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Background: The treatment landscape for men with metastatic hormone-naïve prostate cancer (mHNPC) has dramatically changed with the approval of next-generation anti-androgen drugs. We compared the treatment efficacy of abiraterone with that of combined androgen blockade (CAB) therapy and androgen deprivation therapy (ADT) alone in men with high-risk mHNPC., Methods: In total, 146 Japanese men with high-risk mHNPC were retrospectively analyzed. As initial hormonal therapy, 30, 83, and 33 men were treated with ADT plus abiraterone (ABI group), ADT plus bicalutamide (CAB group), and ADT alone (ADT group), respectively. Treatment efficacy was compared using time to castration resistance (TTCR) and prostate-specific antigen (PSA) response among the groups. Propensity score matching analysis was also performed to adjust for baseline differences., Results: The median (95% confidence interval [CI]) TTCR in the ABI, CAB, and ADT groups were not reached, 10.7 (7.6-13.8) months and 11.0 (7.9-12.4) months, respectively, and it was significantly longer in the ABI group than in the other groups (p = 0.0012, p = 0.0008). In propensity score matching analysis, the median TTCR was also significantly longer in the ABI group than in the other groups (hazard ratio [HR], 0.47; 95% CI, 0.22-0.98; p = 0.010; HR, 0.32; 95% CI, 0.12-0.85; p = 0.004). The number of men who achieved PSA levels ≤0.2 ng/mL after propensity score matching were significantly higher in the ABI group than in the other groups., Conclusions: Our results provide important evidence regarding the superiority of abiraterone over CAB therapy and ADT alone for initial treatment for men with newly diagnosed mHNPC., Competing Interests: The authors have declared that no competing interests exist.

Background: Regulatory T cells (Tregs) play important roles in the suppression of immune responses, including antitumor immune responses. C-C chemokine receptor 4 (CCR4) is highly expressed on effector Tregs, and anti-CCR4 antibody is attracting attention as a novel immunotherapeutic agent for solid tumors. This study aimed to evaluate the expression of CCR4-positive Tregs (CCR4+Tregs) in prostate cancer and estimate the clinical potential of CCR4-targeting therapy for prostate cancer., Methods: A total of 15 radical prostatectomy (RP) specimens and 60 biopsy specimens from individuals diagnosed with prostate cancer were analyzed to evaluate the infiltration of CCR4+Tregs in prostate cancer. The relationships between the number of CCR4+Tregs and clinical parameters were investigated in RP and biopsy specimens. Moreover, the total number of Tregs, CCR4+Tregs, and T cells and the ratio of CCR4+Tregs to Tregs and T cells in biopsy specimens were compared between patients with poor prognosis who progressed to castration-resistant prostate cancer (CRPC) within 12 months (n = 13) and those with good prognosis who were stable with hormone-sensitive prostate cancer over 12 months (n = 47). Furthermore, biopsy specimens were divided into two groups: low and high CCR4+Treg expression groups and the prognosis was compared between them., Results: There was a higher expression of CCR4+Tregs in RP specimens with a higher (≥8) Gleason score than in those with a lower (<8) Gleason score (P = .041). In biopsy specimens, 65.9% Tregs were positive for CCR4. The number of CCR4+Tregs positively correlated with clinical stage (P < .001) and Gleason score (P = .006). The total number of Tregs and CCR4+Tregs significantly increased in the poor prognosis group compared with that in the good prognosis group (P = .024 and .01, respectively). Furthermore, patients with lower CCR4+Treg expression levels showed a significantly longer time to progression to CRPC (not reached vs 27.3 months; P < .001) and median survival time (not reached vs 69.0 months; P = .014) than those with higher expression levels., Conclusions: CCR4+Tregs are highly infiltrated in the prostate tissue of patients with poor prognosis with potential to progress to CRPC. Furthermore, the degree of infiltration of CCR4+Tregs is related to the prognosis of prostate cancer., (© 2019 Wiley Periodicals, Inc.)

