary Arteriovenous Malformations: Draining Vein Size Outcomes.

PURPOSE: To investigate and compare venous sac and feeding artery embolization (VFE) with feeding artery embolization (FAE) alone for treatment of pulmonary arteriovenous malformations (PAVMs), based on difference in outcomes in decrease of the size of the draining vein. MATERIALS AND METHODS: Twenty-six patients (7 male and 19 female; median age [interquartile range], 58 years [46-65 years]) with 42 simple PAVMs treated with coil embolization between August 2005 and December 2018 were retrospectively evaluated. Twenty PAVMs were treated with FAE early in the study period and compared with 22 PAVMs treated with VFE later in the study period. Follow-up computed tomography images obtained 8-20 months after embolotherapy were used for outcome analysis. Data related to patient demographics; follow-up period; baseline diameters of the feeding artery, venous sac, and draining vein; draining vein diameter after treatment; and decrease in the size of the draining vein, including the number reaching a threshold of 70% decrease, were compared between the 2 groups. RESULTS: The draining vein decreased in size by a median of 46.4% in the FAE group and 66.3% in the VFE group, and the difference between the 2 groups was statistically significant (P = .009). There were no significant differences in the other parameters. CONCLUSIONS: VFE leads to a greater decrease in the size of the draining vein than FAE, suggesting that VFE results in more complete occlusion than FAE for treatment of PAVMs.

Prognostic impact of prior local therapy in castration-resistant prostate cancer.

OBJECTIVE: This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC). METHODS: The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis. RESULTS: In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95% confidence interval, 0.40-0.79; P = 0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis. CONCLUSIONS: This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC.

Clinical advantages of robot-assisted partial nephrectomy versus laparoscopic partial nephrectomy in terms of global and split renal functions: A propensity score-matched comparative analysis.

OBJECTIVES: To identify predictors of renal function preservation, and to compare the global and split renal function outcomes of robot-assisted partial nephrectomy and laparoscopic partial nephrectomy. METHODS: Demographic, operative and pathological data, as well as renal function outcomes, of 251 patients who underwent laparoscopic (n = 104) and robot-assisted (n = 147) partial nephrectomy between 2008 and 2018 were retrospectively analyzed. Propensity score matching (1:1) was carried out to adjust for potential baseline confounders. Functional outcomes were assessed based on the estimated glomerular filtration rate and dynamic renal scintigraphy (using 99m Tc-mercaptoacetyltriglycine), including renal volumetric analysis. RESULTS: A total of 98 patients were allocated to each partial nephrectomy group. Ischemic (laparoscopic vs robot-assisted partial nephrectomy: 29 vs 15 min, P < 0.001) and operative times (181 vs 100 min, P < 0.001) were shorter in robot-assisted partial nephrectomy. The preservation ratio of global renal function at 3 months (88.3% vs 91.4%, P = 0.040) and 12 months (87.8% vs 91.5%, P = 0.010) postoperatively, and the renal function of the operated kidney (80.3% vs 88.2%, P < 0.001) were greater after robot-assisted partial nephrectomy. In robot-assisted partial nephrectomy, the volume of resected parenchyma was significantly smaller (27.2 vs 15.5 mL, P < 0.001), resulting in greater postoperative normal parenchymal volumes (120 vs 132 mL, P < 0.001) and a greater parenchymal preservation ratio (81.1% vs 90.1%, P < 0.001). The parenchymal preservation ratio was the strongest predictor of renal function preservation after surgery (P < 0.001, odds ratio 6.02). CONCLUSIONS: Robot-assisted partial nephrectomy allows better preservation of split renal function than laparoscopic partial nephrectomy by increasing the parenchymal preservation ratio. This translates into better postoperative global renal function.

FOXO1 inactivation induces cisplatin resistance in bladder cancer.

We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.

High-throughput screen identifies 5-HT receptor as a modulator of AR and a therapeutic target for prostate cancer.

