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Background: For prostate cancer, accurate prediction of the pathological stage before surgery is very important. Therefore, the aim of the present study was establishing the prostate-specific antigen (PSA) threshold nomogram to predict pathologically advanced prostate cancer using the novel method of area under the receiver operating characteristic curve boosting (AUCBoost)., Methods: The medical records of patients with clinically localized prostate cancer who underwent robot-assisted radical prostatectomy were retrospectively reviewed. Multivariate logistic regression analysis was performed to identify clinical covariates significantly associated with pathological tumor stage ≥3a. The best combination of the variables was determined by validated values of the area under the curve (AUC). The optimal individualized PSA threshold values were developed using AUCBoost., Results: In the multivariate logistic regression analysis, PSA, prostate volume, clinical tumor stage, Gleason Grade Group, the number of positive cores, and the percentage of positive cores were independent predictive factors for pathological tumor stage ≥3a. A combination model comprising PSA, prostate volume, clinical tumor stage, percent positive core, and Gleason Grade Group produced the highest AUC for predicting pathological tumor stage ≥3a (AUC = 0.777). The PSA threshold values for detecting pathological tumor stage ≥3a were calculated and a table of individualized PSA threshold nomogram was developed using AUCBoost., Conclusions: We developed a nomogram of the PSA threshold values for predicting adverse pathological tumor stages of prostate cancer using a novel statistical method. Further validation is necessary; however, the individualized PSA threshold nomogram may be useful in determining treatment strategies before surgery., Competing Interests: Conflicts of interest and Financial disclosures The authors have no conflicts of interest directly relevant to the content of this article. The corresponding author (T.H.) was supported by JSPS KAKENHI Grant Number 18K09209. The second author (O.K.) was supported by JSPS KAKENHI Grant Number 18K11190., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: To determine prognostic factors associated with progression to castration-resistant prostate cancer following biochemical recurrence which is lethal prostate cancer and establish a risk stratification model of progression to castration-resistant prostate cancer., Methods: We retrospectively reviewed the data of 550 patients who experienced biochemical recurrence after radical prostatectomy. The endpoint of the present study was progression to castration-resistant prostate cancer. The actuarial probabilities of progression to castration-resistant prostate cancer-free survival were determined using Kaplan-Meier analysis. Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent predictors of biochemical recurrence., Results: Fifty-two patients experienced progression to castration-resistant prostate cancer during the follow-up period. The progression to castration-resistant prostate cancer-free survival rate after biochemical recurrence at 10 years was 76.8%. In multivariate analysis, pathological Gleason score ≥ 9, lymphovascular invasion, and prostate-specific antigen velocity ≥ 0.4 ng/mL/year were independent predictive factors for progression to castration-resistant prostate cancer. The patients were stratified into three groups using a risk stratification model incorporating these variables. The 10-year progression to castration-resistant prostate cancer-free survival rates were 96.7% in the low-risk group, 84.7% in the intermediate-risk group, and 24.5% in the high-risk group., Conclusions: The present results suggest that the pathological Gleason score, lymphovascular invasion, and prostate-specific antigen velocity were independent predictive factors for progression to castration-resistant prostate cancer. The risk stratification model established in the present study could be useful for patient counseling and in identifying patients with a poor prognosis.

Background: The development process of recurrence in prostate cancer patients with pathologically organ-confined (pT2) disease and negative surgical margins is unclear. The aim of the present study was to determine factors associated with the development of biochemical recurrence following robot-assisted radical prostatectomy among those prostate cancer patients., Methods: We retrospectively reviewed the data of patients who underwent robot-assisted radical prostatectomy without neoadjuvant endocrine therapy. We evaluated prognostic factors in 1096 prostate cancer patients with pT2 disease and negative surgical margins. Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent predictors for biochemical recurrence., Results: Of the 1096 patients, 55 experienced biochemical recurrence during the follow-up period. The 5-year biochemical recurrence-free survival rate for patients with pT2 and negative surgical margins was 91.8%. On univariate analysis, clinical stage, biopsy Gleason score, percent of positive core, pathological Gleason score, and the presence of micro-lymphatic invasion were significantly associated with biochemical recurrence. On a multivariate analysis, the presence of micro-lymphatic invasion and a pathological Gleason score ≥ 4 + 3 were significant prognostic factors for biochemical recurrence. Based on these factors, we developed a risk stratification model. The biochemical recurrence-free survival rate differed significantly among the risk groups., Conclusions: The prognosis of prostate cancer patients with pT2 disease and negative surgical margins is favorable. However, patients with the presence of micro-lymphatic invasion and a pathological Gleason score ≥ 4 + 3 tend to experience biochemical recurrence more often after surgery. Therefore, careful follow-up might be necessary for those patients.

Purpose: The endocrine therapy is effective for patients with advanced prostate cancer, but the disease eventually becomes refractory to treatment. The aim of this study was to investigate prognostic factors and to develop a risk stratification model for survival in patients with advanced prostate cancer undergoing endocrine therapy., Materials and Methods: This study included 197 patients with stage IV prostate cancer who were treated with endocrine therapy as primary treatment at Tokyo Medical University, Tokyo, Japan, between January 1999 and November 2012. Prognostic values including baseline clinical laboratory values before endocrine therapy for stage IV prostate cancer were examined. Patients (n = 30) who were not followed or for whom data were unavailable or who were treated with radiotherapy were excluded from the study. Excluding these patients, we retrospectively analyzed 167 patients who were treated with endocrine therapy as the primary treatment. Disease-specific survival (DSS) was evaluated using the Kaplan-Meier method, and prognostic factors were identified using the Cox proportional hazard model analysis., Results: In univariate analyses, patients with a performance status (PS) ? 2, platelet count ? 3.0× 105 µ/L, prostate specific antigen (PSA) > 50 ng/mL, alkaline phosphatase (ALP) > 350 U/L, lactate dehydrogenase (LDH) > 240 IU/L, and Gleason score (GS) ? 8, hemoglobin (Hb) < 12 g/dL, extent of disease (EOD) ? 3 and poorly differentiated adenocarcinoma showed significantly lower DSS than their respective counterparts. Neutrophil-to-Lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and white blood cell (WBC) count were not significantly associated with DSS. In a multivariate Cox proportional hazard model, PS and platelet count were independent prognostic factors. Based on the hazard rate (HR) calculated by the following formula: HR = exp (0.82 × PS + 1.38 × platelet count) patients were stratified into 3 risk groups. The differences in DSS rates among the 3 groups were statistically significant., Conclusion: These results suggest that PS and platelet count are independent prognostic factors and that a combination of these factors can be used to stratify metastatic prostate cancer patients treated with endocrine therapy according to their DSS risk.

