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Background: Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals allow whole-body imaging to detect prostate cancer (PC). Positron emission tomography imaging using gallium-68 ( 68 Ga)-PSMA-11 has been shown to have a favorable safety and tolerability profile and high diagnostic performance. The study evaluates the safety and pharmacokinetics of 68 Ga-PSMA-11 in Japanese patients with primary, recurrent, or suspected recurrent prostate cancer., Methods: This single arm study enrolled Japanese patients with primary PC (n = 3), suspected recurrent PC following radical prostatectomy (n = 4), or suspected recurrent PC following radical radiotherapy (n = 3). All patients received a single intravenous dose of 68 Ga-PSMA-11 2.0 MBq/kg (±10%) followed by PSMA PET imaging and safety and pharmacokinetic evaluations. Based on the blood concentrations of 68 Ga-PSMA-11 and the radioactivity distribution rate in each organ/tissue, the absorbed doses in major organs/tissues and the whole-body effective dose were calculated by the Medical Internal Radiation Dose method., Results: Ten patients were enrolled. Mean age was 73.3 ± 4.8 years, and median prostate-specific antigen was 8.250 ng/mL. Five patients (50%) experienced a total of 6 adverse events, and no grade ≥ 2 adverse events or serious adverse events were reported. No clinically significant changes in vital signs, haematology parameters, or blood chemistry or ECG abnormalities were observed. The estimated whole body effective dose of 68 Ga-PSMA-11 (mean ± standard deviation) was 2.524 × 10 -2  ± 2.546 × 10 -3  mSv/MBq. Time to maximum concentration (1.16 × 10 -4  ± 1.3 × 10 -5 % ID/mL) in whole blood was 2.15 ± 0.33 min., Conclusions: 68 Ga-PSMA-11 has a favourable safety and tolerability profile in Japanese patients with primary, recurrent, or suspected recurrent prostate cancer, which is comparable to previous observations in other populations., (© 2024. The Author(s).)

Background/aim: The percentage of positive cores (PPC) is increasingly recognized as a prognostic factor in prostate cancer. However, the usefulness of PPC for patients undergoing androgen deprivation therapy (ADT) and high-risk group has not been adequately studied., Patients and Methods: A retrospective analysis was conducted of 255 patients who underwent prostate biopsy (all-case group). We examined the efficacy of PPC as a prognostic biomarker., Results: Eighty-nine patients were treated with ADT alone (ADT group), and 107 patients were classified as high-risk (high-risk group). The median duration of follow-up was 112.4 months, 85.3 months, and 110.0 months for the all-case, ADT, and high-risk groups, respectively. Patients with PPC >60% had significantly shorter prostate cancer-specific survival (CSS) and castration-resistant prostate cancer-free survival (CFS) in the all-case and ADT groups. In the high-risk group, patients with PPC >60% had shorter CFS but no difference in CSS. Multivariate analysis showed that significant independent predictors of prostate CSS were the presence of metastasis at diagnosis and PPC >60% in the all-case and ADT groups., Conclusion: PPC may be a prognostic factor in ADT treated and high-risk prostate patients., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Despite treating advanced prostate cancer (PCa) with androgen deprivation therapy, it eventually progresses to castration-resistant PCa. Subsequently, taxanes are administered, but when PCa becomes resistant to taxanes, another treatment is needed, which has not yet been established. We previously synthesized a novel α-trifluoromethyl chalcone, YS71, and reported its antitumor effects against PCa cells. In this study, we confirmed its efficacy against androgen-sensitive, androgen-independent, and taxane-resistant PCa cells., Materials and Methods: The PCa cell lines used were LNCaP, PC-3, DU145, PC-3-TxR (paclitaxel-resistant), PC-3-TxR/CxR (paclitaxel- and cabazitaxel-resistant), DU145-TxR, and DU145-TxR/CxR. The antiproliferative effects of YS71 were evaluated using proliferation assay. The reverse transcriptase transcription-polymerase chain reaction and western blot were performed to determine the expression level of androgen receptor (AR), whereas luciferase assay was performed to determine the AR activity. Furthermore, TUNEL assay and western blot were performed to investigate the mechanism of the antiproliferative effect., Results: YS71 exerted a dose-dependent antitumor effect, inhibited AR activity, and induced apoptosis in all PCa cells in a dose-dependent manner. Western blot showed that YS71 increased the levels of apoptosis-related proteins, cleaved caspase-3, and cleaved PARP, and decreased the levels of the antiapoptotic proteins, Bcl-xL and Bcl-2. In addition, microarray analysis revealed that YS71 decreased several cancer-related genes., Conclusion: YS71 exhibits antitumor activity by inducing apoptosis in PCa cells, including taxane-resistant cells. It could be a potential future therapeutic option for hormone- and chemotherapy-resistant PCa., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Although many reports have shown that Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) is effective for postoperative urinary continence, the postoperative voiding status and sexual function associated with this technique have not yet been adequately compared with those associated with conventional RARP (C-RARP). In this study, the lower urinary tract function, erectile function, and cancer control after C-RARP and RS-RARP were compared chronologically., Materials and Methods: We selected 50 cases of C-RARP and RS-RARP each by propensity score matching and evaluated them over time using various questionnaires. Urinary continence recovery rates and biochemical recurrence (BCR)-free survival rates were calculated using the Kaplan-Meier method and compared between the two groups using the log-rank test., Results: When urinary continence was defined as 0 pads per day, 0 pads per day + 1 security linear, or ≤1 pad per day, the postoperative improvement in urinary continence was better with RS-RARP over the course of up to 1 year for all definitions. The International Consultation on Incontinence Questionnaire-Short Form total scores and the Overactive Bladder Symptom Scores were better in the postoperative RS-RARP group. There were no significant differences in the International Prostate Symptom Score total score, QOL score, and erectile hardness score between the two groups during the observation period. The BCR-free survival did not differ significantly between the two groups CONCLUSIONS: Postoperative urinary continence was better in the RS-RARP group than in the C-RARP group; however, the voiding function, erectile function, and cancer control did not differ significantly., (© 2023 Wiley Periodicals LLC.)