BACKGROUND: Eradication of persistent androgen receptor (AR) activity in castration-resistant prostate cancer may be a promising strategy to overcome castration resistance. We aimed to identify novel compounds that inhibit AR activity and could be potential therapeutic agents for prostate cancer. METHODS: A high-throughput screening system involving cell lines stably expressing AR protein and AR-responsive luciferase was employed for the 1260 compound library. Molecular and antitumor effects on candidate pathways that interacted with AR signaling were examined in prostate cancer cells expressing AR. RESULTS: The high-throughput screening identified various potential compounds that interfered with AR signaling through known and novel pathways. Among them, a 5-hydroxytryptamine 5A (5-HT5A) receptor antagonist suppressed AR activity through protein kinase A signaling, which was confirmed by 5-HT5A receptor knockdown. Consistently, 5-HT5A receptor inhibitors showed cytotoxic effects toward prostate cancer cells. CONCLUSIONS: Taken together, this study identifies 5-HT5A receptor as a promising therapeutic target for prostate cancer via its interaction with AR signaling.

Diagnostic Impacts of Clinical Laboratory Based p2PSA Indexes on any Grade, Gleason Grade Group 2 or Greater, or 3 or Greater Prostate Cancer and Prostate Specific Antigen below 10 ng/ml.

PURPOSE: The PROPHET (Prostate Cancer: Prostate Health Index Trial) is a prospective study to clarify the diagnostic impact of laboratory based and prostate volume adjusted p2PSA ([-2] proenzyme prostate specific antigen) related indexes on prostate cancer and clinically significant prostate cancer with prostate specific antigen less than 10 ng/ml. MATERIALS AND METHODS: Between April 2015 and March 2017, 421 men 50 to 79 years old in the prostate specific antigen range above age specific cutoffs and below 10 ng/ml were registered in the PROPHET. We investigated the diagnostic impacts of various clinical laboratory based free prostate specific antigen related and p2PSA related indexes on any grade and high Gleason grade group prostate cancer. RESULTS: Of the 363 eligible participants 179, 141 and 80 were diagnosed with any grade, and Gleason Grade Group 2-5 and 3-5 prostate cancer, respectively. The AUC-ROCs distinguishing nonprostate cancer vs prostate cancer, nonprostate cancer plus low Gleason Grade Group and low volume vs remaining prostate cancer with a higher Gleason Grade group or a higher volume on the PHI (Prostate Health Index) were significantly superior to the AUC-ROCs of prostate specific antigen and free-to-total prostate specific antigen. At 90% sensitivity in all investigated p2PSA related indexes the false-positive rate was superior to that of prostate specific antigen and free-to-total prostate specific antigen in any group comparison in terms of the Gleason Grade Group and positive biopsy cores. In 35% to 42% of men without prostate cancer and/or those with less aggressive prostate cancer the PHI would avoid unnecessary biopsy. CONCLUSIONS: Laboratory based p2PSA related indexes were significantly superior for detecting clinically significant prostate cancer compared to free-to-total prostate specific antigen. The indexes those would avoid up to 42% of prostate biopsies in men without aggressive cancer while maintaining 90% sensitivity.

Effect of Smoking on Oncological Outcome among Prostate Cancer Patients after Radical Prostatectomy with Neoadjuvant Hormonal Therapy.

We analyzed the association between smoking and oncological outcome after radical prostatectomy with neoadjuvant hormonal therapy. This study included men who had undergone radical prostatectomy with neoadjuvant hormonal therapy between 2003 and 2016. We evaluated the association between clinicopathological factors and smoking status as well as the prognostic significance of smoking status in biochemical recurrence. The patients' backgrounds were comparable between smokers and nonsmokers. Smoking status were identified as significant risk factors of biochemical recurrence. Smoking was a risk factor of biochemical recurrence, suggesting that smoking may promote cancer recurrence after surgical treatment combined with hormonal therapy.