Objectives: To evaluate the impact of a novel biopsy instrument that extends the length of the side-notch on the detection of prostate cancer in transrectal needle biopsy., Methods: We collaborated with a biopsy needle manufacturer and developed a novel biopsy instrument (PRIMECUT II long-notch type) with a 25-mm side-notch length and 28-mm stroke length to take longer tissue cores. The sampled core length, cancer detection rate, pain and complications of 489 patients who underwent transrectal biopsy using the long-notch needle were compared with those of 469 patients who underwent biopsy using a normal instrument with a 19-mm side-notch length and 22-mm stroke length., Results: The mean length of tissue taken by the long-notch needle was significantly longer than that of tissue taken by the normal-notch needle (16.3 vs 22.4 mm, P < 0.001). The overall cancer detection rate was 42.0% for the normal-notch needle and 51.1% for the long-notch needle (P = 0.005). In patients with a prostate volume of 20-40 mL, the cancer detection rate for the long-notch needle was especially higher than that for the normal-notch needle (74.2% vs 47.5%, P < 0.001). Multivariate analysis showed that the long-notch needle improved cancer detection significantly (odds ratio 1.702, P < 0.001). There were no differences of pain during biopsy and complication between the two groups., Conclusions: The novel biopsy instrument with a 25-mm side-notch can take longer tissue samples safely and has a significantly higher rate of prostate cancer detection in transrectal biopsy., (© 2018 The Japanese Urological Association.)

Background: Introducing a new surgical technology may affect behaviors and attitudes of patients and surgeons about clinical practice. Robot-assisted laparoscopic radical prostatectomy (RALP) was approved in 2012 in Japan. We investigated whether the introduction of this system affected the treatment of organ-confined prostate cancer (PCa) and the use of radical prostatectomy (RP)., Methods: We conducted a retrospective multicenter study on 718 patients with clinically determined organ-confined PCa treated at one of three Japanese academic institutions in 2011 (n = 338) or 2013 (n = 380). Two patient groups formed according to the treatment year were compared regarding the clinical characteristics of PCa, whether referred or screened at our hospital, comorbidities and surgical risk, and choice of primary treatment., Results: Distribution of PCa risk was not changed by the introduction of RALP. Use of RP increased by 70% (from 127 to 221 cases, p < 0.0001), whereas the number of those undergoing radiotherapy or androgen deprivation therapy decreased irrespective of the disease risk of PCa. Increased use of RP (from 34 to 100 cases) for intermediate- or high-risk PCa patients with mild perioperative risk (American Society of Anesthesiologists score 2) accounted for 70% of the total RP increase, whereas the number of low- or very low-risk PCa patients with high comorbidity scores (Charlson Index ≥ 4) increased from 8 to 25 cases, accounting for 18%. Use of expectant management (active surveillance, watchful waiting) in very low-risk PCa patients was 15% in 2011 and 12% in 2013 (p = 0.791)., Conclusions: Introduction of a robotic surgical system had little effect on the risk distribution of PCa. Use of RP increased, apparently due to increased indications in patients who are candidates for RP but have mild perioperative risk. Although small, there was an increase in the number of RPs performed on patients with severe comorbidities but with low-risk or very low-risk PCa.

Objectives: To compare various methods for measuring tumor extent in prostate biopsy specimens to identify small-volume prostate cancer., Methods: A total of 100 radical prostatectomy specimens were retrospectively analyzed. Receiver operating characteristic analysis was used to compare the abilities of prostate-specific antigen density, and four measures of tumor extent in prostate biopsy specimens - positive core number, greatest percentage of cancer in a single core, greatest length of cancer in cores and total length of cancer in cores - to identify small volume prostate cancer. Four definitions of insignificant cancer volume were used in this analysis: index and total tumor volume <0.5 mL, index tumor volume <1.3 mL and total tumor volume <2.5 mL. Multivariate analysis was also used to evaluate variables for predicting small-volume prostate cancer., Results: Total length of cancer in cores had the highest areas under the curve of all the measures defining small-volume prostate cancer: index tumor volume <0.5 mL (0.855), total tumor volume <0.5 mL (0.877), index tumor volume <1.3 mL (0.784) and total tumor volume <2.5 mL (0.818). On multivariate analysis total length of cancer in cores was an independent predictive factor for prostate cancers with index tumor volume <0.5 mL (P < 0.001), <1.3 mL (P < 0.001) and total tumor volume <0.5 mL (P < 0.001), respectively., Conclusion: Our data suggest that total length of cancer in cores is the optimal measure of tumor extent in prostate biopsy specimens for identifying small-volume prostate cancer., (© 2015 The Japanese Urological Association.)