The suppression of androgen receptor (AR) expression exacerbates the migration potential of prostate cancer. This study identified a previously unrecognized regulation of the AR-controlled pathway that promotes migration potential in prostate cancer cells. Prostate cancer cells that pass through a transwell membrane (mig cells) have a higher migration potential with a decreased AR expression than parental cells. In this study, we aimed to elucidate the mechanism of migration enhancement associated with the suppression of AR signaling. Expression of C-C motif ligand 20 (CCL20) is upregulated in mig cells, unlike in the parental cells. Knockdown of AR with small interfering RNA (siAR) in LNCaP and C4-2B cells increased CCL20 secretion and enhanced the migration of cancer cells. Mig cells, CCL20-treated cells, and siAR cells promoted cell migration with an enhancement of AKT phosphorylation and Snail expression, while the addition of a C-C chemokine receptor 6 (CCR6, the specific receptor of CCL20) inhibitor, anti-CCL20 antibody, and AKT inhibitor suppressed the activation of AKT and Snail. With 59 samples of prostate cancer tissue, CCL20 secretion was profuse in metastatic cases despite low AR expression levels. Snail expression was associated with the expression of CCL20 and CCR6. A xenograft study showed that the anti-CCL20 antibody significantly inhibited Snail expression, thereby suggesting a new therapeutic approach for castration-resistant prostate cancer with the inhibition of the axis between CCL20 and CCR6., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: Prostate-specific antigen is considered the most useful biomarker for prostate cancer, but not in all cases. In a previous study, we have shown that a risk classification combining prostate-specific antigen ≥100 ng/mL and chemokine (CC motif) ligand 2 ≥ 320 pg/mL can predict survivals. We investigated the long-term usefulness of serum chemokine (CC motif) ligand 2 as a complementary biomarker to prostate-specific antigen and developed a novel risk classification system., Methods: Serum samples were collected from 379 patients who underwent prostate biopsy at Kanazawa University Hospital between 2007 and 2013, and 255 patients with histologically diagnosed prostate cancer were included in this study. We retrospectively examined the efficacy of serum chemokine (CC motif) ligand 2 as a prognostic biomarker., Results: Patients with chemokine (CC motif) ligand 2 ≥ 320 pg/mL exhibited a significantly shorter overall survival, prostate cancer-specific survival and castration-resistant prostate cancer-free survival than those with chemokine (CC motif) ligand 2 < 320 pg/mL. Multivariate analysis was performed to determine whether chemokine (CC motif) ligand 2 was a useful prognostic factor. Independent significant predictors of worse overall survival were prostate-specific antigen ≥ 100 ng/mL, Gleason score ≥ 8 and chemokine (CC motif) ligand 2 ≥ 320 pg/dL. Prognostic predictors of prostate cancer-specific survival or cancer-free survival in multivariate analysis were prostate-specific antigen ≥ 100 ng/mL and Gleason score ≥ 8. A novel risk classification system was created to predict overall survival in patients based on the number of risk factors present (chemokine (CC motif) ligand 2 ≥ 320 pg/mL, prostate-specific antigen ≥ 100 ng/mL, Gleason score ≥ 8). Scores 2 or 3, 1 and 0 indicated Poor, Intermediate and Good risk groups, respectively., Conclusions: This study demonstrated the utility of serum chemokine (CC motif) ligand 2 level as a predictive biomarker of long-term overall survival in prostate cancer. A novel risk classification system that predicts long-term overall survival based on the combined indications of chemokine (CC motif) ligand 2 level, prostate-specific antigen level and Gleason score may be a useful prognostic tool for prostate cancer., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background/aim: Neuroendocrine prostate cancer (NEPC) is rare and has a poor prognosis; its clinical course and treatment outcomes are also unclear. This study investigated the clinical characteristics, clinical course, and treatment outcomes of patients with NEPC., Patients and Methods: This retrospective study investigated 14 patients histologically diagnosed with NEPC at Kanazawa University Hospital between 2000 and 2019. Overall survival (OS) and progression-free survival (PFS) were retrospectively analyzed using the Kaplan-Meier method. Additionally, log-rank tests were used to compare survival distributions., Results: We included 14 patients histologically diagnosed with NEPC among 1,845 patients with prostate cancer. Four patients (0.22%) were diagnosed with de novo NEPC, and ten patients were diagnosed with NEPC during treatment. First-line platinum-based therapy's objective response rate (ORR) was 66.7%, and disease control rate was 91.7%; median PFS was 7.5 months. The median OS from NEPC diagnosis was 20.3 months. The median OS of the liver metastasis (-) group was 31.6 months, and that of the (+) group was 9.4 months (p=0.03, hazard ratio=0.24). The median OS of the somatostatin receptor scintigraphy (SRS)-positive group was 31.6 months, and that of the SRS-negative group was 10.6 months (p=0.04, hazard ratio=0.14)., Conclusion: Platinum-based chemotherapy is effective to some extent, but the duration of response is not sufficient; therefore, new treatment options are needed. This is the first study to show that SRS findings and the presence of liver metastases might be prognostic predictors of NEPC., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: No standard treatment exists for locally advanced prostate cancer (PC). This study evaluated the long-term treatment outcomes and toxicity in patients with clinically locally advanced and/or lymph node (LN)-positive PC who underwent high-dose-rate brachytherapy (HDR-BT) with external beam radiotherapy (EBRT)., Methods: The treatment outcomes and toxicities of 152 patients with PC who underwent HDR-BT with EBRT and had at least 2 years of observation were examined. The treatment dose was 19- and 13-Gy HDR-BT in two and single fractions, respectively, both combined with external irradiation of 46 Gy in 23 fractions. Long-term androgen deprivation therapy (ADT) for patients harboring very high-risk tumors was used in combination., Results: The median observation period was 59.7 (24.4-182.1) months. The 5-year prostate cancer-specific and recurrence-free (RFS) survival rates were 99.0% and 91.8%, respectively, with only two PC mortalities. When 5-year RFS was examined for each parameter, RFS was significantly lower in pre-radiotherapy (pre-RT) prostate-specific antigen (PSA) > 0.5 ng/mL (77.1%; p = 0.008), and presence of LN metastasis (68.1%; p = 0.017). Multivariable analysis demonstrated that pre-RT PSA (HR, 4.68; 95% CI, 1.39-15.67; p = 0.012) and presence of LN metastasis (HR, 4.70; 95% CI, 1.24-17.74; p = 0.022) were independent recurrence predictors. The 5-year cumulative incidence rate of grade ≥ 2 toxicities in genitourinary and gastrointestinal tracts were 15.4% and 1.3%, respectively., Conclusions: HDR-BT combined with EBRT and long-term ADT shows promising disease control and tolerant toxicities for clinically locally advanced and LN-positive PC., (© 2021. Japan Society of Clinical Oncology.)

Background/aim: Pelvic drain (PD) placement is commonly performed after robot-assisted radical prostatectomy (RARP), but the need for PD placement is unclear. This study aimed to assess the need for PD placement after RARP., Patients and Methods: This retrospective study analysed the effect of PD placement on postoperative complications in patients who underwent RARP between 2009 and 2018. All patients prior to October 1, 2016 had a PD placed; those after did not., Results: Of the 308 study patients, 231 received a PD (PD group) and 77 did not (ND group). The incidence of ileus, urinary tract infection and anastomotic leak did not differ significantly between the groups; nor did the incidence of asymptomatic and symptomatic lymphocele at 2 weeks and 1 year after surgery. Multivariate analysis showed that lymph node dissection is a predictor of asymptomatic lymphocele development two weeks after surgery., Conclusion: PD placement is not necessary after RARP., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Our previous report has shown that the flavonoid 2'-hydroxyflavanone (2'-HF) showed inhibition of androgen receptor (AR) activity against androgen-sensitive prostate cancer (PCa) cells, LNCaP, and exhibited antitumor effects against androgen-insensitive PCa cells, PC-3, and DU145. In the present study, we prepared a derivative of 2'-HF, 16MS7F1924, and confirmed the effects of this derivative on PCa cells., Methods: The antiproliferation effects of 16MS7F1924 were investigated in PCa cells using LNCaP, PC-3, DU145 and docetaxel-resistant and cabazitaxel-resistant cell lines of PC-3-TxR/CxR and DU145-TxR/CxR. Prostate-specific antigen (PSA) and AR expression level in whole cells and the nucleus were confirmed in LNCaP by reverse transcriptase polymerase chain reaction and Western blot analysis. AR activity in LNCaP cells was confirmed by luciferase assay using PSA promoter-driven reporter. To analyze the antiproliferative effects, cell-based assays using flow cytometry, immunocytochemistry, and TUNEL assay as well as Western blot analysis were employed. Furthermore, PC-3, DU145 and each chemoresistant strain of human PCa cells were subcutaneously xenografted. The antitumor effects of 16MS7F1924 were evaluated in vivo., Results: 16MS7F1924 showed antitumor effect on all PCa cells in a dose-dependent manner. 16MS7F1924 reduced the expression of PSA messenger RNA (mRNA) and protein and inhibited AR activity in a dose-dependent manner, while expression of AR protein and mRNA was reduced by 16MS7F1924. 16MS7F1924 induced mitotic catastrophe and apoptosis. Apoptotic cells were increased in a dose-dependent manner, and the apoptosis was mediated through the Akt pathway. Tumor growth was safely and significantly inhibited by both intraperitoneal and oral administration of 16MS7F1924 in vivo., Conclusion: 16MS7F1924 had sufficient antitumor activity against androgen-sensitive and cabazitaxel-resistant PCa cells and may be useful as a novel therapeutic agent overcoming hormone- and chemoresistant PCas., (© 2021 Wiley Periodicals LLC.)

