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

Docetaxel (DOC) is one of the most effective chemotherapeutic agents against castration-resistant prostate cancer (CRPC). Despite an impressive initial clinical response, the majority of patients eventually develop resistance to DOC. In tumor metabolism, where tumors preferentially utilize anaerobic metabolism, lactate dehydrogenase (LDH) serves an important role. LDH controls the conversion of pyruvate to lactate, with LDH-A, one of the predominant isoforms of LDH, controlling this metabolic process. In the present study, the role of LDH-A in drug resistance of human prostate cancer (PC) was examined by analyzing 4 PC cell lines, including castration-providing strains PC3, DU145, LNCaP and LN-CSS (which is a hormone refractory cell line established from LNCaP). Sodium oxamate (SO) was used as a specific LDH-A inhibitor. Changes in the expression level of LDH-A were analyzed by western blotting. Cell growth and survival were evaluated with a WST-1 assay. Cell cycle progression and apoptotic inducibility were evaluated by flow cytometry using propidium iodide and Annexin V staining. LDH expression was strongly associated with DOC sensitivity in PC cells. SO inhibited growth of PC cells, which was considered to be caused by the inhibition of LDH-A expression. Synergistic cytotoxicity was observed by combining DOC and SO in LN-CSS cells, but not in LNCaP cells. This combination treatment induced additive cytotoxic effects in PC-3 and DU145 cells, caused cell cycle arrest in G2-M phase and increased the number of cells in the sub-G1 phase of cell cycle in LN-CSS cells. SO promoted DOC induced apoptosis in LN-CSS cells, which was partially caused by the inhibition of DOC-induced increase in LDH-A expression. The results strongly indicated that LDH-A serves an important role in DOC resistance in advanced PC cells and inhibition of LDH-A expression promotes susceptibility to DOC, particularly in CRPC cells. The present study may provide valuable information for developing targeted therapies for CRPC in the future.

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Abstract. It has not been elucidated whether certain types of M1b prostate cancer (M1b PC) are associated with a poor outcome. The present study retrospectively identified predictive factors related to the outcome of M1b PC. The subjects were 104 patients who attended our hospital and received a diagnosis of M1b PC. The observation period ranged from 4 to 122 months (median, 43 months). The parameters investigated were: T classification, N classification, Gleason score (GS), pretreatment prostate-specific antigen (PSA) level, extent of disease (EOD) grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), calcium, and hemoglobin (Hb) levels, platelet count, and the status of HER-2 overexpression as determined with a Hercep Test™ Kit using initial needle biopsy specimens for diagnosis. Log-rank test and Cox univariate analysis identified the following factors with statistically significant differences: pretreatment PSA ≥192, N1, GS ≥8, EOD grade 3+4, high LDH, high ALP, low Hb, and HER-2 overexpression. Multivariate Cox proportional hazard analysis identified the factors GS ≥8, high LDH, and HER-2 overexpression with significant differences. The hazard ratio was 5.962, 2.465, and 2.907, respectively, and the probability value was P=0.0218, P=0.0207 and P=0.0090, respectively. When the subjects with GS ≥8, high LDH, and HER-2 over-expression were classified as the high-risk group, the 5-year cause-specific survival rate was 51.2, 29.6, and 20.0%, respectively. The present study showed that M1b PC patients with GS ≥8, high LDH, and HER-2 overexpression have a very poor outcome and thus, should be treated as a high-risk group requiring close follow-up. IntroductionOf cancer deaths, in the USA, the incidence of prostate cancer (PC) ranks first in men, while the mortality from PC ranks second after lung cancer. In Europe, about 260,000 people are diagnosed with PC every year (1), and PC accounts for 9% of cancer deaths in men (2). The frequency of PC varies from country to country; it has been reported to be lowest in the Far East, particularly in mainland China and Japan (3). In Japan, however, the frequency in 2015 is expected to increase to about 4.6 times that in 1985 (4), and a recent study reported that PC screening would reduce mortality from PC by 20% (5). PC will thus become an increasingly important disease in men. Patients with PC have only vague symptoms in the early phase of the disease; it is not rare for patients to present with chief complaint of bone pain or neurological symptoms and found to already have PC with bone metastases at the time of diagnosis (6). Most PC is androgen-dependent. Patients with metastatic PC are rarely cured, and most of them are treated by hormone therapy. The majority of such patients, however, progress to castration-resistant prostate cancer (CRPC) within several years. Hormone resistance is considered to be acquired through abnormalities in the androgen receptor as well as a mechanism other than the androgen receptor (7). At present, however, the characteristics of ...

Abstract. The aim of this study was to investigate the relationship between tissue concentrations and exposure times or therapeutic effect of an anthracycline anticancer drug, pirarubicin, in bladder cancer tissue after single intravesical administration against superficial bladder cancer. The concentrations of pirarubicin in tumor tissues and serum were measured at designated collection times after a single intravesical administration of pirarubicin (30 mg) in 22 patients with superficial bladder cancer. A wide range of concentrations of pirarubicin in bladder cancer tissue was observed (2.3-125 µg/g of tissue), although serum pirarubicin concentrations were not detected in any of the patients. Recurrence of superficial bladder cancer after transurethral resection of the bladder tumor (TUR-BT) was observed in 2 patients (9%). The concentration of pirarubicin in the tumor tissue tended to be higher as the exposure time increased. There was a weak relationship between the pirarubicin tissue concentration and tumor size. However, no significant relationship between tissue pirarubicin concentrations and the prophylactic effect against intravesical recurrence of bladder cancer after TUR-BT was observed. All patients had no adverse events, such as bladder irritation and local toxicity, caused by the treatment with pirarubicin. These findings suggest that prior to single intravesical administration of pirarubicin to patients with superficial bladder cancer the exposure time and tumor size should be considered.