Purpose: To investigate the impact of the time interval (TI) between prostate biopsy and robot-assisted radical prostatectomy (RARP) on the risk of biochemical recurrence (BCR)., Methods: We retrospectively reviewed the medical records of 793 consecutive patients who were treated with RARP at our institution. Patients were divided into three groups, according to TI, to compare BCR-free survival (BCRFS) rates: Group 1 (n = 196), TI < 3 months; Group 2 (n = 513), 3 ≤ TI < 6 months; Group 3 (n = 84), TI ≥ 6 months. Eighty-three patients with TI ≥ 6 months were matched with an equal number of patients with TI < 6 months based on propensity scores by using four preoperative factors: prostate-specific antigen (PSA), primary (pGS) and secondary (sGS) Gleason score and positive prostate biopsy., Results: The 5-year BCRFS rates for TI Groups 1, 2, and 3 were 76%, 80.7% and 82.6% (P = 0.99), respectively. The multivariate analysis revealed that PSA, pGS, sGS and a positive prostate biopsy were independent preoperative risk factors for BCR. The propensity adjusted 5-year BCRFS for patients with TI ≥ 6 months was 84.0%. This was not worse than that of patients with TI < 6 months (71.0%, P = 0.18)., Conclusions: In our cohorts, a delay in the time from biopsy to RARP did not significantly affect recurrence. Therefore, hasty treatment decisions are unnecessary for at least 6 months after diagnosis of early prostate cancer., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: To assess the impact of preoperatively estimated prostate volume (PV) using transrectal ultrasonography (TRUS) on surgical and oncological outcomes in robot-assisted radical prostatectomy (RARP)., Methods: We analyzed the experience of a single surgeon at our hospital who performed 436 RARPs without neoadjuvant hormone therapy between August 2006 and December 2013. Patients were divided into three groups according to their preoperative PV calculated using TRUS (PV ≤ 20 cm(3): group 1, n = 61; 20 < PV < 50 cm(3): group 2, n = 303; PV ≥ 50 cm(3): group 3, n = 72)., Results: Blood loss was significantly higher in group 3 than in group 1 and group 2. In stage pT2 patients, the rate of positive surgical margin (PSM) was significantly lower in group 3 than in group 1. In addition, perioperative complications significantly increased with increasing PV, while the extraprostatic extension (EPE) rate significantly decreased with increasing PV. The preoperative biopsy Gleason score, prostate-specific antigen (PSA) density, and clinical T2 stage were inversely correlated with increasing PV. Biochemical recurrence-free survival after RARP was significantly lower in group 1 than in groups 2 and 3., Conclusions: A large prostate size was significantly associated with increased blood loss and a higher rate of perioperative complications. A small prostate size was associated with a higher PSM rate, PSA density, Gleason score, EPE rate, and biochemical recurrence rate. These results suggest that RARP was technically challenging in patients with large prostates, whereas small prostates were associated with unfavorable oncological outcomes.

Background: To identify preoperative predictive factors for biochemical recurrence (BCR) and to further stratify its risk in high-risk localized prostate cancer patients receiving radical prostatectomy (RP)., Methods: Subjects included 195 high-risk prostate cancer patients undergoing RP from 2000 to 2012. RP consisted of retropubic radical prostatectomy and robot-assisted radical prostatectomy, involving 84 cases and 111 cases, respectively. BCR was defined as a prostate serum antigen (PSA) level ≥0.2 ng/mL. BCR-free survival (BCRFS) was calculated using the Kaplan-Meier method. Preoperative predictors of BCR were assessed with Cox's proportional hazard regression analysis., Results: Eighty-nine patients (45.6 %) experienced recurrence. BCRFS rates 3 and 5 years after RP were 58 and 50 %, respectively. Prostate volume, transition zone volume, and Gleason score were not significantly associated with BCR. Patients with higher preoperative PSA, PSA density (PSAD), PSA density of the transition zone, percentage of positive cores (PPC), and PPC from the dominant side showed significantly lower BCRFS. The PPC from the dominant side and PSAD were significant independent prognostic factors for BCR. Using these variables, the hazard ratio of BCR could be calculated and patients stratified into three risk groups. The 5-year BCRFS rates for Groups 1, 2, and 3 were 64.9 %, 48.1 %, and 21.3 %, respectively., Conclusions: Patients with high-risk localized prostate cancer as currently defined do not have uniformly poor prognosis after RP. PPC from the dominant side and PSAD are significant predictors of BCR. These factors can identify high-risk patients with very poor prognosis.

Objectives: The aim of this study was to investigate the effect of positive surgical margin (PSM) without extraprostatic extension after robot-assisted radical prostatectomy (RARP)., Materials and Methods: We retrospectively reviewed 837 patients who underwent RARP for clinically localized prostate cancer without neoadjuvant endocrine therapy. The pT2+category lesions were defined according to World Health Organization classification. The actuarial probabilities of biochemical recurrence-free survival (BCR-FS) were determined using Kaplan-Meier analysis. Univariate and multivariate Cox proportional hazards regression analyses were also used to identify independent predictors for BCR., Results: Of the 837 patients, 102 (12.2%) experienced BCR during the follow-up period. The BCR-FS rate was significantly higher in patients with pT2+category tumors than in those with pT3a category tumors, and significantly lower in patients with pT2+category tumors than that in those with pT2 category tumors without PSM. The BCR-FS rate of patients with pT2+category tumors was significantly higher than that with pT3a category tumors with PSM but not significantly different from that with pT3a category tumors without PSM. In a multivariate analysis, the pathological T category considering pT2+category was one of independent predictive factors for BCR., Conclusions: This study support the hypothesis that the pT2+category disease is associated with a significantly increased risk of BCR in patients with organ-confined prostate cancer after RARP. As PSM can be avoided in some cases, urologists should continually seek to improve their operative skills and to reduce the rate of PSM, especially in patients with organ-confined prostate cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To examine biochemical recurrence after robot-assisted radical prostatectomy in Japanese patients, and to develop a risk stratification model for biochemical recurrence., Methods: The study cohort consisted of 784 patients with localized prostate cancer who underwent robot-assisted radical prostatectomy without neoadjuvant or adjuvant endocrine therapy. The relationships of biochemical recurrence with perioperative findings were evaluated. The prognostic factors for biochemical recurrence-free survival were evaluated using Cox proportional hazard model analyses., Results: During the follow-up period, 80 patients showed biochemical recurrence. The biochemical recurrence-free survival rates at 1, 3, and 5 years were 92.2%, 85.2% and 80.1%, respectively. In univariate analysis, the prostate-specific antigen level, prostate-specific antigen density, biopsy Gleason score, percent positive core, pathological T stage, pathological Gleason score, lymphovascular invasion, perineural invasion and positive surgical margin were significantly associated with biochemical recurrence. In multivariate analysis, prostate-specific antigen density ≥0.4 (P = 0.0011), pathological T stage ≥3a (P = 0.002), pathological Gleason score ≥8 (P = 0.007) and positive surgical margin (P < 0.0001) were independent predictors of biochemical recurrence. The patients were stratified into three risk groups according to these factors. The 5-year biochemical recurrence-free survival rate was 89.4% in the low-risk group, 65.6% in the intermediate-risk group and 30.3% in the high-risk group., Conclusions: The prostate-specific antigen density, pathological T stage, pathological Gleason score and positive surgical margin were independent prognostic factors for biochemical recurrence. The risk stratification model developed using these four factors could help clinicians identify patients with a poor prognosis who might be good candidates for clinical trials of alternative management strategies., (© 2014 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.)