Objectives: To compare perioperative, oncological and functional outcomes of robot-assisted radical prostatectomy between experienced and novice open radical prostatectomy surgeons in a laparoscopically naïve center with a limited caseload., Methods: Six surgeons carried out robot-assisted radical prostatectomy in 154 patients, which were divided into the following three groups: group 1 (n = 90), including patients operated on by a surgeon with experience in both open radical prostatectomy and robot-assisted radical prostatectomy; group 2 (n = 36), including patients operated on by two surgeons with experience in open radical prostatectomy only; and group 3 (n = 28), including patients operated on by three surgeons with limited experience in both open radical prostatectomy or robot-assisted radical prostatectomy., Results: Groups 2 and 3 did not differ significantly in their median values of external blood loss (P = 0.165) or console time (P = 0.103). Positive surgical margin rates for pT2 patients were also similar in these two groups: 21.2% (7/33) in group 2 and 22.7% (5/22) in group 3 (P = 0.894). Kaplan-Meier analysis showed that 12 months after robot-assisted radical prostatectomy the prostate-specific antigen-free rate for pT2 patients was 96.0% in group 2 and 100% in group 3, but the pad-free continence rate was just 91.0% in group 1, 88.0% in group 2 and 75.5% in group 3 (group 1 vs group 3, P = 0.037; group 2 vs group 3, P = 0.239). The major complication rate after robot-assisted radical prostatectomy was 3.3% (3/90) in group 1, 11.1% (4/36) in group 2 and 17.9% (5/28) in group 3 (group 1 vs group 3, P = 0.008; group 2 vs group 3; P = 0.441)., Conclusions: Robot-assisted radical prostatectomy offers satisfactory postoperative outcomes even when carried out by surgeons with limited experience in open radical prostatectomy., (© 2015 The Japanese Urological Association.)

Objective: To individualize prostate-specific antigen threshold values to avoid overdiagnosis of prostate cancer and reduce unnecessary biopsy in elderly men., Methods: A total of 406 men aged over 70 years old with prostate-specific antigen levels between 4.0 and 20.0 ng/ml, normal digital rectal examination results and diagnosed by transrectal needle biopsy were retrospectively analyzed. The patients were divided into a no/favorable-risk cancer group or an unfavorable-risk cancer group based on their Gleason score and the number of positive cores. Prostate-specific antigen levels, percent free prostate-specific antigen level, prostate transition zone volume and the number of previous biopsies were used to discriminate between the two groups. The optimal individualized prostate-specific antigen threshold values based on the other variables that gave a sensitivity of 95% for the detection of unfavorable-risk cancer were calculated using a boosting method for maximizing the area under the receiver operating characteristic curve., Results: A total of 66 men had favorable-risk cancer, and 139 had unfavorable-risk cancer. The area under the receiver operating characteristic curve of the combination model determined by the boosting method for maximizing the area under the receiver operating characteristic curve was 0.852. The sensitivity and specificity of the threshold values for the detection of unfavorable-risk cancer were 95 and 36%, respectively. By using the threshold values, 100 (25%) of the subjects with no/favorable-risk cancer could have avoided undergoing biopsies, with a <5% risk of missing the detection of unfavorable-risk cancer., Conclusions: These individualized prostate-specific antigen threshold values may be useful for determining an indication of prostate biopsy for elderly men to avoid overdiagnosis of prostate cancer and reduce unnecessary biopsy., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate the suitability of preoperative multiparametric magnetic resonance imaging (MRI) positivity as a predictor of biochemical recurrence after radical prostatectomy (RP)., Patients and Methods: We reviewed the clinical records of patients who underwent either standard RP or laparoscopic RP between January 2005 and December 2009 at our institution. Patients who received radiotherapy or androgen deprivation therapy before surgery were excluded. A total of 314 patients met the study inclusion criteria. Cox proportional hazard regression models were used for analyses. In accordance with the criteria in the established guidelines, a radiologist scored the probability of the presence of prostate cancer using a five-point scale of diagnostic confidence level. The highest confidence level of any pulse sequence was considered as the evaluation result., Results: MRI positivity was significantly associated with a high clinical stage (cT ≥ 2; P = 0.039), a high positive biopsy core rate (≥0.2; P < 0.001), a high biopsy Gleason score ([GS] ≥8; P < 0.001) and a high pathological GS (≥8; P = 0.005). Univariate analysis and multivariate analysis showed that MRI positivity was a prognostic indicator in the analysis that included only preoperative variables and also in the analysis including preoperative and pathological variables., Conclusion: Multiparametric MRI positivity can independently predict biochemical recurrence after RP., (© 2013 The Authors. BJU International © 2013 BJU International.)

