目的:放射性肺炎(RP)是胸部放疗的常见副作用,通常病程较长,以急性加重和发展为永久性肺纤维化为特征。在诊断为RP的患者中没有有效的预后生物标志物。
方法:我们分析了血清趋化因子的时程,细胞因子,以及来自2级RP患者的其他蛋白质,在一项类固醇锥度加尼达尼布的随机临床试验中,一种多重酪氨酸激酶抑制剂,与安慰剂加类固醇锥度治疗RP相比。使用加权基因相关网络分析(WGCNA)和单变量零膨胀泊松模型来鉴定相关分析物组及其与临床结果的关联。
结果:30名入选患者有可用的生物标志物数据,17名患者接受了足够的分析物进行网络分析。WGNCA鉴定出十种分析物,包括转化生长因子β-1(TGF-β1),单核细胞趋化蛋白-1(MCP-1),和血小板衍生生长因子(PDGF),总体上与肺加重的发生相关(p=0.008),急性肺加重的总数(p=0.002),和治疗臂(p=0.036)。通过单变量分析,RP模块的两个组成部分的变化率增加与肺加重的发生率增加相关:白细胞介素5(IL-5,发生率比(IRR)1.02,95%CI1.01-1.04,p=0.002),和肿瘤坏死因子超家族12(TNFSF12,IRR1.06,CI1-1.11,p=0.036)。表皮生长因子(EGF)斜率增加与恶化发生率降低相关(IRR0.94,CI0.89-1,p=0.036)。
结论:我们确定了一组血清生物标志物,显示与RP患者的尼达尼布治疗和急性肺加重相关。需要进行验证性研究来验证该小组作为RP患者的预后工具。
Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP.
We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical
trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes.
Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036).
We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory
study will be needed to validate this panel for use as a prognostic tool in patients with RP.