A standard modality for prostate cancer detection in men 75 years and older has not been established. A simple screening method for elderly patients is needed to avoid unnecessary biopsies and to effectively diagnose prostate cancer. A retrospective study was conducted on elderly patients who had prostate biopsy at Kanazawa University Hospital (Kanazawa, Japan) between 2000 and 2017. Of the 2251 patients who underwent prostate biopsy, 254 had clinically significant prostate cancer (CSPC) with a Gleason score (GS) of≥7 and 273 had a GS of <7 or no malignancy. In this study, patients aged 75 years or older were classified as elderly patients. GS ≥ 7 was characterized by a prostate-specific antigen (PSA) of the maximum area under the curve of 12 ng ml -1 with a sensitivity of 76.2% and a specificity of 73.2%. For PSA levels between 4 ng ml -1 and 12 ng ml -1 , based on the maximum area under the curve, patients with three or four of the following factors may present a GS of ≥ 7: percent free PSA >24, PSA density≥ 0.24 ng ml -2 , positive findings on digital rectal examination, and transrectal with 90.0% sensitivity and 67.4% specificity. In this study, we found that raising the PSA cutoff to 12 ng ml -1 for CSPC in elderly individuals can significantly reduce unnecessary prostate biopsies. Furthermore, CSPC could be efficiently discovered by combining the four supplementary markers in patients with a PSA level of 4-12 ng ml -1 . By performing this screening for elderly men over 75 years of age, unnecessary biopsies may be reduced and CSPC may be detected efficiently., Competing Interests: None

Background/aim: To investigate whether surgical margin (SM) status would affect the biochemical recurrence (BCR) after robot-associated RP (RARP)., Patients and Methods: We evaluated BCR after RARP and the association between pre- and postoperative predictive factors and BCR., Results: Positive SM (PSM) was observed in 97 out of 365 enrolled patients. On multivariate analysis, preoperative prostate specific antigen, biopsy Gleason score (GS), clinical stage, GS ≥7 at the PSM and pathological GS ≥7 were predictive factors for BCR. The 5-year BCR-free survival rate was 84.1% in the negative SM (NSM), 87.4% when GS=6 at the PSM, and 47.6% when GS ≥7 at the PSM. There was no statistically significant difference in BCR-free survival between the NSM group and GS=6 at the PSM group (p=0.966)., Conclusion: It would be desirable to evaluate GS at PSM when PSM is present in a specimen removed by RP., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To investigate the time course of total testosterone (TT) recovery after cessation of androgen deprivation therapy (ADT) in Japanese patients treated with brachytherapy., Methods: In total, 125 patients with prostate cancer received 6 months of neoadjuvant ADT (nADT) followed by low-dose rate (LDR) brachytherapy. TT was measured every 3 months after cessation of nADT, and some predictive factors affecting TT recovery were analyzed., Results: The cumulative incidence rates of TT recovery to normal levels (TT ≥ 3.0 ng/mL) after 12 and 24 months cessation were 49.6% and 81.6%, respectively. The median interval to recover to normal TT was 15 months. In multivariate analysis, the use of a gonadotropin-releasing hormone (GnRH) antagonist as nADT significantly earlier improved to recovery to normal TT level ( p  = 0.046). Conversely, higher body mass index (BMI) and hypertension significantly prolonged TT recovery to normal ( p  = 0.026 and p  = 0.026, respectively)., Conclusions: Approximately one-fifth of patients still had low TT levels 2 years after the cessation of 6 months nADT before LDR brachytherapy. Use of a GnRH agonist, higher BMI, and hypertension were the predictive factors for slower TT recovery to normal TT levels after the cessation of nADT.

Background: Coffee inhibits the progression of prostate cancer; however, the direct mechanism through which coffee acts on prostate cancer cells remains unclear. This study aimed to identify the key compounds of coffee that possess anti-cancer effects and to investigate their mechanisms of action., Methods: The anti-proliferation and anti-migration effects of six potentially active types of coffee compounds, including kahweol acetate, cafestol, caffeine, caffeic acid, chlorogenic acid, and trigonelline hydrochloride, were evaluated using LNCaP, LNCaP-SF, PC-3, and DU145 human prostate cancer cells. The synergistic effects of these compounds were also investigated. Apoptosis-related and epithelial-mesenchymal transition-related proteins, androgen receptor in whole cell and in nucleus, and chemokines were assessed. A xenograft study of SCID mice was performed to examine the in vivo effect of coffee compounds., Results: Among the evaluated compounds, only kahweol acetate and cafestol inhibited the proliferation and migration of prostate cancer cells in a dose-dependent manner. The combination treatment involving kahweol acetate and cafestol synergistically inhibited proliferation and migration (combination index <1) with the induction of apoptosis, the inhibition of epithelial-mesenchymal transition, and decrease in androgen receptor, resulting in the reduction of nuclear androgen receptor in androgen receptor-positive cells. Moreover, kahweol acetate and cafestol downregulated CCR2 and CCR5 without an increase in their ligands, CCL2 and CCL5. The xenograft study showed that oral administration of kahweol acetate and cafestol significantly inhibited tumor growth., Conclusion: Kahweol acetate and cafestol synergistically inhibit the progression of prostate cancer. These coffee compounds may be novel therapeutic candidates for prostate cancer., (© 2018 Wiley Periodicals, Inc.)

Objective: To conduct a prospective randomized trial to evaluate the efficacy of a novel prophylactic procedure for inguinal hernia (IH) after transperitoneal robot-assisted radical prostatectomy (RARP)., Methods: The prophylactic procedure for IH after RARP involved the dissection of the peritoneum ∼5 cm outward from internal inguinal ring (IIR), separating the spermatic cord and vessels from the peritoneum. This was randomly performed on one side (left or right)., Results: A total of 148 cases were included, and IH after RARP was observed in 19 (12.8%) cases, with 11 (7.4%) cases in the right side only, 3 (2.0%) in the left side only, and 5 (3.4%) bilaterally. IHs developed in 9 (6.1%) sides that underwent prophylactic procedure and in 15 (10.1%) that did not. Kaplan-Meier curve analysis revealed no significant difference between the preventive and nonpreventive sides (p = 0.197). Based on the observation during laparoscopic hernioplasty, the prophylactic procedure that strengthened the abdominal wall was by adhesion conglutination of the exfoliated peritoneum in the effective side, and IIRs were opened and developed IH in the ineffective sides. Predictive factors for IH after RARP were not found using Cox proportional hazard model., Conclusion: The preventive procedure for IH used in this study reduced the incidence of IH after RARP, but the difference was not significant.