Objective: To investigate whether transrectal needle biopsy can be optimised to detect nearly all prostate cancer with a tumour volume (TV) of ≥0.5 mL., Materials and Methods: Retrospectively analysed 109 whole-mounted and entirely submitted radical prostatectomy specimens with prostate cancer. All tumours in each prostate were outlined on whole-mount slides and digitally scanned to produce tumour maps. Tumour map images were exported to three-dimensional (3D) slicer software (http://www.slicer.org) to develop a 3D-prostate cancer model. In all, 20 transrectal biopsy schemes involving two to 40 cores and two to six anteriorly directed biopsy (ADBx) cores (including transition zone, TZ) were simulated, as well as models with various biopsy cutting lengths. Detection rates for tumours of different volumes were determined for the various biopsy simulation schemes., Results: In 109 prostates, 800 tumours were detected, 90 with a TV of ≥0.5 mL (mean TV 0.24 mL). Detection rate for tumours with a TV of ≥0.5 mL plateaued at 77% (69/90) using a 12-core (3 × 4) scheme, standard 17-mm biopsy cutting length without ADBx cores. In all, 20 of 21 (95%) tumours with a TV of ≥0.5 mL not detected by this scheme originated in the anterior peripheral zone or TZ. Increasing the biopsy cutting length and depth/number of ADBx cores improved the detection rate for tumours with a TVof ≥0.5 mL in the 12-core scheme. Using a 22-mm cutting length and a 12-core scheme with additional volume-adjusted ADBx cores, 100% of ≥0.5 mL tumours in prostates ≤ 50 mL in volume and 94.7% of ≥0.5 mL tumours in prostates > 50 mL in volume were detected., Conclusions: Our 3D-prostate cancer model analysis suggests that nearly all prostate cancers with a TV of ≥0.5 mL can be detected by 14-18 transrectal needle-biopsy cores. Using longer biopsy cutting lengths and increasing the depth and number of ADBx cores (including TZ) according to prostate volume are necessary as well., (© 2013 BJU International.)