Purpose: We investigated oncological outcomes in Japanese patients who underwent robot-assisted radical prostatectomy (RARP)., Materials and Methods: This study included 389 patients who underwent RARP at a single institution with a follow-up period of at least 1 year. Preoperative findings were compared with biochemical recurrence (BCR). Predictors of BCR-free survival (BCRFS) were evaluated by univariate and multivariate Cox proportional hazard model analyses, and a risk stratification model based on the relative risks of BCR was established., Results: Fifty incidences of BCR were noted during a median follow-up period of 28.7 months (range, 12.1-80.0 months). The BCRFS rate for the entire cohort at the median follow-up time was 85.9 %; the 1-, 3-, and 5-year estimates were 91.0, 85.1, and 81.1 %, respectively. From univariate analyses, prostate-specific antigen (PSA), PSA density, biopsy Gleason score, and percent positive core were significantly associated with BCR. Multivariate analysis showed that PSA [hazard ratio (HR), 2.75; p = 0.001], percent positive core (HR, 2.22; p = 0.001), and biopsy Gleason score (HR, 2.61; p = 0.007) were independent predictors of BCR., Conclusion: This study at a single Japanese center demonstrates that RARP provides a satisfactory BCRFS rate. This report provides a framework with which to estimate oncological outcomes in patients who underwent RARP for localized prostate cancer. Our results support the increased use of RARP for the treatment of localized prostate cancer in Japan.

The present study was undertaken to examine biochemical progression in patients who received salvage hormonal therapy (HT) for biochemical disease recurrence (BCR) after radical prostatectomy (RP), and to determine the optimal timing for the administration of HT. The study population consisted of 156 patients who underwent RP and received salvage HT for BCR. The starting point of this study was the timing of RP, and the endpoint was biochemical prostate-specific antigen (PSA) progression (castration-resistance) after HT. The mean follow-up period after surgery was 8.1 years. First, we excluded 18 patients with persistent PSA (≥ 0.2 ng/mL) after RP from an analysis below because their prognoses were significantly poorer compared with 138 patients whose PSA nadirs had reached <0.2 ng/mL. Multivariate analysis demonstrated that Gleason score ≥ 8 (p = 0.010, hazard ratio (HR) 3.02), and PSA doubling time (PSA-DT) <6 months (p = 0.001, HR 7.39) was independently associated with subsequent biochemical progression after HT. Using these two variables (Gleason score and PSA-DT), we could stratify patients into three risk groups for BCR after salvage HT. Regarding the optimal timing for HT administration for these high-risk patients with both risk factors (relative risk = 22.3), the PSA cutpoint of 1.0 ng/mL at the initiation of HT showed a significant difference in progression-free survival rates (p = 0.023). The findings indicated that for high-risk patients, salvage HT for BCR after PSA nadir (<0.2 ng/mL) should be started before the PSA level exceeds 1.0 ng/mL; otherwise, there is a significant risk of subsequent biochemical progression after HT.

Objective: To develop a nomogram based on postoperative factors and prostate-specific antigen levels to predict the non-biochemical recurrence rate after radical prostatectomy ina Japanese cohort., Methods: A total of 606 Japanese patients with T1-3N0M0 prostate cancer who underwent radical prostatectomy and pelvic lymph node dissection at Tokyo Medical University hospital from 2000 to 2010 were studied. A nomogram was constructed based on Cox hazard regression analysis evaluating the prognostic significance of serum prostate-specific antigen and pathological factors in the radical prostatectomy specimens. The discriminating ability of the nomogram was assessed by the concordance index (C-index), and the predicted and actual outcomes were compared with a bootstrapped calibration plot., Results: With a mean follow up of 60.0 months, a total of 187 patients (30.9%) experienced biochemical recurrence, with a 5-year non-biochemical recurrence rate of 72.3%. Based on a Cox hazard regression model, a nomogram was constructed to predict non-biochemical recurrence using serum prostate-specific antigen level and pathological features in radical prostatectomy specimens. The concordance index was 0.77, and the calibration plots appeared to be accurate., Conclusions: The postoperative nomogram described here can provide valuable information regarding the need for adjuvant/salvage radiation or hormonal therapy in patients after radical prostatectomy.

Purpose: We aimed to determine which of the following magnetic resonance (MR) imaging sequences is most effective for detecting prostate cancer: T2-weighted (T2W), dynamic contrast-enhanced (DCE) T1-weighted (T1W), or diffusion-weighted (DWI) imaging or apparent diffusion coefficient (ADC) mapping., Materials and Methods: We included 37 male patients with prostate cancer who underwent MR imaging before radical prostatectomy in this retrospective study. Sixty-four foci (>5 mm in size; 35 in the peripheral zone [PZ], 29 in the transitional zone [TZ]) were histopathologically determined to be prostate cancer. We determined the capacity of T2W, DCE-T1W, DWI, ADC mapping alone, and the combination of ADC mapping with DWI, and conventional MR sequences to detect prostate cancer, including their sensitivity and positive predictive value (PPV), with reference to the results obtained in histopathological examinations of whole-mount sections., Results: In the PZ, sensitivities were 31.4% (T2W), 37.1% (DCE-T1W), 51.4% (DWI), and 71.4% (ADC mapping); PPVs were 78.6% (T2W), 92.9% (DCE-T1W), 94.7% (DWI), and 96.0% (ADC mapping). Sensitivity was significantly higher of ADC mapping than other sequences. In the TZ, sensitivities were 55.1% (T2W), 44.8% (DCE-T1W), 82.8% (DWI), and 89.7% (ADC mapping); PPVs were 64.0% (T2W), 46.4% (DCE-T1W), 70.6% (DWI), and 72.2% (ADC mapping). Sensitivity was significantly higher of ADC mapping and DWI than conventional MR imaging, but there was no significant correlation between DWI/ADC mapping and T2W/DCE-T1W with respect to PPVs. Combining sequences did not improve sensitivity; only the PPV in the TZ improved when ADC mapping was combined with DCE-T1W., Conclusion: ADC mapping is the most effective standard MR imaging tool for detecting prostate cancer. The addition of DCE-T1W may improve the PPV of ADC mapping for diagnosing cancer in the TZ.

Objective: Positive surgical margin after radical prostatectomy has been shown to be an independent predictive factor for biochemical and local recurrence in patients with prostate cancer. The present study was undertaken to identify predictive factors for positive surgical margin after robot-assisted radical prostatectomy in Japanese patients., Methods: Between August 2006 and September 2011, a cohort of 244 men underwent robot-assisted radical prostatectomy carried out by a single surgeon. Univariate and multivariate logistic regression analyses were carried out to identify clinical covariates significantly associated with an increased positive surgical margin. The preoperative variables included age, body mass index, prostate-specific antigen level, prostate-specific antigen density, clinical T stage, prostate volume, surgeon volume, number of positive cores and percentage of positive cores., Results: In the univariate analyses, serum prostate-specific antigen level, prostate-specific antigen density and surgeon volume were significantly associated with positive surgical margin. In the multivariate analysis, prostate-specific antigen density (hazard ratio 3.13, 95% confidence interval 1.57-6.24; P = 0.001) and surgeon volume (hazard ratio 2.15, 95% confidence interval 1.06-4.35; P = 0.034) were independent predictive factors for positive surgical margin. Using these two independent factors, we divided the patients into four groups and calculated the predictive probability of positive surgical margin. The predictive probability for positive surgical margin in each group was well correlated with the rates at 10.8% and 10.2%, 19.8% and 20.0%, 26.4% and 26.4%, an 43.5% and 43.3%, respectively., Conclusion: Prostate-specific antigen density and surgeon volume are independent predictors of positive surgical margin after robot-assisted radical prostatectomy. A combination of these two factors can provide useful information about positive surgical margins., (© 2013 The Japanese Urological Association.)

