炎症生物标志物在肝癌肝切除术后的预后意义。

Prognostic significance of inflammatory biomarkers in hepatocellular carcinoma following hepatic resection.

机构信息

Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

Department of Surgery Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers Fukuoka Japan.

出版信息

BJS Open. 2019 Apr 29;3(4):500-508. doi: 10.1002/bjs5.50170. eCollection 2019 Aug.

BACKGROUND

Cancer-related inflammation has been correlated with cancer prognosis. This study evaluated inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), programmed death ligand (PD-L) 1 expression, and tumour microenvironment in relation to prognosis and clinicopathological features of patients with hepatocellular carcinoma (HCC) undergoing curative hepatic resection.

METHODS

Patients who had liver resection for HCC in 2000-2011 were analysed. Univariable and multivariable analyses were conducted for overall (OS) and recurrence-free (RFS) survival. Immunohistochemical analyses of PD-L1, CD8 and CD68 expression were performed. HCC cell lines were evaluated for PD-L1 expression. A subgroup analysis was conducted to determine patient features, survival and the tumour microenvironment. Results were validated in a cohort of patients with HCC treated surgically in 2012-2016.

RESULTS

Some 281 patients who underwent hepatic resection for HCC were included. Multivariable analysis showed that low LMR was an independent prognostic factor of OS (hazard ratio (HR) 1·59, 95 per cent c.i. 1·00 to 2·41; = 0·045) and RFS (HR 1·47, 1·05 to 2·04; = 0·022) after resection. Low preoperative LMR values were correlated with higher α-fetoprotein values ( < 0·001), larger tumour size ( < 0·001), and high rates of poor differentiation ( = 0·035) and liver cirrhosis ( = 0·008). LMR was significantly lower in PD-L1-positive patients than in those with PD-L1 negativity ( < 0·001). Results were confirmed in the validation cohort. PD-L1 expression was upregulated in HCC cell lines treated with interferon-γ and co-cultured with THP-1 monocyte cells.

CONCLUSION

LMR is an independent predictor of survival after hepatic resection in patients with HCC. Modulation of the immune checkpoint pathway in the tumour microenvironment is associated with a low LMR.

背景

癌症相关炎症与癌症预后相关。本研究评估了炎症生物标志物，包括中性粒细胞与淋巴细胞比值（NLR）、血小板与淋巴细胞比值（PLR）和淋巴细胞与单核细胞比值（LMR）、程序性死亡配体 1（PD-L1）表达以及肿瘤微环境与接受根治性肝切除术的肝细胞癌（HCC）患者的预后和临床病理特征的关系。

方法

分析了 2000-2011 年接受肝切除术治疗 HCC 的患者。对总生存（OS）和无复发生存（RFS）进行单变量和多变量分析。进行了 PD-L1、CD8 和 CD68 表达的免疫组织化学分析。评估了 HCC 细胞系的 PD-L1 表达。进行了亚组分析以确定患者特征、生存和肿瘤微环境。结果在 2012-2016 年接受手术治疗的 HCC 患者队列中得到验证。

结果

纳入了 281 例接受肝切除术治疗 HCC 的患者。多变量分析显示，低 LMR 是 OS（风险比（HR）1.59，95%可信区间 1.00 至 2.41；=0.045）和 RFS（HR 1.47，1.05 至 2.04；=0.022）的独立预后因素。术前低 LMR 值与较高的甲胎蛋白值（<0.001）、肿瘤较大（<0.001）、分化不良率较高（=0.035）和肝硬化发生率较高（=0.008）相关。PD-L1 阳性患者的 LMR 明显低于 PD-L1 阴性患者（<0.001）。结果在验证队列中得到证实。IFN-γ 处理的 HCC 细胞系与 THP-1 单核细胞共培养后，PD-L1 表达上调。