Purpose: To prospectively evaluate diagnostic performance of T2-weighted magnetic resonance (MR) imaging and MR spectroscopic imaging in detecting lesions stratified by pathologic volume and Gleason score in men with clinically determined low-risk prostate cancer., Materials and Methods: The institutional review board approved this prospective, HIPAA-compliant study. Written informed consent was obtained from 183 men with clinically low-risk prostate cancer (cT1-cT2a, Gleason score≤6 at biopsy, prostate-specific antigen [PSA] level<10 ng/mL [10 μg/L]) undergoing MR imaging before prostatectomy. By using a scale of 1-5 (score 1, definitely no tumor; score 5, definitely tumor), two radiologists independently scored likelihood of tumor per sextant on T2-weighted images. Two spectroscopists jointly recorded locations of lesions with metabolic features consistent with tumor on MR spectroscopic images. Whole-mount step-section histopathologic analysis constituted the reference standard. Diagnostic performance at sextant level (T2-weighted imaging) and detection sensitivities (T2-weighted imaging and MR spectroscopic imaging) for lesions of 0.5 cm3 or larger were calculated., Results: For T2-weighted imaging, areas under the receiver operating characteristic curves for sextant-level detection were 0.77 (reader 1) and 0.82 (reader 2). For lesions of ≥0.5 cm3 and, 1

Objectives: To develop and assess a new nomogram incorporating pre-biopsy clinical data to predict significant prostate cancer in Japanese men with a serum prostate-specific antigen (PSA) level of less than 10 ng/mL., Methods: We collected pre-biopsy data from 620 men with a serum total PSA of less than 10 ng/mL. They included 491 men with a negative biopsy and 129 men who were confirmed to have histological prostate cancer and subsequently underwent radical prostatectomy. Clinically significant tumors were defined as those with a tumor volume larger than 0.5 mL and/or a Gleason score of 7 or more., Results: One hundred and seven prostatectomy patients had clinically significant cancers. Stepwise multivariate logistic regression analysis showed that digital rectal examination findings, PSA adjusted for transition zone volume and free-to-total PSA ratio were the significant independent predictors of significant cancers (P < 0.0001). Using these pre-biopsy independent factors, a nomogram was developed to predict significant cancers. According to a receiver operating characteristics analysis, the nomogram showed an area under the curve of 0.831., Conclusion: This represents the first nomogram to predict the probability of clinically significant cancers before biopsy. This tool is most likely to be useful in the management of patients with moderate to elevated PSA.

Objectives: To evaluate the relationship between serum interleukin (IL)-6 and cachexia in patients with prostate cancer., Methods: Serum levels of IL-6, total protein, albumin, total cholesterol, and hemoglobin concentration were determined in 164 blood samples from patients with prostate cancer. The body mass index and performance status were also determined., Results: The serum total protein, albumin, and cholesterol levels, hemoglobin levels, and body mass index of the patients whose serum IL-6 level was 7 pg/mL or greater were significantly lower (P <0.05) than the corresponding values in patients with a serum IL-6 level of less than 7 pg/mL. The serum IL-6 level of patients with a serum albumin level of less than 3.5 g/dL, serum total protein level of less than 7.0 g/dL, serum total cholesterol level of less than 180 mg/dL, hemoglobin level of less than 11.0 g/dL, and body mass index of less than 21 kg/m2 were significantly greater (P <0.05) than the values in their respective counterparts. A significant correlation was found between the elevation of serum IL-6 and performance status (P <0.05). The mortality rate of patients with greater serum IL-6 levels was significantly greater than that of those with lower serum IL-6 levels in patients with untreated disease, patients in remission, and patients with relapse (all P <0.05)., Conclusions: These findings suggest that IL-6 may be one of the factors contributing to the complex syndrome of cachexia in patients with prostate cancer (all P <0.05).