Background/aim: To evaluate the treatment outcomes, toxicity and health-related quality of life (HRQOL) in prostate cancer (PCa) patients who underwent single-fraction high-dose-rate brachytherapy (single-fraction HDR-BT) with external beam radiotherapy (EBRT)., Materials and Methods: From April 2014 to October 2017, treatment outcomes and toxicity of 85 patients who underwent single-fraction HDR-BT of 13 Gy, followed by 46 Gy EBRT in 23 fractions, were examined. HRQOL of 53 patients was evaluated using the Expanded Prostate Cancer Index Composite (EPIC), International Prostate Symptom Score (IPSS)/QOL index, International Index of Erectile Function 5 (IIEF-5), and 36-Item Short Form Survey (SF-36) scores through one year., Results: The median follow-up period was 28.8 months. Only three patients had biochemical recurrence. Toxicities included less than grade 3 lower urinary tract symptoms and grade 1 diarrhea. Urethral stricture, a problem related to late toxicity in conventional HDR-BT, was not observed. The urinary and bowel functions in EPIC scores significantly worsened until three or six months after treatment, respectively., Conclusion: Single-fraction HDR-BT with EBRT showed promising biochemical control, tolerant toxicities, and preservation of HRQOL, and can be efficiently performed in a shorter time than conventional HDR-BT., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Understanding the mechanism of chemoresistance and disease progression in patients with prostate cancer is important for developing novel treatment strategies. In particular, developing resistance to cabazitaxel is a major challenge in patients with docetaxel-resistant and castration-resistant prostate cancer (CRPC) because cabazitaxel is often administered as a last resort. However, the mechanism by which cabazitaxel resistance develops is still unclear. C-C motif chemokine ligands (CCL) were shown to contribute to the castration resistance of prostate cancer cells via an autocrine mechanism. Therefore, we focused on CCL as key factors of chemoresistance in prostate cancer cells. We previously established a cabazitaxel-resistant cell line, DU145-TxR/CxR, from a previously established paclitaxel-resistant cell line, DU145-TxR. cDNA microarray analysis revealed that the expression of CCL2 was upregulated in both DU145-TxR and DU145-TxR/CxR cells compared with DU145 cells. The secreted CCL2 protein level in DU145-TxR and DU145-TxR/CxR cells was also higher than in parental DU145 cells. The stimulation of DU145 cells with CCL2 increased the proliferation rate under treatments with cabazitaxel, and a CCR2 (a specific receptor of CCL2) antagonist suppressed the proliferation of DU145-TxR and DU145-TxR/CxR cells under treatments of cabazitaxel. The CCL2-CCR2 axis decreased apoptosis through the inhibition of caspase-3 and poly(ADP-ribose) polymerase (PARP). CCL2 is apparently a key contributor to cabazitaxel resistance in prostate cancer cells. Inhibition of the CCL2-CCR2 axis may be a potential therapeutic strategy against chemoresistant CRPC in combination with cabazitaxel., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Prostate - specific antigen (PSA) is a useful biomarker for detection of prostate cancer (PCa) and for risk classification in addition to TNM classification and Gleason score (GS). We reported the role of PSA in patients with low (< 20 ng / mL) and extremely high (≥ 100 ng / mL) PSA levels. However, it is unclear whether a correlation exists between middle range PSA levels (20 - 100 ng / mL) at diagnosis and prognosis., Materials and Methods: Between January 2000 and December 2014, 1873 patients underwent prostate biopsy at Kanazawa University Hospital. Of 802 patients who were diagnosed with PCa, 148 patients with middle range PSA levels (20 - 100 ng / mL) were retrospectively analyzed., Results: The percentage of patients with T3 - 4 consistently increased as PSA levels increased from 20 to 100 ng / mL. Although the percentage of patients with GS ≥ 8 or metastases increased as PSA levels increased up to approximately 70 ng / mL, there was no significant increase between 70 and 100 ng / mL. PCa - specific and castration - resistant PCa - free survivals were adversely associated with PSA levels up to 70 ng / mL, but not between 70 and 100 ng / mL., Conclusion: PSA is a useful biomarker for predicting prognosis at levels between 20 and 70 ng / mL. However, PSA cannot be used as a prognostic factor in patients with PCa and PSA levels ≥ 70 ng / mL. When the PSA level reaches approximately 70 ng / mL, prognosis might bottom and reach a plateau., Competing Interests: Conflict of interest: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Understanding the mechanism of lymph node metastasis, a poor prognostic sign for prostate cancer, and the further dissemination of the disease is important to develop novel treatment strategies. Recent studies have reported that C-C chemokine receptor 7 (CCR7), whose ligand is CCL21, is abundantly expressed in lymph node metastasis and promotes cancer progression. Tumor necrosis factor-α (TNF-α) is chronically produced at low levels within the tumor microenvironment. The aim of this study was to determine whether TNF-α promotes prostate cancer dissemination from metastatic lymph nodes through activation of the CCL21/CCR7 axis. First, human prostate cancer cells were determined to express both TNF-α and CCR7. Second, low concentrations of TNF-α were confirmed to induce CCR7 in prostate cancer cells through phosphorylation of ERK. Finally, CCL21 was found to promote the migration of prostate cancer cells through phosphorylation of the protein kinase p38. Our results suggest that TNF-α leads to the induction of CCR7 expression and that the CCL21/CCR7 axis might increase the metastatic potential of prostate cancer cells in lymph node metastasis., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Aim: To investigate how androgen-sensitive LNCaP cells crosstalk with androgen-insensitive DU145 or PC-3 cells., Materials and Methods: The numbers of LNCaP cells were counted when co-cultured with DU145 or PC-3 cells and vise versa. Androgen receptor (AR) activity in LNCaP cells was examined by luciferase reporter assay after transfection with a luciferase reporter driven by PSA promoter in the presence of DU145 or PC-3 cells. Concentration of androgens in the medium was measured by liquid chromatography-mass spectrometry (LC-MS/MS). The ability of migration and invasion of PC-3 and DU145 cells was investigated using a 2-layer chamber, in the presence of LNCaP cells., Results: Co-culture of LNCaP cells with DU145 cells resulted in the conversion of dehydroepiandrosterone (DHEA) to dihydrotestosterone (DHT), which stimulated cell proliferation and PSA promoter activity in LNCaP cells. The increased cell proliferation rate and AR activity, induced in LNCaP cells after DHT treatment, was further enhanced by co-culture with DU145 cells. LNCaP cells also stimulated the proliferation of DU145 and PC-3 cells, via secreting soluble factors. Finally, LNCaP cells promoted migration and invasion of PC-3 cells, in a co-culture system; however inhibited migration and invasion of DU145 cells., Conclusion: Crosstalk between androgen-sensitive PCa cells and androgen-insensitive PCa cells might develop the progression of PCa., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Chemokines and their receptors have key roles in cancer progression. The present study investigated chemokine activity in the prostate cancer bone metastasis microenvironment. Growth and migration of human prostate cancer cells were assayed in cocultures with bone stromal cells. The migration of LNCaP cells significantly increased when co-cultured with bone stromal cells isolated from prostate cancer bone metastases. Cytokine array analysis of conditioned medium from bone stromal cell cultures identified CCL5 as a concentration-dependent promoter of LNCaP cell migration. The migration of LNCaP cells was suppressed when C-C motif ligand 5 (CCL5) neutralizing antibody was added to cocultures with bone stromal cells. Knockdown of androgen receptor with small interfering RNA increased the migration of LNCaP cells compared with control cells, and CCL5 did not promote the migration of androgen receptor knockdown LNCaP. Elevated CCL5 secretion in bone stromal cells from metastatic lesions induced prostate cancer cell migration by a mechanism consistent with CCL5 activity upstream of androgen receptor signaling., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/aim: Androgen-androgen receptor (AR) signal is known as a powerful driver of prostate cancer progression. We previously reported the limitation of prostate-specific antigen (PSA) at diagnosis as a prognostic biomarker of prostate cancer. Although serum total testosterone (TT) level has been reported as a prognostic biomarker for prostate cancer, its usability is still controversial. We examined the potential and characteristics of TT as a biomarker., Patients and Methods: Serum TT levels of patients who underwent prostate biopsy were measured, and prostate cancer-specific survival (PCaSS), overall survival (OS), and the correlation between staging and serum TT level were analyzed., Results: Of 379 biopsied patients, 255 were diagnosed with prostate cancer. The patients were divided into five groups according to their serum TT levels; patients with serum TT levels of <2 or ≥8 ng/ml (ENDs) had worse PCaSS and OS compared with those with middle serum TT levels between 2 and 8 ng/ml (MIDs). Moreover, ENDs showed a tendency of having castration-resistant cancer with advanced stage (T4 or N1 or M1). The TNM stage in ENDs was significantly higher than in MIDs., Conclusion: Although low serum TT level has been reported to indicate worse outcome in patients with prostate cancer, this study showed that both low as well as high serum TT levels indicate poor prognosis., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To measure changes in penile length (PL) over time before and after radical prostatectomy (RP), and to investigate the underlying mechanisms for these changes., Patients and Methods: The stretched PL (SPL) of 102 patients was measured before, 10 days after, and at 1, 3, 6, 9, 12, 18 and 24 months after RP. The perpendicular distance from the distal end of the membranous urethra to the midline of the pelvic outlet was measured on mid-sagittal magnetic resonance imaging (MRI) slice at three time points: preoperatively; 10 days after RP; and 12 months after RP. Pre- and postoperative SPLs were compared using paired Student's t-test. Predictors of PL shortening at 10 days and at 12 months after RP were evaluated on univariate and multivariate analyses., Results: The SPL was shortest 10 days after RP (mean PL shortening from preoperative level: 19.9 mm), and gradually recovered thereafter. SPL at 12 months after RP was not significantly different from preoperative SPL. On MRI examination, the distal end of membranous urethra was found to have moved proximally (mean proximal displacement: 3.9 mm) at 10 days after RP, and to have returned to the preoperative position at 12 months after RP. On univariate analysis, only the volume of the removed prostate was a predictor of SPL change at 10 days after surgery; on multivariate analysis, the association was not statistically significant. No predictor of SPL change was found at 12 months after RP., Conclusion: The SPL was shortest at 10 days after RP and gradually recovered thereafter in the present study. Anatomically, the glans and corpus spongiosum surrounding the urethra are an integral structure, and the proximal urethra is drawn into the pelvis during urethrovesical anastomosis. This is the first report showing that slight vertical repositioning of the membranous urethra after RP causes changes in SPL over time. These results can help inform patients about changes in penile appearance after RP., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Recent studies reveal that hypogonadism with low serum androgen levels is associated with advanced cancer and induction of most cancer-related symptoms. We designed an ARTFORM study to evaluate the efficacy of androgen replacement therapy in male advanced cancer patients. The ARTFORM study is an investigator-initiated, randomised controlled trial comparing intramuscle injection of testosterone enanthate with non-administration in male advanced cancer patients with non-curative locally advanced or metastatic lesions. Serum total and free testosterone levels are measured and patients with low testosterone level are randomised. The primary endpoint is the difference in validated health-related quality of life questionnaires at week 12. Trial registration of the ARTFORM study is assigned to University hospital Medical Information Network, Center identifier UMIN 000010939. J. Med. Invest. 64: 202-204, August, 2017.

