Miyata Yasuyoshi, Mitsunari Kensuke, Akihiro Asai, Watanabe Shin-Ichi, Matsuo Tomohiro, Ohba Kojiro, Sakai Hideki
Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.
Oncol Lett. 2017 Feb;13(2):811-818. doi: 10.3892/ol.2016.5484. Epub 2016 Dec 12.
In patients with advanced urothelial cancer (UC), a combination of cisplatin (CDDP) and gemcitabine (GEM) is the most commonly used first-line systematic chemotherapy regimen. Although no standard regime for the treatment of CDDP-resistant UC has been established, GEM-based regimens are frequently used in these patients. In other types of cancer, human antigen R (HuR) status in cancer cells is closely associated with patient response to GEM. The aim of the present study was to establish the predictive potential of HuR expression for disease progression and survival in patients with UC who were treated with GEM-based regimens as a first or second-line chemotherapy. A total of 50 patients with advanced UC were enrolled in the current study. As first-line chemotherapy, methotrexate, vinblastine, epirubicin and CDDP (MVEC) combination therapy and GEM and CDDP combination therapy were administered in 34 (68.0%) and 16 patients (32.0%), respectively. Following progression, 45 patients (90.0%) were treated with combined GEM and paclitaxel therapy, and 5 patients (10.0%) were treated with GEM monotherapy. Cytoplasmic and nuclear HuR expression was evaluated using immunohistochemical techniques. The associations between HuR expression levels and local tumor response and treatment outcomes were analyzed. In first-line chemotherapy, no anticancer effects were observed to be significantly associated with nuclear or cytoplasmic HuR expression. In second-line chemotherapy nuclear HuR expression also exhibited no significant association with anticancer effects; however, the local tumor response was significantly improved if positive cytoplasmic HuR expression was present (P=0.002). Multivariate analyses revealed that cytoplasmic HuR expression levels were a significant predictive marker for longer OS (hazard ratio, 0.22; 95% confidence interval, 0.09-0.56; P=0.001). No significant association was observed between nuclear HuR expression levels and the overall survival. Therefore, cytoplasmic HuR expression is a significant predictive marker of response to GEM-based chemotherapy in patients with CDDP-resistant UC. Despite the limitations of a small and retrospective study, the results of the present study may facilitate the development of novel treatment strategies and provide a focus for additional basic and clinical studies.
在晚期尿路上皮癌（UC）患者中，顺铂（CDDP）和吉西他滨（GEM）联合是最常用的一线全身化疗方案。尽管尚未确立治疗顺铂耐药UC的标准方案，但基于GEM的方案常用于这些患者。在其他类型的癌症中，癌细胞中人抗原R（HuR）状态与患者对GEM的反应密切相关。本研究的目的是确定HuR表达对接受基于GEM方案作为一线或二线化疗的UC患者疾病进展和生存的预测潜力。本研究共纳入50例晚期UC患者。作为一线化疗，分别对34例（68.0%）和16例（32.0%）患者给予甲氨蝶呤、长春碱、表柔比星和顺铂（MVEC）联合治疗以及GEM与CDDP联合治疗。病情进展后，45例（90.0%）患者接受GEM与紫杉醇联合治疗，5例（10.0%）患者接受GEM单药治疗。采用免疫组化技术评估细胞质和细胞核HuR表达。分析HuR表达水平与局部肿瘤反应及治疗结果之间的关联。在一线化疗中，未观察到抗癌效果与细胞核或细胞质HuR表达有显著关联。在二线化疗中，细胞核HuR表达也与抗癌效果无显著关联；然而，如果存在细胞质HuR阳性表达，则局部肿瘤反应显著改善（P = 0.002）。多因素分析显示，细胞质HuR表达水平是OS更长的显著预测标志物（风险比，0.22；95%置信区间，0.09 - 0.56；P = 0.001）。未观察到细胞核HuR表达水平与总生存之间存在显著关联。因此，细胞质HuR表达是顺铂耐药UC患者对基于GEM化疗反应的显著预测标志物。尽管本研究存在样本量小和回顾性研究的局限性，但本研究结果可能有助于开发新的治疗策略，并为更多基础和临床研究提供重点。
