Protease-activated receptor 2 contributes to placental development and fetal growth in mice.

BACKGROUND: Protease-activated receptor 2 (PAR2) is activated by serine proteases such as coagulation tissue factor/VIIa complex, factor Xa or trypsin and is pro-angiogenic in several disease models. Impaired angiogenesis in placenta causes placental dysfunction and fetal growth restriction. PAR2 is expressed in the placenta trophoblast. However, the role of PAR2 in pregnancy remains unknown. OBJECTIVE: The present study aimed to examine the role of PAR2 in placental development and fetal growth using a murine model. METHODS: PAR2-/- or PAR2+/+ mice in the ICR background were used. Female PAR2-/- mice were mated with male PAR2-/- mice, and female PAR2+/+ mice were mated with male PAR2+/+ mice to obtain PAR2-/- and PAR2+/+ fetuses, respectively. The day a virginal plug was observed in the morning was determined as 0.5-day post-coitum (dpc). Pregnant mice were sacrificed on 13.5 or 18.5 dpc to collect samples. RESULTS: A deficiency of PAR2 significantly reduced the fetal and placental weight and impaired placental labyrinth development in mice on 18.5 dpc. Collagen IV expression in placenta labyrinth was smaller in PAR2 knockout mice compared to that of wild-type mice. A deficiency of PAR2 also reduced the expression levels of genes related to angiogenesis and coagulation in placenta. CONCLUSION: Our data suggest that PAR2 is required for fetal growth and angiogenesis in the placenta and is thus important for a normal pregnancy.

Neoadjuvant androgen-deprivation therapy with radical prostatectomy for prostate cancer in association with age and serum testosterone.

BACKGROUND: We aimed to identify the candidate prostate cancer patients suitable for neoadjuvant androgen-deprivation therapy (ADT) with radical prostatectomy (RP). MATERIALS AND METHODS: This study included 711 Japanese patients with clinically localized prostate cancer who were treated with RP between 2000 and 2013. Patients were treated with or without neoadjuvant ADT before RP. The prognostic significance of neoadjuvant ADT on biochemical recurrence (BCR) was analyzed according to various clinicopathological characteristics. RESULTS: BCR occurred in 186 (26.2%) of 711 patients. The group treated with neoadjuvant ADT showed higher levels of prostate-specific antigen at diagnosis and advanced clinical T-stage, but suppressed pathological T-stage. Neoadjuvant ADT was not associated with the risk of BCR. In subgroup analysis, neoadjuvant ADT was significantly associated with increased BCR in patients aged >65 years [hazard ratio (95% confidence interval), 2.04 (1.13-3.43), P = 0.020]. Among the 53 patients with available serum testosterone levels, neoadjuvant ADT was associated with the risk of BCR according to serum testosterone levels. CONCLUSION: This study demonstrated that neoadjuvant ADT showed potential deleterious effects in older patients and patients with lower serum testosterone levels, while a possible improved prognosis in patients with high serum testosterone levels treated with neoadjuvant ADT was suggested, warranting further exploration.

Prognostic and Predictive Factors for Anti-androgen Withdrawal in Castration-resistant Prostate Cancer.

BACKGROUND/AIM: We aimed to identify prognostic and predictive factors for anti-androgen withdrawal syndrome (AWS) to help guide decisions on anti-androgen withdrawal in castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: This study included 95 patients with prostate cancer which progressed to CRPC despite primary androgen-deprivation therapy (ADT). AWS was defined as >50% prostate-specific antigen decline after anti-androgen withdrawal. Associations between AWS, and clinicopathological factors and prognosis were investigated. RESULTS: Among the 95 patients, 84 (88.4%) underwent anti-androgen withdrawal, among whom AWS was recognized in nine (10.8%). Gleason score and response duration to primary ADT were predictors of AWS. Long duration of response to primary ADT was also associated with better progression-free survival [hazard ratio (HR)=0.021, 95% confidence interval (CI)=0.0025-0.14, p<0.0001] and overall survival (HR=0.0042, 95% CI=0.0001-0.089, p<0.0001). Age (HR=7.19, 95% CI=1.08-54.27, p=0.041) and radiological/clinical progression (HR=3.14, 95% CI=1.35-6.43, p=0.010) were associated with worse overall survival. Intriguingly, radiological/clinical progression was associated with the differential effect of anti-androgen withdrawal on overall survival (interaction p=0.031). CONCLUSION: Patients who suffer radiological/clinical progression are unsuitable candidates for anti-androgen withdrawal.

Differential Risk of Castration Resistance After Initial Radical Prostatectomy or Radiotherapy for Prostate Cancer.

BACKGROUND/AIM: Salvage androgen-deprivation therapy (ADT) is standard treatment for recurrent prostate cancer after curative therapy. However, the prognostic impact of different treatment modalities on the time to castration resistance remains unclear. In this study, we investigated the prognosis of men treated with salvage ADT after initial radical prostatectomy or radiotherapy for prostate cancer. PATIENTS AND METHODS: Between 2000 and 2013, 149 Japanese men with recurrent prostate cancer who were initially treated with radical prostatectomy (n=95) or radiotherapy (n=54) and were subsequently treated with salvage ADT after disease recurrence were enrolled in this study. The prognostic significance of the curative treatment modality and clinicopathological findings were analyzed. RESULTS: During a median follow-up period of 4.7 years after recurrence, castration-resistant progression was observed in 22 men. The 5-year progression-free survival, metastasis-free survival, cause-specific survival, and overall survival rates for all patients were 86.3%, 81.4%, 95.7%, and 94.5%, respectively. Multivariate analysis identified the biopsy Gleason score at initial diagnosis and the initial curative treatment modality as significant predictors of castration resistance. CONCLUSION: This study showed that low biopsy Gleason score (≤7) at diagnosis and radical prostatectomy as the curative treatment may be favorable prognostic factors for treatment with salvage ADT.