Objectives: To investigate the clinical implication of legumain, an asparaginyl endopeptidase that is highly expressed in several types of cancer, expression in prostate cancer., Methods: Legumain expression in prostate cancer cell lines was determined by real-time reverse transcriptase PCR and Western blot. Furthermore, legumain expression in 88 prostatectomy specimens was evaluated by immunohistochemistry. The association between legumain expression and clinicopathological factors was analyzed., Results: Legumain expression was confirmed at the mRNA and protein levels in all the cells. Although all the cancer tissues were positive for legumain, 2 staining patterns were observed in the cytoplasm: diffuse cytoplasmic and vesicular positivity. The rates of Gleason score ≥8, extracapsular extension, and perineural invasion in the group with vesicular staining were significantly higher than those in the diffuse cytoplasmic group (p < 0.05). The maximum size of the tumor with vesicular staining was significantly greater than that of the tumor with diffuse cytoplasmic staining (p = 0.0302). The 5-year biochemical recurrence-free rate in the patients with vesicular legumain staining was 53.2%; this rate was significantly lower than that (78.8%) in the patients with diffuse cytoplasmic staining (p = 0.0269)., Conclusions: Tumors that showed a vesicular staining pattern of legumain had the potential of being highly invasive and aggressive in patients with prostate cancer who were treated with radical prostatectomy. This suggests that legumain might contribute to the invasiveness and aggressiveness of prostate cancer.

Purpose: Few studies have evaluated changes in erectile function with time before and after prostate brachytherapy using the International Index of Erectile Function-15, a sensitive, validated tool for assessing male sexual dysfunction. In this prospective study we evaluated the natural history of erectile function after prostate brachytherapy without supplemental therapy (external beam radiotherapy, phosphodiesterase-5 inhibitors or androgen deprivation therapy) using the International Index of Erectile Function-15., Materials and Methods: We identified 119 patients who were followed at least 12 months after prostate brachytherapy between 2004 and 2010. Sexual and erectile function status were assessed before brachytherapy (baseline), and 3, 6, 12, 18, 24 and 36 months postoperatively using the International Index of Erectile Function-15., Results: Mean total International Index of Erectile Function-15 score, and scores on the erectile function, orgasmic function, sexual desire and intercourse satisfaction domains 3 months after brachytherapy were significantly lower than at baseline (p <0.05). They remained lower until 36 months after prostate brachytherapy. Erectile function was maintained 12 months after brachytherapy in 16 of the 48 men (33.3%) with a baseline erectile function domain score of 11 or greater. There was no significant difference in clinical features except the age of patients who maintained the erectile function domain score and their counterparts 12 months after brachytherapy. Multivariate analysis revealed that age 70 years or greater was the only predictive factor for deteriorating erectile function after brachytherapy (p = 0.035)., Conclusions: Findings indicate a global decrease in all domains of the International Index of Erectile Function-15 score 12 months after prostate brachytherapy. Also, patient age may influence the preservation of brachytherapy related potency., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To report a rare case of seed migration to a left varicocele after transperineal interstitial prostate brachytherapy with loose iodine-125 ((125)I) seeds., Methods and Materials: A 73-year-old man presented with a serum prostate-specific antigen level of 5.21 ng/mL, Gleason score of 7 (3+4), and clinical T1c adenocarcinoma of the prostate. The patient underwent transperineal interstitial prostate brachytherapy with loose (125)I seeds followed by external beam radiation therapy. Two weeks after seed implantation, a followup pelvic radiograph was obtained. One month after seed implantation, a pelvic computed tomography scan for postimplant dosimetric analysis was carried out. Subsequent ultrasound examination of the scrotum was undertaken., Results: Two weeks after seed implantation, an anteroposterior pelvic radiograph showed that a migrated seed was overlapped by the scrotum. Postimplant pelvic computed tomography revealed that a seed had migrated to the left side of the scrotum. Subsequent ultrasound examination of the scrotum revealed that the patient had a left varicocele to which the seed had migrated. The patient had no symptoms related to the migrated seed., Conclusions: This is the first report of seed migration to a left varicocele after transperineal interstitial prostate brachytherapy with loose (125)I seeds. For the present case, we suggest that the seed moved from the prostate to the left varicocele through the pelvic veins, bypassing the systemic circulation., (Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

We investigated the usefulness of the fusion image created by transrectal ultrasonography (TRUS) and large-bore computed tomography (CT) for predicting pubic arch interference (PAI) during prostate seed brachytherapy. The TRUS volume study was performed in 21 patients, followed by large-bore computed tomography of patients in the lithotomy position. Then, we created TRUS-CT fusion images using a radiation planning treatment system. TRUS images in which the prostate outline was the largest were overlaid on CT images with the narrowest pubic arch. PAI was estimated in the right and left arch separately and classified to three grades: no PAI, PAI positive within 5 mm and PAI of >5 mm. If the estimated PAI was more than 5 mm on at least one side of the arch, we judged there to be a significant PAI. Brachytherapy was performed in 18 patients who were evaluated as not having significant PAI on TRUS. Intra-operative PAI was observed in one case, which was also detected with a fusion image. On the other hand, intra-operative PAI was not observed in one case that had been evaluated as having significant PAI with a fusion image. In the remaining three patients, TRUS suggested the presence of significant PAI, which was also confirmed by a fusion image. Intra-operative PAI could be predicted by TRUS-CT fusion imaging, even when it was undetectable by TRUS. Although improvement of the reproducibility of the patients' position to avoid false-positive cases is warranted, TRUS-CT fusion imaging has the possibility that the uncertainty of TRUS can be supplemented.

Background: Inducible activation of nuclear factor (NF)-κB is one of the principal mechanisms through which resistant prostate cancer cells are protected from radiotherapy. We hypothesised that inactivation of inducible NF-κB with a novel NF-κB inhibitor, DHMEQ, would increase the therapeutic effects of radiotherapy., Methods: PC-3 and LNCaP cells were exposed to irradiation and/or DHMEQ. Cell viability, cell cycle analysis, western blotting assay, and NF-κB activity were measured. The antitumour effect of irradiation combined with DHMEQ in vivo was also assessed., Results: The combination of DHMEQ with irradiation resulted in cell growth inhibition and G2/M arrest relative to treatment with irradiation alone. Inducible NF-κB activity by irradiation was inhibited by DHMEQ treatment. The expression of p53 and p21 in LNCaP, and of 14-3-3σ in PC-3 cells, was increased in the combination treatment. In the in vivo study, 64 days after the start of treatment, tumour size was 85.1%, 77.1%, and 64.7% smaller in the combination treatment group than that of the untreated control, DHMEQ-treated alone, and irradiation alone groups, respectively., Conclusion: Blockade of NF-κB activity induced by radiation with DHMEQ could overcome radio-resistant responses and may become a new therapeutic modality for treating prostate cancer.