Objectives: To evaluate the association of signal transducer and activator of transcription 3 (STAT3) with the invasiveness and aggressiveness of localized prostate cancer., Methods: Paraffin-embedded specimens from 92 patients with clinically localized prostate cancer who underwent radical prostatectomy without neoadjuvant treatment were analyzed by immunohistochemistry using two antibodies: anti-phospho-specific STAT3 (p-STAT3) antibody, which recognized only activated STAT3, and anti-total STAT3 antibody, which recognized both activated and inactivated STAT3. The patients were separated into one of four groups according to the percentage of the cells with positive nuclear staining using a 0 to 3+ scoring system. The associations between the immunostaining and invasiveness and aggressiveness of clinically localized prostate cancer were analyzed., Results: Pathologically, 66 patients (71.7%) had organ-confined disease. Of the 92 tumors examined, 8, 20, 23, and 41 showed staining patterns for p-STAT3 of 0, 1+, 2+, and 3+, respectively. In addition, 0, 3, 2, and 87 tumors showed staining patterns for STAT3 of 0, 1+, 2+, and 3+, respectively. The staining patterns for p-STAT3 correlated significantly with pathologic stage, Gleason score, and extracapsular extension. No significant correlation was found between p-STAT3 immunostaining and microvascular invasion, perineural invasion, or seminal vesicle invasion. Patients with 3+ immunostaining of p-STAT3 had a significantly greater biochemical prostate-specific antigen failure rate than those with 2+ or less immunostaining., Conclusions: Increased p-STAT3 immunoreactivity showed a highly invasive and aggressive potential in patients with localized prostate cancer treated with radical prostatectomy. This suggests that STAT3 signaling contributes to the invasiveness and aggressiveness of prostate cancer.

Purpose: To investigate the association between serum interleukin-6 (IL-6) and cachexia in patients with prostate cancer and the inhibitory effect of a new nuclear factor kappaB (NF-kappaB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on IL-6 production and cachexia in an animal model of hormone-refractory prostate cancer., Experimental Design: The association between serum IL-6 levels and variables of cachexia was evaluated in 98 patients with prostate cancer. The inhibitory effects of DHMEQ on IL-6 secretion and cachexia were investigated in in vitro and in vivo studies using JCA-1 cells derived from human prostate cancer., Results: Serum IL-6 levels were significantly elevated and cachexia developed in JCA-1 tumor-bearing mice as well as in prostate cancer patients with progressive disease. IL-6 secretion was significantly inhibited in JCA-1 cells exposed to DHMEQ. Intraperitoneal administration of DHMEQ (8 mg/kg) to tumor-bearing mice produced a significant amelioration of the reduction in body weight, epididymal fat weight, gastrocnemius muscle weight, hematocrit, and serum levels of triglyceride and albumin when compared with administration of DMSO or no treatment. DHMEQ caused a significant decrease of serum IL-6 level in JCA-1 tumor-bearing mice (all P < 0.05)., Conclusions: These results suggested an association between serum IL-6 and cachexia in patients with prostate cancer and in JCA-1 tumor-bearing mice and that a new NF-kappaB inhibitor, DHMEQ, could prevent the development of cachexia in JCA-1 tumor-bearing mice presumably through the inhibition of IL-6 secretion. DHMEQ seems to show promise as a novel and unique anticachectic agent in hormone-refractory prostate cancer.

Purpose: The indications for repeat prostate biopsy for persistently increased prostate specific antigen (PSA) in men with prostate cancer never detected on previous biopsy are not clear. In this study we determined that PSA adjusted for transition zone (TZ) epithelial volume is the most powerful predictor for detecting prostate cancer on repeat biopsy., Materials and Methods: Repeat prostate biopsies including additional TZ cores were performed in 75 men with PSA between 4.0 and 10.0 ng/ml. TZ epithelial volume was calculated by multiplying TZ volume by the percent of epithelium, which was measured by morphometric analysis using image analysis computer software., Results: Prostate cancer was detected on repeat biopsy in 19 of the 75 patients. Patients with prostate cancer had a significant smaller percent area of epithelium or glandular lumen than those without cancer. In patients without prostate cancer TZ epithelial volume significantly correlated with total PSA. According to ROC analysis PSA adjusted for TZ epithelial volume had the greatest AUC for cancer detection (0.879). This parameter was able to avoid more than 90% of unnecessary repeat biopsies with 90% sensitivity. Multiple logistic regression analysis showed that PSA complex adjusted for TZ epithelial volume was the significant independent predictor of cancer., Conclusions: PSA adjusted for TZ epithelial volume is the most powerful predictor of cancer in men who have undergone previous negative prostate biopsies and in whom PSA remains between 4.0 and 10.0 ng/ml.