The aims of the study were to investigate desirable evaluation methods for post-prostatectomy incontinence (PPI) by analyzing the urinary status before robot-assisted radical prostatectomy (RARP).Questionnaires were evaluated from 155 patients prior to operation. The 24-h pad test before RARP revealed a weight of 1.1 g. The mean scores were as follows: total International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) score, 1.2; total International Prostate Symptom Score (IPSS), 10.0; IPSS quality of life, 2.7; Overactive Bladder Symptom Score (OABSS), 2.9; and Expanded Prostate Cancer Index Composite urinary summary, 92.8. The abdominal leak point pressure test in 111 patients before RARP was negative in all cases. Desirable evaluation methods for PPI should be based on a combination of subjective and objective evaluations and comparisons between pre- and post-RP. ICIQ-SF is considerably convenient for evaluating incontinence, and the 24-h pad test enables evaluation of the incontinence volume in a highly objective manner., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: To investigate the clinical outcomes of metastatic prostate cancer patients and the relationship between nadir prostate-specific antigen (PSA) levels and different types of primary androgen deprivation therapy (PADT). This study utilized data from the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database., Methods: A total of 2982 patients treated with PADT were enrolled. Kaplan-Meier analysis was used to compare progression-free survival (PFS) and overall survival (OS) in patients treated using combined androgen blockade (CAB) and non-CAB therapies. The relationships between nadir PSA levels and PADT type according to initial serum PSA levels were also investigated., Results: Among the 2982 enrolled patients, 2101 (70.5 %) were treated with CAB. Although CAB-treated patients had worse clinical characteristics, their probability of PFS and OS was higher compared with those treated with a non-CAB therapy. These results were due to a survival benefit with CAB in patients with an initial PSA level of 500-1000 ng/mL. Nadir PSA levels were significantly lower in CAB patients than in non-CAB patients with comparable initial serum PSA levels., Conclusions: A small survival benefit for CAB in metastatic prostate cancer was demonstrated in a Japanese large-scale prospective cohort study. The clinical significance of nadir PSA levels following PADT was evident, but the predictive impact of PSA nadir on OS was different between CAB and non-CAB therapy.