The dose received by 90% of the prostate volume (D90) is the key parameter of dosimetric analysis in prostate brachytherapy. The aim of this analysis was to identify preimplant factors affecting prostate D90 after transperineal interstitial prostate brachytherapy with loose (125)I seeds. We reviewed the records of 210 patients who underwent transperineal interstitial prostate brachytherapy with loose (125)I seeds for clinical T1/T2 prostate cancer at our institution. Patients who received supplemental external-beam radiation therapy were excluded. One hundred and nine patients (51.9%) received neoadjuvant hormonal therapy (NHT). One month after seed implantation, postimplant computed tomography and dosimetric analysis were performed. Univariate and multivariate analyses were carried out to identify preimplant factors affecting postimplant prostate D90. The postimplant prostate D90 values ranged from 123.3 to 234.1 Gy (mean ± standard error, 177.1 ± 1.4 Gy). Postimplant prostate D90 differed significantly between patients who had and had not undergone NHT (P = 0.001). In addition, simple regression analyses showed positive correlations with the estimated preimplant prostate D90, preimplant prostate volume by transrectal ultrasound (TRUS), total radioactivity, number of needles, and number of seeds. On stepwise multiple regression analysis, postimplant prostate D90 showed significant negative correlations with NHT and preimplant prostate volume by TRUS, and a significant positive correlation with total radioactivity. In conclusion, NHT, preimplant prostate volume by TRUS, and total radioactivity are significant preimplant factors affecting postimplant prostate D90 in prostate cancer patients treated with transperineal interstitial prostate brachytherapy with loose (125)I seeds.

Background: The aim was to determine the incidence of seed migration not only to the chest, but also to the abdomen and pelvis after transperineal interstitial prostate brachytherapy with loose (125)I seeds., Methods: We reviewed the records of 267 patients who underwent prostate brachytherapy with loose (125)I seeds. After seed implantation, orthogonal chest radiographs, an abdominal radiograph, and a pelvic radiograph were undertaken routinely to document the occurrence and sites of seed migration. The incidence of seed migration to the chest, abdomen, and pelvis was calculated. All patients who had seed migration to the abdomen and pelvis subsequently underwent a computed tomography scan to identify the exact location of the migrated seeds. Postimplant dosimetric analysis was undertaken, and dosimetric results were compared between patients with and without seed migration., Results: A total of 19,236 seeds were implanted in 267 patients. Overall, 91 of 19,236 (0.47%) seeds migrated in 66 of 267 (24.7%) patients. Sixty-nine (0.36%) seeds migrated to the chest in 54 (20.2%) patients. Seven (0.036%) seeds migrated to the abdomen in six (2.2%) patients. Fifteen (0.078%) seeds migrated to the pelvis in 15 (5.6%) patients. Seed migration occurred predominantly within two weeks after seed implantation. None of the 66 patients had symptoms related to the migrated seeds. Postimplant prostate D90 was not significantly different between patients with and without seed migration., Conclusion: We showed the incidence of seed migration to the chest, abdomen and pelvis. Seed migration did not have a significant effect on postimplant prostate D90.

Objective: We prospectively evaluated the effect of external beam radiotherapy on erectile function in patients with localized or locally advanced prostate cancer using the Japanese version of the International Index of Erectile Function (IIEF) survey., Patients and Methods: From 2000 to 2007, we identified 55 patients who underwent external beam radiotherapy at our institution for localized or locally advanced prostate cancer and could respond to the IIEF survey. The patients did not receive neo- and/or adjuvant hormone therapy and they were followed-up for at least 12 months after radiotherapy. Mean patient age was 69 years and the mean PSA level before radiotherapy was 24.9 ng/ml., Results: First we evaluated the change of the erectile function domain score over time before and after radiotherapy. The population of severe erectile dysfunction (ED) increased while those with no or mild ED decreased after radiotherapy. The erectile function and intercourse satisfaction domain score of the IIEF declined significantly after radiotherapy, however, the orgasmic function, sexual desire, and overall satisfaction domain scores did not change after external beam radiation. Of the 34 patients who had erectile function at baseline, 10 patients could maintain erectile function 12 months after radiotherapy. Though there were no significant differences in clinical features between patients who could maintain erectile function and those who had worsening erectile function 12 months after radiotherapy, the sexual desire domain score before radiotherapy was significantly higher in patients who could maintain erectile function than their counterparts., Conclusion: Using the IIEF survey, external beam radiation was found to affect erectile function in patients with localized or locally advanced prostate cancer.

Background: The aim was to identify preimplant factors affecting postimplant prostate volume and the increase in prostate volume after transperineal interstitial prostate brachytherapy with 125I free seeds., Methods: We reviewed the records of 180 patients who underwent prostate brachytherapy with 125I free seeds for clinical T1/T2 prostate cancer. Eighty-one (45%) of the 180 patients underwent neoadjuvant hormonal therapy. No patient received supplemental external beam radiotherapy. Postimplant computed tomography was undertaken, and postimplant dosimetric analysis was performed. Univariate and multivariate analyses were performed to identify preimplant factors affecting postimplant prostate volume by computed tomography and the increase in prostate volume after implantation., Results: Preimplant prostate volume by transrectal ultrasound, serum prostate-specific antigen, number of needles, and number of seeds implanted were significantly correlated with postimplant prostate volume by computed tomography. The increase in prostate volume after implantation was significantly higher in patients with neoadjuvant hormonal therapy than in those without. Preimplant prostate volume by transrectal ultrasound, number of needles, and number of seeds implanted were significantly correlated with the increase in prostate volume after implantation. Stepwise multiple linear regression analysis showed that preimplant prostate volume by transrectal ultrasound and neoadjuvant hormonal therapy were significant independent factors affecting both postimplant prostate volume by computed tomography and the increase in prostate volume after implantation., Conclusions: The results of the present study show that preimplant prostate volume by transrectal ultrasound and neoadjuvant hormonal therapy are significant preimplant factors affecting both postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.

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.

The present study was undertaken to investigate the predictors in patients who received hormonal therapy (HT) for prostate-specific antigen recurrence (PSAR) after surgery. Predictors for the progression-free survival were assessed in 55 patients who received HT for PSAR after surgery. In multivariate analysis, primary Gleason grade > or =4 and PSA doubling time (PSA-DT) <6 months were independent predictors. The patients were stratified into low-risk group (Gleason grade <4 and PSA-DT > or =6), high-risk group (Gleason grade > or =4 and PSA-DT <6) and intermediate-risk group (all others). In the intermediate- and high-risk groups, progression-free survival rate was significantly higher in patients with PSA level <2 than in those with PSA level > or =2 at the initiation of HT. Primary Gleason grade > or =4 and PSA-DT <6 months are independent predictors. Patients in the intermediate- and high-risk groups may benefit from early HT for PSAR after surgery.

Objective: The objective of this study was to evaluate the efficacy and toxicity of docetaxel in combination with prednisolone in Japanese patients with hormone refractory prostate cancer., Methods: Twenty patients with hormone refractory prostate cancer (HRPC) were administered a treatment regimen consisting of docetaxel 75 mg/m(2) once every 3 or 4 weeks and prednisolone 5 mg twice daily at our institution between 2006 and 2008., Results: The patients received a median of 5.5 cycles of treatment (range, 2-12 cycles). Nine of the 20 patients (45%) had a >or=50% decrease in serum prostate-specific antigen (PSA). The median duration of response was 4 months (range, 1-11 months). The number of cycles performed, the presence of bone metastasis and the extent of disease had statistically significant associations with the response. Three patients had a transient PSA rise among the patients who ultimately had a response. Grade 3/4 leukopenia and neutropenia occurred in 80.0% and 85.0% of the patients, respectively. Interstitial pneumonia occurred in only one patient; however, the patient recovered. Finally, no treatment-related deaths were seen during the observation period., Conclusions: The combination of docetaxel 75 mg/m(2) every 3 weeks and prednisolone 10 mg daily was effective and well tolerated in Japanese patients with HRPC. The results of this study suggest that a decision concerning discontinuation of this treatment should be carefully considered because a transient PSA rise was observed. Although interstitial pneumonia was rare, the potential risk of its development should be taken into consideration.

