@article{oai:kanazawa-u.repo.nii.ac.jp:00044173,
 author = {林, 智之 and 山下, 太郎 and 寺島, 健志 and 須田, 烈史 and 岡田, 光 and 朝日向, 良朗 and 丹尾, 幸樹 and 砂子阪, 肇 and 鷹取, 元 and 荒井, 邦明 and 山下, 竜也 and 水腰, 英四郎 and 本多, 政夫 and 金子, 周一 and Hayashi, Tomoyuki and Yamashita, Taro and Terashima, Takeshi and Suda, Tsuyoshi and Okada, Hikari and Asahina, Yoshiro and Hayashi, Takehiro and Hara, Yasumasa and Nio, Kouki and Sunagozaka, Hajime and Takatori, Hajime and Arai, Kuniaki and Yamashita, Tatsuya and Mizukoshi, Eishiro and Honda, Masao and Kaneko, Shuichi},
 issue = {1},
 journal = {BMC Cancer},
 month = {Dec},
 note = {Background: Sorafenib is a multiple receptor tyrosine kinase inhibitor known to prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Predicting this drug's survival benefits is challenging because clinical responses are rarely measurable during treatment. In this study, we hypothesized that serum cytokines levels could predict the survival of advanced HCC patients, as sorafenib targets signaling pathways activated in the tumor stromal microenvironment and potentially affects serum cytokine profiles. Methods: Of 143 patients with advanced-stage HCC, 104 who were recruited between 2003 and 2007 received hepatic arterial infusion chemotherapy (HAIC) that mainly targets tumor epithelial cells at S-phase (cohort 1); additionally, 39 recruited between 2010 and 2012 received sorafenib, which primarily targets the stromal vascular endothelial cells. Serum samples were collected and aliquoted prior to the treatment. Serum EGF, bFGF, HGF, IFN-γ, IL-10, IL-12, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10, MIG, PDGF-BB, SCF, SDF1, TGF-β, TGF-α, TNF-α, and VEGF-A were measured via enzyme-linked immunosorbent assays. The Modified Response Evaluation Criteria in Solid Tumors were used to assess tumor responses. Results: The median survival time of HCC patients in cohorts 1 (HAIC-treated) and 2 (sorafenib-treated) were 12.0 and 12.4 months, respectively. Kaplan-Meier analysis revealed no significant survival differences between the 2 groups. Patients who survived more than 2 years after sorafenib treatment exhibited higher serum levels of IL-10, IL-12, TNF-a, IL-8, SDF-1, EGF, PDGF-BB, SCF, and TGF-α. Furthermore, cohort 2 patients with higher serum IL-5 (>12 pg/mL), IL-8 (>10 pg/mL), PDGF-BB (>300 pg/mL), and VEGF-A (>50 pg/mL) levels achieved longer survival; cohort 1 patients did not. Hierarchical cluster analysis of 6 cytokines robustly enriched for comparison analysis between cohorts 1 and 2 (IL-5, IL-8, TGF-α, PDGF-BB, CXCL9, and VEGF-A) revealed that elevation of these cytokines correlated with better survival when treated with sorafenib but not with HAIC. Conclusions: Patients who exhibited survival benefits owing to sorafenib treatment tended to present higher serum cytokines levels, potentially reflecting the activation of stromal signaling in the tumor microenvironment. Our study thus introduces novel biomarkers that may identify advanced HCC patients who may experience survival benefits with sorafenib treatment. © 2017 The Author(s)., 金沢大学先進予防医学研究科},
 title = {Serum cytokine profiles predict survival benefits in patients with advanced hepatocellular carcinoma treated with sorafenib: A retrospective cohort study},
 volume = {17},
 year = {2017}
}