Prostate-specific antigen (PSA) is regarded as the most sensitive biomarker for prostate cancer. Although androgen/androgen receptor (AR) signaling promotes prostate cancer progression, suppression of AR signaling induces chemokine (CC motif) ligand 2 (CCL2), which enables prostate cancer cells to gain metastatic potential. AR-controlled PSA alone may be an unreliable biomarker for patients receiving androgen deprivation therapy. Therefore, we investigated the validity of CCL2 as a complementary biomarker to PSA for prostate cancer. Our in vitro approach of enriching for prostate cancer cells with higher migration potential showed that CCL2 activated cellular migration. Importantly, we found that CCL2 levels were significantly different between men (n = 379) with and without prostate cancer. Patients with CCL2 ≥ 320 pg/mL had worse overall survival and prostate cancer -specific survival than those with CCL2 < 320 pg/mL. A novel risk classification was developed according to the risk factors CCL2 ≥ 320 pg/mL and PSA ≥ 100 ng/mL, and scores of 2, 1, and 0 were defined as poor, intermediate, and good risk, respectively, and clearly distinguished patient outcomes. CCL2 may serve as a novel biomarker for prostate cancer. The novel risk classification based on combining CCL2 and PSA is more reliable than using either alone.

Purpose: The current tumor-node-metastasis (TNM) classification system has been used for many years. The prognosis of patients with metastatic prostate cancer (mPC) treated using primary androgen deprivation therapy (PADT) was analyzed according to the TNM classification., Methods: A total of 5618 cases with lymph node metastases only (N1M0), non-regional lymph node metastasis (M1a), bone metastasis (M1b), and distant metastasis (M1c) were selected from the Japanese Study Group of Prostate Cancer database. Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were calculated using Kaplan-Meier analysis. The influence of clinical variables on patient prognosis was evaluated using the Cox proportional hazard regression model., Results: The 5-year OS, CSS, and PFS were 76.0, 83.2, and 38.8% in N1M0, 57.5, 69.0, and 23.0% in M1a, 54.0, 63.1, and 23.0% in M1b, and 40.0, 51.5, and 16.6% in M1c, respectively. OS, CSS, and PFS worsened as the stages progressed. OS, CSS, and PFS were all significantly worse in N1M1b compared with N0M1b. Multivariate analysis revealed that OS and CSS were worse in patients with a Gleason score ≥8 and that combined androgen blockade (CAB) treatment provided better OS than non-CAB treatments at any tumor stage. However, OS and CSS were worse in individuals with a prostate-specific antigen >100 ng/ml only in M1b., Conclusions: Patient prognosis worsened with stage progression; therefore, current TNM classification system of mPC for PADT was shown to be trustworthy. Each PC cell that develops bone or lymphoid metastasis may exhibit different characteristics.

Background: Prostate-specific antigen (PSA) is a useful biomarker for risk classification in patients with prostate cancer. However, it is unclear whether a correlation exists between low PSA levels (<10 ng/ml) at diagnosis and prognosis., Methods: Of the 642 Japanese patients who underwent prostate biopsy and were diagnosed with prostate cancer at Kanazawa University Hospital from 2000 to 2010, 406 patients with a PSA level <20 ng/ml were retrospectively reviewed., Results: PSA levels in 275 (68%) patients were <10 ng/ml. Although the percentage of Gleason score 8-10 in patients with a PSA level of <3.5 ng/ml was higher than that in patients with a PSA level between 3.5 and 10 ng/ml, it was not statistically significant. On the other hand, the percentage of higher stage (T3 and T4) patients with a PSA level <3.5 ng/ml was significantly greater than that in patients with a PSA level between 3.5 and 10 ng/ml (P < 0.0001). The percentage of metastases (N1 and M1) in patients with a PSA level <3.5 ng/ml was also significantly higher than that in patients with a PSA level between 3.5 and 10 ng/ml (P = 0.0112)., Conclusions: Patients with prostate cancer with a PSA level <3.5 ng/ml at diagnosis had a more advanced stage of cancer compared with those with a PSA level between 3.5 and 10 ng/ml. Therefore, risk classification using PSA levels at diagnosis may need to take into consideration this specific PSA range in order to better predict survival., (© 2015 Wiley Periodicals, Inc.)

Objective: To examine chronological changes in urethral and bladder functions before, immediately after, and 1 year after robot-assisted radical prostatectomy (RARP), urodynamic studies were prospectively performed., Methods: Sixty-three consecutive patients underwent pressure-flow studies, urethral pressure profiles, and abdominal leak point pressure (ALPP) tests 1-2 days before, immediately after, and 1 year after RARP., Results: The mean bladder compliance was 28.3 mL/cm H₂O before RARP; it worsened to 16.3 mL/cm H₂O immediately after RARP and recovered to 27.1 mL/cm H₂O at 1 year. The mean detrusor pressure at maximum flow rate was 61.9 cm H₂O before RARP; it decreased to 34.3 cm H₂O immediately after RARP and remained at 35.6 cm H₂O at 1 year. The mean maximum urethral closure pressure was 84.2 cm H₂O before RARP; it decreased to 33.4 cm H₂O immediately after RARP and recovered to 63.0 cm H₂O at 1 year. Intrinsic sphincter deficiency (ISD) evaluated by the ALPP test was observed in 53 patients immediately after RARP, although no patient showed ISD before RARP. ISD remained in 7 patients at 1 year. Both ALPP and maximum urethral closure pressure at 1 year were significant factors for continence in multivariate analysis., Conclusion: Urethral sphincter and bladder function worsen immediately after RARP and recover over time. The bladder storage function after RARP returns to almost the same level before RARP, and the voiding function improves compared with the condition before RARP; however, the urethral sphincter function does not return to its preoperative level. Urethral sphincter dysfunction is considered the main factor for urinary incontinence after RARP., (Copyright © 2015 Elsevier Inc. All rights reserved.)

To clarify the recent trends in prostate-specific antigen (PSA) distribution in men in Japan, we analyzed the PSA distributions of men undergoing PSA-based population screening. We summarized the annual individual data of PSA-based population screening in Kanazawa, Japan, from 2000 to 2011, and analyzed baseline serum PSA values of the participants at the first population screening. Serum PSA distributions were estimated in all participants and those excluding prostate cancer patients according to age. From 2000 to 2011, 19 620 men participated aged 54-69 years old in this screening program. Mean baseline serum PSA level of all participants at the first screening was 2.64 ng ml⁻¹ in 2000, and gradually decreased to approximately 1.30 ng ml⁻¹ in 2006. That of participants excluding prostate cancer patients was 1.46 ng ml⁻¹ in 2000, and there was no remarkable change during the study period. The 95 th percentiles in the participants excluding prostate cancer patients detected at the first population screening of men aged 54-59, 60-64, and 65-69 years old were 2.90, 3.60, and 4.50 ng ml⁻¹, respectively. After the commencement of population screening, the proportion of prostate cancer patients with high serum PSA levels decreased. However, there were no changes in serum PSA levels in men without prostate cancer. Age-specific PSA reference level of men without prostate cancer in Japan was similar to that in China and Korea.