Objectives: To evaluate the correlation between preoperatively predicted and pathologically measured prostate cancer volumes and to investigate the clinical use of preoperatively predicted cancer volume in predicting pathological stage., Methods: Correlations between pathological findings and various preoperative parameters, including the cancer volumes as predicted by using two methods (Vca and estimated PCvol), were analyzed in 196 patients who underwent radical prostatectomy for clinically localized prostate cancer., Results: Pathologically measured prostate cancer volume was significantly correlated with the Vca and estimated PCvol, but the correlation coefficients were respectively only 0.46 and 0.35. Prostate-specific antigen (PSA), PSA density (PSAD), primary Gleason score, Vca, Vca fraction (Vcafx), and estimated PCvol were significantly higher in 82 patients with extraprostatic cancer than in 114 patients with organ-confined cancer. Magnetic resonance imaging (MRI) findings were significantly correlated with pathological stage. Multivariate logistic regression analysis indicated that the Vcafx and MRI findings were significant predictors of extraprostatic cancer, but receiver operating characteristic analysis revealed that the combination of Vcafx and MRI findings had no advantage over the combination of Gleason score, PSAD, and MRI findings., Conclusions: Vca and estimated PCvol are significantly correlated with the pathologically measured cancer volume but their ability to accurately predict cancer volume is limited. Vcafx and MRI findings were statistically significant predictors of extraprostatic cancer but their combination was not superior to the combination of Gleason score, PSAD, and MRI findings.

Background: We aimed to calculate the frequency and features of the development of a prostate-specific antigen (PSA) bounce after prostate brachytherapy alone, to correlate the bounce with clinical and dosimetric factors and to identify factors that predict PSA bounce., Methods: PSA bounce was evaluated in 86 patients with T1-T2 prostate cancer who underwent radioactive seed implantation using iodine-125 (I-125) without hormonal therapy or external-beam radiation therapy (EBRT) from September 2004 to December 2007. A PSA bounce was defined as a rise of at least 0.4 ng/ml greater than a previous PSA level with a subsequent decline equal to, or less than, the initial nadir., Results: Calculated by the Kaplan-Meier method, the incidence of PSA bounce at a 2-year follow-up was 26%. Median time to the PSA bounce was 15 months. Univariate analysis demonstrated that age, dose received by 90% of the prostate gland (D90), volume of gland receiving 100% of the prescribed dose (V100), and V150 were significantly associated with the PSA bounce, while pretreatment PSA level, Gleason score, pretreatment prostate volume, clinical T stage, and V200 were not. In multivariate analysis, age 67 years or less and D90 more than 180 Gy were identified as independent factors for predicting the PSA bounce (P < 0.05)., Conclusion: PSA bounce is not a rare phenomenon after prostate brachytherapy. It is more common in younger patients and patients receiving higher doses of radiation.

Objective: To investigate the possible significance of tumour dimensional variables, including maximum tumour diameter (MTD), maximum tumour area (MTA) and total tumour volume (TTV), with standard prognostic factors for predicting prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP)., Patients and Methods: Serial whole sections of the prostate from 164 patients who had RP for localized prostate cancer were investigated. Cox proportional hazards regression models were used for univariate and multivariate analyses to test the relationships between biochemical failure and clinicopathological factors, including tumour dimensional variables. The results were analysed retrospectively to develop a prognostic factor-based model for risk stratification., Results: In the univariate Cox proportional hazard model, pathological T stage, Gleason score, perineural invasion, microvascular invasion, positive surgical margins, MTD, MTA and TTV were significantly associated with biochemical failure. In the multivariate Cox proportional hazard model using a stepwise inclusion of these factors, Gleason score, positive surgical margins and MTD were independent indices in association with biochemical failure. Using the three statistically significant variables, the relative risk of biochemical failure could be calculated., Conclusion: These results imply that MTD is possibly one of the most important prognostic factors for predicting biochemical recurrence after RP. As calculating the MTD on the section a rapid, simple and objective method, it can be used instead of the TTV calculation. The prognostic factor- based risk stratification might help clinicians to predict biochemical failure after RP.

Objectives: To assess the outcomes of patients undergoing radical retropubic prostatectomy (RRP) with a running vesicourethral anastomosis and catheter removal on postoperative day 3 or 5., Methods: From February 2006 through December 2007, 55 patients underwent RRP at our institution. All procedures were performed by a single surgeon using a running suture for the vesicourethral anastomosis. A cystogram was carried out before catheter removal in all patients. The initial 23 of 55 patients (Group 1; n = 23) had the cystogram on postoperative day 5, the other 32 patients (Group 2; n = 32) had the cystogram on postoperative day 3. Removal of the catheter was only carried out if there was no anastomotic extravasation., Results: The success rate of catheter removal in group 1 and 2 was 100% and 96.9%, respectively. Overall continence rates were 83.3%, 87% and 90.7% at 24, 48 and 72 h after removal of the catheter, respectively. There was no significant difference in terms of continence rate between groups 1 and 2. None of the patients had acute urinary retention and/or anastomotic stricture after catheter removal., Conclusions: These findings suggest that an advanced running vesicourethral anastomosis during RRP is technically feasible, allowing safe early catheter removal in most patients.

Purpose: The present study was undertaken to determine the incidence and predictors of seed migration after transperineal interstitial prostate brachytherapy using I-125 free seeds., Methods and Materials: Between September 2004 and November 2007, 158 patients who underwent transperineal interstitial prostate brachytherapy as monotherapy for clinical T1/T2 carcinoma of the prostate gland were reviewed. Implants had been performed with standard techniques. All 158 patients underwent followup radiographs (orthogonal chest radiographs, a kidney-ureter-bladder radiograph, and a posteroanterior pelvic radiograph) to assess the presence of seed migration at 3 months after transperineal interstitial prostate brachytherapy. Patient characteristics and treatment status were recorded. Univariate and multivariate analyses were performed to identify predictors of seed migration., Results: Seed migration occurred in 35 of 158 patients (22.2%). Univariate analyses revealed that preoperative prostate volume estimated by transrectal ultrasound, the number of needles, the number of seeds implanted, and the presence or absence of pubic arch interference (PAI) were significantly associated with seed migration. These results indicated that larger prostate glands were more likely to have seed migration. However, the absolute difference in prostate size was not overly impressive (22.4 vs. 26.3cm(3)). Multivariate analysis revealed that the number of seeds implanted and the presence or absence of PAI were significant predictors of seed migration., Conclusion: The number of seeds implanted and the presence or absence of PAI provide the most predictive information on seed migration.

Objectives: To investigate the clinical value of prostate specific antigen velocity (PSAV) in predicting the extraprostatic extension of clinically localized prostate cancer., Methods: One hundred and three patients who underwent radical prostatectomy for clinically localized prostate cancer were included in the analysis. The correlation between preoperative parameters, including PSA-based parameters, clinical stage, and histological biopsy findings, and the pathological findings were analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for the local extent of the disease., Results: Sixty-four (60.2%) patients had organ confined prostate cancer and 39 (39.8%) patients had extraprostatic cancer. The biopsy Gleason score, PSA, PSA density, PSA density of the transition zone, and PSAV were significantly higher in the patients with extraprostatic cancer than in those with organ confined cancer. Multivariate logistic regression analysis indicated that the biopsy Gleason score, endorectal magnetic resonance imaging findings, and PSAV were significant predictors of extraprostatic cancer (P < 0.01). Probability curves for extraprostatic cancer were generated using these three preoperative parameters., Conclusions: The combination of PSAV, endorectal magnetic resonance imaging findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy.

