We retrospectively reviewed the outcome of docetaxel, EMP, and carboplatin (DEC) as second-line chemotherapy in castration-resistant prostate cancer (CRPC) patients previously treated with docetaxel-prednisolone (DP)....We retrospectively reviewed the outcome of docetaxel, EMP, and carboplatin (DEC) as second-line chemotherapy in castration-resistant prostate cancer (CRPC) patients previously treated with docetaxel-prednisolone (DP). Nineteen patients pretreated with DP received a DEC regimen which consisted of a 28-day cycle of docetaxel [60 mg/m<sup>2</sup> intravenously (IV) on day 1)], carboplatin (IV to an area under the curve of 5 on day 1), and EMP (560 mg orally daily). The DEC therapy was continued intermittently after two consecutive courses. End points were DEC effect on prostate-specific antigen (PSA), radiographic response, progression-free survival (PFS), and overall survival (OS). All patients received DP before DEC administration with a median of 6 cycles (range, 1 - 12). Mean follow-up duration was 19.0 months after starting DEC therapy;median total number of the therapy cycles was 2 (range, 1 - 11). Thirteen patients (68.4%) showed a PSA decrease;6 (31.6%) showed a decrease in the PSA level of ≥50%, including 4 with no PSA response to DP. Grade 3/4 neutropenia and febrile neutropenia were observed in 13 (68.4%) and 2 (10.5%) patients, respectively. The median PFS following DEC was 3.7 months. The median OS was 18.0 months. In univariate analyses, patients with ≤12 months from CRPC to DEC had shorter PFS and OS, whereas PSA response to DP was not associated with PFS or OS in CRPC patients treated with DEC after DP. In conclusion, DEC retains some clinical benefits for CRPC patients pretreated with DP, even in patients without any response to DP. Therefore, they may be an effective and feasible treatment option for CRPC patients after first-line docetaxel therapy, particularly for those deemed unfit for novel endocrine and chemotherapeutic drugs.展开更多
Background:Recent studies have indicated that a high-fat diet(HFD)and/or HFD-induced obesity may influence prostate cancer(PCa)progression,but the role of HFD in PCa microenvironment is unclear.This study aimed to del...Background:Recent studies have indicated that a high-fat diet(HFD)and/or HFD-induced obesity may influence prostate cancer(PCa)progression,but the role of HFD in PCa microenvironment is unclear.This study aimed to delineate the molecular mechanisms of PCa progression underHFDmilieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1(MIC-1)activation.Methods:We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet.Further,we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts.Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated.Results:HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin(IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mousemodel.In addition,periprostatic adipocytes directly stimulatedMIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release.The increased serum MIC-1 was significantly correlated with human PCa stroma activation,high serum IL-8,IL-6,and lipase activity,advanced PCa progression,and high body mass index of the patients.Glial-derived neurotrophic factor receptor α-like(GFRAL),a specific receptor of MIC-1,was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts,and the expression levelwas decreased by androgen deprivation therapy and chemotherapy.Conclusion:HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression.展开更多
文摘We retrospectively reviewed the outcome of docetaxel, EMP, and carboplatin (DEC) as second-line chemotherapy in castration-resistant prostate cancer (CRPC) patients previously treated with docetaxel-prednisolone (DP). Nineteen patients pretreated with DP received a DEC regimen which consisted of a 28-day cycle of docetaxel [60 mg/m<sup>2</sup> intravenously (IV) on day 1)], carboplatin (IV to an area under the curve of 5 on day 1), and EMP (560 mg orally daily). The DEC therapy was continued intermittently after two consecutive courses. End points were DEC effect on prostate-specific antigen (PSA), radiographic response, progression-free survival (PFS), and overall survival (OS). All patients received DP before DEC administration with a median of 6 cycles (range, 1 - 12). Mean follow-up duration was 19.0 months after starting DEC therapy;median total number of the therapy cycles was 2 (range, 1 - 11). Thirteen patients (68.4%) showed a PSA decrease;6 (31.6%) showed a decrease in the PSA level of ≥50%, including 4 with no PSA response to DP. Grade 3/4 neutropenia and febrile neutropenia were observed in 13 (68.4%) and 2 (10.5%) patients, respectively. The median PFS following DEC was 3.7 months. The median OS was 18.0 months. In univariate analyses, patients with ≤12 months from CRPC to DEC had shorter PFS and OS, whereas PSA response to DP was not associated with PFS or OS in CRPC patients treated with DEC after DP. In conclusion, DEC retains some clinical benefits for CRPC patients pretreated with DP, even in patients without any response to DP. Therefore, they may be an effective and feasible treatment option for CRPC patients after first-line docetaxel therapy, particularly for those deemed unfit for novel endocrine and chemotherapeutic drugs.
基金This work was supported by the Japan Society for the Pro-motion of Science(JSPS,Grant No.:16H02679,16K10992,19K09663)AMED-CREST,Japan Agency for Medical Research and Development(AMED).
文摘Background:Recent studies have indicated that a high-fat diet(HFD)and/or HFD-induced obesity may influence prostate cancer(PCa)progression,but the role of HFD in PCa microenvironment is unclear.This study aimed to delineate the molecular mechanisms of PCa progression underHFDmilieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1(MIC-1)activation.Methods:We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet.Further,we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts.Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated.Results:HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin(IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mousemodel.In addition,periprostatic adipocytes directly stimulatedMIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release.The increased serum MIC-1 was significantly correlated with human PCa stroma activation,high serum IL-8,IL-6,and lipase activity,advanced PCa progression,and high body mass index of the patients.Glial-derived neurotrophic factor receptor α-like(GFRAL),a specific receptor of MIC-1,was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts,and the expression levelwas decreased by androgen deprivation therapy and chemotherapy.Conclusion:HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression.
