Supplementary Material for: Development of a Novel Inflammation-Based Index for Hepatocellular Carcinoma

Background: The aim of current study was to (1) construct and validate a novel hepatocellular carcinoma (HCC)-specific inflammatory index; (2) compare the performances of the Integrated Liver Inflammatory Score (ILIS) to existing 4 inflammatory indices in HCC; (3) explore the association between the inflammatory indices and systemic/intratumoral inflammatory markers. Methods: Two cohorts from Hong Kong (HK; n = 1,315) and Newcastle (n = 574) were studied. A novel index was constructed from the HK training set (n = 627). The index was constructed from the training set by combing independent prognostic circulating parameters, followed by validating in the validation set of HK cohort (n = 688) and the Newcastle cohort. Its prognostic performance was compared to 4 inflammatory indices, namely, the neutrophil to lymphocyte ratio, platelet-to-lymphocyte ratio, prognostic nutrition index, and systemic immune-inflammation index, were compared in the HK cohort. Circulating cytokines and intratumoral gene expression were analyzed in a subset of patients with available samples and correlated with the inflammatory indices. Results: In the training set of the HK cohort, the ILIS, was generated: –0.057 × albumin (g/L) + 0.978 × log (Bilirubin, µmol/L) + 1.341 × log (alkaline phosphatase, IU/L) + 0.086 × Neutrophil (109/L) + 0.301 × log (alpha-fetoprotein, µg/L). With cutoff of 2.60 and 3.87, the ILIS could categorize patients into 3 risk groups in the both validation cohorts. ILIS outperforms other inflammatory indices and remains an independent prognosticator for overall survival after adjustment with Barcelona Clinic Liver Cancer (hazard ratio 31.90, p < 0.001). The ILIS had the best prognostic performances as compared to other inflammatory indices. In exploratory analyses, the ILIS correlated with circulating inflammatory cytokines (e.g., IL-8) but not with any intratumoral inflammatory gene expression. Conclusions: ILIS is an HCC-specific prognostic index built on 5 readily available blood parameters. Its versatility is validated both Eastern and Western population of HCC. The score is correlated with levels of circulating cytokines.

背景：本研究旨在：(1) 构建并验证一种新型肝细胞癌（hepatocellular carcinoma, HCC）特异性炎症指标；(2) 对比整合性肝脏炎症评分（Integrated Liver Inflammatory Score, ILIS）与现有4种HCC相关炎症指标的临床效能；(3) 探究炎症指标与全身/瘤内炎症标志物之间的关联。方法：本研究纳入来自中国香港（HK；n=1315）与纽卡斯尔（n=574）的两个队列。首先以香港队列的训练集（n=627）构建新型炎症指标：通过整合独立的预后性循环参数生成该指标，随后分别在香港队列的验证集（n=688）与纽卡斯尔队列中对其进行验证。在香港队列中，将该指标的预后效能与4种经典炎症指标——中性粒细胞与淋巴细胞比值（neutrophil to lymphocyte ratio）、血小板与淋巴细胞比值（platelet-to-lymphocyte ratio）、预后营养指数（prognostic nutrition index）及全身免疫炎症指数（systemic immune-inflammation index）——进行对比。同时，对存在可用样本的亚组患者进行循环细胞因子与瘤内基因表达分析，并将其与炎症指标进行关联分析。结果：在香港队列的训练集中，ILIS的计算公式为：–0.057 × 白蛋白（g/L） + 0.978 × 对数转换胆红素（µmol/L） + 1.341 × 对数转换碱性磷酸酶（IU/L） + 0.086 × 中性粒细胞计数（10^9/L） + 0.301 × 对数转换甲胎蛋白（µg/L）。当界值取2.60与3.87时，ILIS可在两个验证队列中将患者划分为3个风险分层。相较于其他炎症指标，ILIS的预后效能更优，且在校正巴塞罗那临床肝癌分期（Barcelona Clinic Liver Cancer）后，仍可作为总生存期的独立预后因素（风险比=31.90，p<0.001）。探索性分析显示，ILIS与循环炎症细胞因子（如IL-8）存在相关性，但与任何瘤内炎症基因表达均无关联。结论：ILIS是一种基于5项易于获取的血液参数构建的HCC特异性预后指标，其在东西方肝细胞癌人群中均得到了验证，且该评分与循环细胞因子水平存在相关性。