Objective: The clinical value of serum tartrate-resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated., Methods: TRACP, PACP, ALP, and PSA serum levels were measured in 215 patients with prostate cancer, including 160 without and 55 with bone metastases. Correlation of serum marker levels with bone metastases was assessed using receiver operating characteristics (ROC) analysis. Sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each serum marker. Multivariate stepwise logistic regression analysis was used to identify independent predictors for the presence of bone metastasis., Results: Mean serum TRACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases compared with those without (P < 0.05). PSA and PACP levels increased significantly with clinical stage of the disease, whereas TRACP and ALP levels only increased significantly in stage D2. Serum TRACP levels correlated significantly with extent of disease on bone scans. ROC analyses showed no significant differences in area under the curve for these markers. Logistic regression analysis demonstrated that PSA, ALP, and TRACP were significant predictors of bone metastasis. Predicted and observed risks of bone metastasis were well correlated when TRACP, ALP, and PSA were combined and bone scan could have been omitted in 70% of patients by assessing these three markers., Conclusions: Serum TRACP can be considered a useful predictor of bone metastases in prostate cancer. A combination of TRACP, ALP, and PSA can obviate the need for a bone scan in 70% of cases.

Background: IL-6 has been reported to be a significant prognostic factor for prostate cancer and induces synthesis of C-reactive protein (CRP) by hepatocytes. The present study was undertaken to evaluate the clinical value of serum CRP in prostate cancer patients with metastases., Methods: The prognostic significance of serum CRP as well as tumor histology, extent of disease (EOD) on bone scan, serum levels of prostate-specific antigen (PSA) and alkaline phosphatase (ALP) and hemoglobin was assessed using Cox's proportional hazards model analyses in 126 prostate cancer patients with metastases treated with endocrine therapy., Results: Serum levels of CRP, PSA and ALP significantly increased and hemoglobin significantly decreased with advancing EOD grade. Univariate analysis demonstrated that EOD, CRP, PSA, ALP, hemoglobin and tumor histology are significantly associated with disease-specific survival. Multivariate analysis demonstrated that serum CRP and EOD were significant prognostic factors. The 5-year survival rates in low-risk patients (CRP < or = 0.15 mg/dl and EOD < or = 1) and high-risk patients (CRP > 0.15 mg/dl and EOD > or = 2) were 74 and 24%, respectively., Conclusion: These results indicate that a combination of serum CRP and EOD can identify patients with a poor prognosis who may be candidates for innovative treatments among prostate cancer patients with metastases.

Objectives: To investigate the clinical significance of local assessment by endorectal magnetic resonance imaging (MRI) in prostate cancer patients with metastases., Methods: The local extent and tumor size were determined by endorectal MRI in 95 prostate cancer patients with metastases, and their clinical implications were assessed., Results: The maximum diameter and tumor volume significantly correlated with the local extent of disease but not with extent of disease (EOD) on bone scan. In univariate analyses, EOD, serum prostate-specific antigen level, serum alkaline phosphatase level, and hemoglobin level were significantly associated with disease-specific survival, whereas tumor size and local extent of primary lesions were not. In a multivariate analysis EOD on bone scan was a significant prognostic factor., Conclusions: Tumor size and local extent of the primary lesion estimated by endorectal MRI were not associated with disease-specific survival. Assessment of the primary lesion by endorectal MRI is of limited value in predicting the prognosis of prostate cancer patients with metastases.

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).

Purpose: To evaluate the clinical value of diffusion-weighted imaging (DWI) and dynamic MRI in combination with T2-weighted imaging (T2W) for the detection of prostate cancer., Materials and Methods: A total of 83 patients with elevated serum prostate specific antigen (PSA) levels (>4.0 ng/mL) were evaluated by T2W, DWI, and dynamic MRI at 1.5 T prior to needle biopsy. The data from the results of the T2W alone (protocol A), combination of T2W and DWI (protocol B), and the combination of T2W+DWI and dynamic MRI (protocol C) were entered into a receiver operating characteristic (ROC) curve analysis, under results of systemic biopsy as the standard of reference., Results: Prostate cancer was pathologically detected in 44 of the 83 patients. The sensitivity, specificity, accuracy, and the area under the ROC curve (Az) for the detection of prostate cancer were as follows: 73%, 54%, 64%, and 0.711, respectively, in protocol A; 84%, 85%, 84%, and 0.905, respectively, in protocol B; and 95%, 74%, 86%, and 0.966, respectively, in protocol C. The sensitivity, specificity, and accuracy were significantly different between the three protocols (P < 0.01)., Conclusion: In patients with elevated serum PSA levels, the combination of T2W, DWI, and dynamic MRI may be a valuable tool for detecting prostate cancer and avoiding an unnecessary biopsy without missing prostate cancer.

Background: Angiotensin II (AII) type 1 receptor (AT1R) antagonists are used widely as antihypertensive agents, and long-term AT1R blockade may have a protective effect against cancer. We previously demonstrated that specific AT1R blockade with candesartan, an AT1R antagonist, inhibited vascular endothelial growth factor (VEGF) production and dramatically decreased lung metastasis of renal cancer by inhibiting tumor angiogenesis. This study was then undertaken to investigate the effects of AT1R blockade using candesartan in prostate cancer (PCa)., Methods: We first determined whether hormone-independence is associated with tumor angiogenesis and AT1R expression. Accordingly, we postulated that AT1R blockade may affect angiogenesis in androgen-independent PCa rather than in androgen-dependent PCa, and investigated the effects of AII and candesartan on PCa cell lines and a tumor xenograft model., Results: A human hormone-refractory PCa (HRPC) and C4-2 androgen-independent PCa cell line showed significantly higher expression of VEGF, MVD, and AT1R than did human androgen-dependent PCa and an LNCaP androgen-dependent PCa cell line. In vitro, AII and candesartan did not directly affect the proliferation of LNCaP and C4-2 cells, but candesartan significantly suppressed VEGF production in C4-2 cells. In vivo, candesartan significantly suppressed VEGF expression, serum PSA concentration and tumor growth (1.1 +/- 0.2, 45.0 +/- 17.6 ng/ml, 235.8 +/- 37.4 mm(3)) in C4-2 xenografts in castrated mice, compared with the controls (2.4 +/- 0.6, 376.7 +/- 74.2 ng/ml, 830.8 +/- 147.6 mm(3))., Conclusions: Candesartan exerted preventive effects on HRPC, rather than on androgen-sensitive PCa, through the inhibition of tumor angiogenesis., ((c) 2006 Wiley-Liss, Inc.)