Background: To investigate the cumulative probability of developing prostate cancer according to prostate-specific antigen (PSA) velocity (PSAV) from first-to second-round PSA-based population screening in men with low baseline serum PSA levels., Patients and Methods: A total of 11,913 men aged between 54 and 69 years with baseline PSA levels of ≤2.0 ng/ml at the first population screening and who underwent population screening at least twice, were enrolled. The cumulative probability of developing prostate cancer according to age, baseline PSA and PSAV was investigated. The clinicopathological features of screen-detected cancer were also investigated., Results: Out of the 11,913 men, 110 (0.92%) were pathologically diagnosed with prostate cancer during the observation period. The cumulative probability of developing prostate cancer in all participants after 5 and 10 years was 0.64% and 1.79%, respectively. Univariate and multivariate analyses determined that baseline PSA levels and PSAVs were significant predictors of developing cancer and the hazard ratio increased with increasing baseline PSA levels and PSAVs. The optimal PSAV cut-off levels for prostate cancer development were 0.069, 0.106 and 0.285 for the baseline PSA ranges of 0.0-1.0, 1.1-1.5 and 1.6-2.0 ng/ml, respectively. There were no significant differences in baseline PSA levels and PSAVs according to the clinical characteristics of the screen-detected prostate cancer patients., Conclusion: The present study demonstrated that serum PSA levels at second round screening were a strong predictor of cancer development in men with baseline PSA levels≤2.0 ng/ml at the first population screening., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: We investigated the relationship between a new index considering the estimated working space and difficulty of robot-assisted radical prostatectomy (RARP) using our database., Patients and Methods: Working height was calculated by the obstetric conjugate diameter minus the bladder and rectal wall thicknesses minus the thickness of postvesical fat minus the rectal fat thicknesses measured using preoperative magnetic resonance imaging (MRI). The proportion of working height was calculated by dividing the working height by the obstetric conjugate diameter., Results: A total of 112 RARP cases were enrolled. The mean obstetric conjugate was 105 mm and the mean proportion of working height was 72.5%. Multivariate linear regression analysis indicated that the proportion of working height was an independent predictive factor for both console time and estimated blood loss., Conclusion: The difficulty of RARP can be predicted by measuring the fat thicknesses around the rectum and bladder by MRI before surgery., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: To evaluate continence status and mechanism of urinary incontinence immediately after robot-assisted radical prostatectomy (RARP) by performing urodynamic evaluation., Methods: A total of 87 patients with localized prostate cancer who underwent RARP were included. Filling cystometry, urethral pressure profilometry, and abdominal leak point pressure (ALPP) tests were performed before and immediately after RARP., Results: The mean urine loss ratio (ULR), calculated by dividing the total urine volume by the weight of urine loss after RARP, was 17.8%. Nerve-sparing (NS) surgery significantly affected ULR compared with non-NS surgery. In the comparison between preoperative and postoperative results, the mean maximal cystometric capacity (MCC) and maximal closure urethral pressure (MUCP) decreased from 341 mL and 84.6 cm H2O to 250 mL and 35.6 cm H2O, respectively. No urine leakage was observed in ALPP test preoperatively; however, urine leakage was observed postoperatively in 75 patients (86%), with a mean ALPP of 47.7 cm H2O. Multivariate analysis revealed that MCC, MUCP, and ALPP after RARP were predictive factors for ULR. Linear correlations were found between ULR and MUCP and between ULR and ALPP after RARP. NS status and MUCP after RARP (r=0.247; P=.021) and the ALPP (r=0.254; P=.018) were significantly correlated., Conclusion: In urodynamic evaluation immediately after RARP, MCC, MUCP, and ALPP were found to predictive factors for urinary incontinence. The NS procedure contributed to continence status after RARP., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The functions of superoxide dismutase-3 (SOD3), which acts on the cell surface and protects cells from oxidative stress, remain uncertain in the progression of prostate cancer., Materials and Methods: To verify SOD3 expression in human prostate tissue, immunohistochemistry was performed using tissue microarrays. To investigate the effects of SOD3 on proliferation, migration, and invasion, SOD3 was overexpressed and recombinant SOD3 was employed in PC-3 prostate cancer cells. H2O2 levels, reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, catalase activity, and 8-oxo-2'-deoxyguanosine (8-OHdG) were estimated in SOD3-overexpressing PC-3 cells., Results: Immunohistochemistry revealed reduced expression of SOD3 in prostate cancer tissue. SOD3 overexpression in PC-3 cells inhibited cell proliferation, migration, and invasion. Recombinant SOD3 had the same effect. H2O2 accumulation was increased by SOD3 overexpression, GSH/GSSG ratio was decreased, and catalase activity was decreased. DNA damage in SOD3-overexpressing cells was confirmed by 8-OHdG elevation., Conclusion: Since SOD3 acts as a tumor suppressor, SOD3 overexpression and recombinant SOD3 might lead to treatment for prostate cancer., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The International Prostate Symptom Score (IPSS) is often used as an interview sheet for assessing lower urinary tract symptoms (LUTS) at the time of prostate-specific antigen (PSA) testing during population-based screening for prostate cancer. However, the relationship between prostate cancer detection and LUTS status remains controversial. To elucidate this relationship, the cumulative probability of prostate cancer detection using IPSS in biopsy samples from patients categorized by serum PSA levels was investigated. The clinical characteristics of prostate cancer detected using IPSS during screening were also investigated. A total of 1,739 men aged 54-75 years with elevated serum PSA levels who completed the IPSS questionnaire during the initial population screening in Kanazawa City, Japan and underwent systematic transrectal ultrasonography-guided prostate biopsy between 2000 and 2013 were enrolled in the present study. Of the 1,739 men, 544 (31.3%) were diagnosed with prostate cancer during the observation period. The probability of cancer detection at 3 years in the entire study population was 27.4% and 32.7% for men with IPSS ≤ 7 and those with IPSS ≥ 8, respectively; there was no statistically significant difference between groups. In men with serum PSA levels of 6.1 to 12.0 ng/ mL at initial screening, the probability of cancer detection was significantly higher in men with IPSS ≤ 7 than in those with IPSS ≥ 8. There were no significant differences in clinical characteristics between groups of patients stratified by IPSS. These findings indicate that the use of IPSS for LUTS status evaluation may be useful for prostate cancer detection in the limited range of serum PSA levels.

Purpose: The aim of this study was to investigate the cumulative probability of prostate cancer detection according to free/total prostate-specific antigen (PSA) ratio in men with PSA levels of 2.1-10.0 ng/ml and also likelihood of detecting clinically insignificant prostate cancer in population-based screening., Methods: A total of 1,277 men aged between 55 and 69 years with total PSA (tPSA) levels of 2.1-10.0 ng/ml screened in population screening in Kanazawa city and underwent systematic transrectal ultrasonography-guided prostate biopsy between 2000 and 2011 were enrolled. The cumulative probability of prostate cancer detection in biopsy according to age, serum tPSA, and free-to-total PSA (f/t PSA) ratio was investigated. The clinicopathological features of screening-detected prostate cancer were also investigated., Results: Of the 1,277 subjects in the study population, 320 (25.0 %) were diagnosed with prostate cancer during the observation period. The probabilities of prostate cancer detection at 3 years were 64.5, 41.2, 28.5, and 14.3 % for the men with f/t PSA ratio ≤0.08, 0.09-0.13, 0.14-0.22, and ≥0.23, respectively; the differences in probabilities of prostate cancer detection among men with different f/t PSA ratios were statistically significant. Among 320 patients, 84 (26.3 %) had favorable clinicopathological features that made them suitable for active surveillance. The f/t PSA ratio in unfavorable cancer patients was significantly lower that that in favorable cancer patients., Conclusion: The present study demonstrated that the f/t PSA ratio was a strong predictor of future cancer detection and unfavorable cancerous features in prostate biopsy in men with total PSA levels of 2.1-10.0 ng/ml at population screening.