Objectives: To determine the usefulness of alpha1-antichymotrypsin-prostate-specific antigen (PSA) complex (PSA-ACT)-based parameters in predicting bone metastasis in patients with prostate cancer., Methods: PSA-ACT, total PSA, free PSA, their volume-adjusted values, and alkaline phosphatase were evaluated in 220 consecutive patients with newly diagnosed prostate cancer., Results: Bone metastases were detected by bone scan in 27 (12.3%) of the 220 patients. The serum levels of PSA-ACT, total PSA, free PSA, PSA density, PSA adjusted for transition zone volume, PSA-ACT density, PSA-ACT adjusted for transition zone volume, alkaline phosphatase, PSA-ACT/PSA ratio, and Gleason score in patients with bone metastases were each significantly greater than in those without bone metastases. On receiver operating characteristic analyses, PSA-ACT had the greatest area under the curve (0.88), but the receiver operating characteristic curve demonstrated that the sensitivity and specificity of PSA-ACT were marginally better than those of total PSA at only a few selected cutoff points. At a sensitivity of 93% (2 patients with bone metastasis missed), unnecessary bone scans would have been avoided in 107 and 102 patients using a PSA-ACT cutoff value of 10 ng/mL and total PSA cutoff value of 11.5 ng/mL, respectively. Multivariate logistic regression analysis demonstrated that PSA-ACT and Gleason score were significant independent predictors of bone metastasis., Conclusions: PSA-ACT is as useful as total PSA for identifying patients with a low probability of having bone metastasis. PSA-ACT could replace PSA for predicting negative bone scans in a clinical setting in which PSA-ACT is used for monitoring and screening patients for prostate cancer.

Background: The present study was undertaken to investigate the association of pathological features, including the total tumor volume (TTV), maximum tumor area (MTA), and maximum tumor diameter (MTD), with the local extent of disease in clinically localized prostate cancer., Methods: Serial whole sections of the prostate from 164 patients who underwent radical prostatectomy for localized prostate cancer were investigated. The correlations between the indicators of tumor size, including the TTV, MTA, and MTD, and other pathological parameters were evaluated., Results: The MTD, MTA, and TTV were significantly correlated with each other. Multivariate stepwise logistic regression analysis indicated that the Gleason score, perineural invasion, microvascular invasion, and MTD were significant independent parameters associated with extraprostatic disease., Conclusion: The histological tumor grade, perineural invasion, microvascular invasion, and tumor size were correlated with the local extent of disease. The MTD, a simple, easy, and inexpensive parameter, is a more significant pathological feature associated with the local extent of disease than the MTA or TTV.

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.

Serum prostate-specific antigen (PSA) is used for the screening and early detection of prostate cancer. We are, however, confronted with the dilemma that a significant number of unnecessary biopsies are unavoidable especially in the serum PSA range of 4 to 10ng/ ml. It has been reported that age-specific PSA reference ranges, PSA velocity, PSA molecular forms and volume-adjusted PSA are valuable tools to improve specificity for early diagnosis of prostate cancer. In recent years, free PSA has been demonstrated to be composed of several isoforms including pPSA, BPSA and so on. Clinical values of these new PSA isoforms as well as human glandular kallikrein 2 are anticipated to be fully investigated to reduce unnecessary biopsies without missing a significant number of prostate cancer in the near future.

Background: The cross-talk between Wnt signaling and the Akt pathway in prostate cancer (Pca) is still unclear. In the present study, we found that WIF-1 downregulates the Akt pathway and also enhances chemosensitivity in PTEN-null Pca cells., Methods: Wnt inhibitory factor-1 (WIF-1), an inhibitor of Wnt proteins, was transfected into PC-3 and DU145 Pca cells., Results: Akt was phosphorylated in PTEN-null PC-3 cells but underphosphorylated in PTEN-expressed DU145 cells. The levels of phosphorylated Akt in WIF-1 overexpressing PC-3 cells were lower than those in native or control vector-transfected PC-3 cells. However, WIF-1 showed no additional inhibition of already reduced Akt activity in DU145 cells. Overexpression of WIF-1 resulted in sensitizing PC-3 cells for paclitaxel to induce apoptosis. DU145 cells were more sensitive to paclitaxel but were not affected by WIF-1 transfection. The PI3K inhibitor LY294002 seemed to restore the chemosensitivity of native PC-3 cells like WIF-1 did., Conclusions: Our results show that Wnt signaling is involved in Akt activation in Pca cells. Our data also indicate the possibility that Wnt and its signaling pathway can be therapeutic targets for PTEN-mutated advanced Pca., (Copyright 2004 Wiley-Liss, Inc.)

Objectives: To assess the value of endorectal magnetic resonance imaging (MRI) for detecting the tumor site, tumor size, and disease extent in patients with localized prostate cancer., Methods: The MRI findings were compared with the histopathologic findings of radical prostatectomy specimens in 95 patients., Results: The histologic examination revealed 186 cancer foci. Endorectal MRI detected 109 cancer foci. The accuracy, sensitivity, and positive predictive value of endorectal MRI for detecting tumor foci greater than 1.0 cm in diameter was 79.8%, 85.3%, and 92.6%, respectively; the corresponding value for detecting tumor foci smaller than 1.0 cm was 24.2%, 26.2%, and 75.9%, respectively. The maximal tumor diameter on endorectal MRI correlated with that shown by histologic examination for tumors larger than 1.0 cm in diameter. However, it did not correlate significantly with the histologic diameter of tumors smaller than 1.0 cm. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of endorectal MRI was 74.7%, 57.1%, 82.1%, 57.1%, and 82.1%, respectively, for the detection of extracapsular extension and was 75.8%, 62.1%, 81.8%, 60.0%, and 83.1%, respectively, for local staging., Conclusions: The results of the present study suggest that endorectal MRI is useful for predicting local extension, as well as tumor site and tumor size, of cancer foci greater than 1.0 cm in diameter.

Background: The present study was designed to identify the preoperative parameters, including PSA-based parameters, and endorectal MRI, predictive of pathological stage in males who underwent radical prostatectomy., Methods: We studied 114 patients who underwent radical retropubic prostatectomy and pelvic lymphadenectomy for clinically localized prostate cancer. Clinical stage was assessed by DRE, pelvic CT scan, endorectal MRI, and bone scan. The correlation between the preoperative parameters, including PSA-based parameters, clinical stage, and histological findings of biopsy specimens, and the pathological stage was analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for local extent of disease., Results: Seventy-six (66.6%) patients had organ confined cancer and 38 (33.4%) patients had extraprostatic cancer. Of the 38 patients with extraprostatic cancer, four had seminal vesicle involvement, while, none had pelvic lymph node involvement. Biopsy Gleason score, PSA, PSA-alpha1-antichymotrypsin (PSA-ACT), PSA-density (PSAD), PSA-transition zone density, PSA-ACT density, and PSA-ACT transition zone (TZ) density were significantly higher and percent free PSA was lower in the patients with organ confined cancer than those with extraprostatic cancer (P < 0.01). PSAD showed the largest area under the ROC curve (AUC) among those parameters (AUC = 0.732). Sixty-eight (74.7%) of 91 patients with T2 on endorectal MRI had organ confined cancer, while 15 (65.2%) of 23 patients with T3 had extraprostatic cancer (P < 0.01). Multivariate logistic regression analysis indicated that Gleason score (> or =7 vs. < or =6), endorectal MRI findings, and PSAD were significant predictors of extraprostatic cancer (P < 0.01)., Conclusions: The present study demonstrated that preoperative PSAD was the most valuable predictor among PSA-based parameters for extraprostatic disease in patients with clinically localized prostate cancer. The combination of PSAD, endorectal MRI findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy., (Copyright 2003 Wiley-Liss, Inc.)