Background: The matricellular protein secreted protein acidic and rich in cysteine (SPARC) plays an important role on tumor metastasis and progression in several cancers. However, the roles of SPARC in prostate cancer (PCa) remain unclear., Methods: To identify SPARC protein in prostate tissue, immunohistochemical analysis of SPARC was conducted using human prostate tissue microarray. To detect SPARC expression in prostate cancer (LNCaP, DU145, and PC-3) and stromal cells, RT-PCR, western blot analysis, and ELISA was conducted. To reveal the function of exogenous SPARC in PCa cells, AKT phosphorylation was confirmed by western blot analysis after coculture with stromal cells. Proliferation and migration of PCa cells were examined by addition of SPARC. The interaction between SPARC and integrin β1 was confirmed by western blot analysis after immunoprecipitation., Results: SPARC protein was expressed well in normal tissue compared with PCa tissue. ELISA showed high secreted SPARC protein in normal prostate-derived stromal cell (PrSC) compared with PCa-derived stromal cell (PCaSC) and PCa. PCa cells cocultured with PrSC showed reduced AKT phosphorylation more than with PCaSC. PCa cells cocultured with PrSC whose SPARC was knocked-down restored AKT phosphorylation. Moreover, PCa cells treated with SPARC led to reduced AKT phosphorylation. Immunoprecipitation with SPARC revealed interaction of SPARC and integrin β1 in PCa cells. Inhibited proliferation and migration of PCa cells by SPARC was restored by integrin β1 neutralizing antibody., Conclusions: Reduced SPARC secretion from stromal cells might affect PCa progression mediating through limiting AKT phosphorylation after interaction with integrin β1., (Copyright © 2013 Wiley Periodicals, Inc.)

Aim: In order to investigate which types of localized prostate cancer can be treated most effectively by androgen deprivation therapy (ADT), cases of no residual cancer in radical prostatectomy specimens (pT0) after neoadjuvant ADT were analyzed., Patients and Methods: Patients with localized prostate cancer who underwent radical prostatectomy after neoadjuvant ADT were investigated retrospectively., Results: Thirty-two patients (24.2%) were diagnosed with pT0 disease by pathological evaluation. The positive-core proportion of prostate biopsy was lower, the duration of neoadjuvant ADT was longer, and prostate-specific antigen (PSA) nadir before radical prostatectomy was lower in pT0 cases compared to non-pT0 cases, and these differences were statistically significant. The percentage of pT0 cases with PSA nadir <0.2 ng/ml and <0.008 ng/ml before radical prostatectomy were 29.2% (21 out of 72 cases) and 83.3% (5 out of 6 cases), respectively. The positive-core proportion of prostate biopsy and PSA nadir before radical prostatectomy had a significant impact on pT0 status after neoadjuvant ADT., Conclusion: ADT for localized prostate cancer is thought to be highly effective in cases with low cancer volume. ADT is effective in cases of localized prostate cancer with PSA below the levels of detection by supersensitive PSA assay, and such cases show no cancer recurrence. Treatment options in such cases include intermittent or discontinuation of ADT.

Background: Ethinylestradiol was used as palliative treatment for patients with advanced prostate cancer (PCa). However, its use has declined after the development of combined androgen blockade. In the present study, we analyzed the effects of ethinylestradiol on pretreated castration-resistant PCa patients., Patients and Methods: Twenty-four Japanese patients were orally administered ethinylestradiol at a dose of 1.5 mg/day and prostate-specific antigen (PSA) was examined. We retrospectively analyzed the proportion of patients achieving a decline in PSA of >50% and progression-free and overall survival rates., Results: All patients had already been treated with combined androgen blockade followed by one or more salvage therapies. Median follow-up time was 227 (range: 42-1490) days and median ethinylestradiol treatment time was 195 (range: 3-791) days. The proportion of patients achieving a decline in PSA >50% was 70%. Median progression-free survival was estimated as 300 days. At the end of the follow-up period, one patient had died from PCa. Adverse events occurred in three patients, namely elevation of liver enzymes, anorexia, and heart failure in one patient each., Conclusion: Oral ethinylestradiol administration may be useful for treatment of advanced castration-resistant PCa after salvage therapy with a high PSA response rate and low adverse event rate.

Background: Tranilast is a therapeutic agent used in treatment of allergic diseases, although it has been reported to show anti-tumor effects on some cancer cells. To elucidate the effects of tranilast on prostate cancer, we investigated the mechanisms of its anti-tumor effect on prostate cancer., Methods: The anti-tumor effects and related mechanisms of tranilast were investigated both in vitro on prostate cancer cell lines and bone-derived stromal cells, and in vivo on severe combined immunodeficient (SCID) mice. We verified its clinical effect in patients with advanced hormone refractory prostate cancer (HRPC)., Results: Tranilast inhibited the proliferation of LNCaP, LNCaP-SF, and PC-3 cells in a dose-dependent manner and growth of the tumor formed by inoculation of LNCaP-SF in the dorsal subcutis and in the tibia of castrated SCID mice. Flow cytometry and TUNEL assay revealed induction of cell cycle arrest and apoptosis by tranilast. Tranilast increased expression of proteins involved in induction of cell cycle arrest and apoptosis. Coculture with bone-derived stromal cells induced proliferation of LNCaP-SF cells. Tranilast also suppressed secretion of transforming growth factor beta1 (TGF-beta1) from bone-derived stromal cells, which induced their differentiation. Moreover, tranilast inhibited TGF-beta1-mediated differentiation of bone-derived stromal cells and LNCaP-SF cell migration induced by osteopontin. In the clinical investigation, PSA progression was inhibited in 4 of 16 patients with advanced HRPC., Conclusions: These observations suggest that tranilast may be a useful therapeutic agent for treatment of HRPC via the direct inhibitory effect on cancer cells and suppression of TGF-beta1-associated osteoblastic changes in bone metastasis.

Objectives: To perform a prospective observational study between risedronate and no risedronate (control) groups to determine the effectiveness of risedronate against bone loss in patients with prostate cancer (PCa) receiving androgen-deprivation therapy (ADT). ADT for PCa has iatrogenic complications (eg, bone loss and fracture)., Methods: We enrolled 60 Japanese patients with PCa who were receiving ADT or were newly scheduled for ADT. The lumbar spine bone mineral density (BMD) was determined by dual-energy x-ray absorptiometry. Patients with a BMD <90% of the young adult mean received risedronate. We analyzed 29 and 27 patients in the risedronate and control groups, respectively. The BMD, urinary deoxypyridinoline, and serum bone alkaline phosphatase were measured as bone turnover markers at 6 and 12 months., Results: The BMD/young adult mean ratio correlated inversely with the duration of ADT. The initial mean BMD was significantly lower in the risedronate group than in the control group (1.02 +/- 0.19 vs 1.19 +/- 0.16 g/cm(2)). We focused on patients treated with ADT for >6 months. The mean percentage of changes in the BMD/young adult mean ratio of the risedronate and control groups was +2.6 +/- 4.5% and -2.8 +/- 2.6% after 1 year, respectively (P = .0001). The urinary deoxypyridinoline and bone alkaline phosphatase in the risedronate group decreased significantly after 12 months compared with the levels in the controls., Conclusions: The results of our study have shown that oral administration of risedronate is effective for the recovery of ADT-induced bone loss in patients with PCa.