循环细胞因子谱预测非小细胞肺癌患者放射性肺纤维化的临床意义

doi:10.3877/cma.j.issn.1674-6902.2025.04.019

中华肺部疾病杂志(电子版) ›› 2025, Vol. 18 ›› Issue (04) : 603 -608. doi: 10.3877/cma.j.issn.1674-6902.2025.04.019

论著

循环细胞因子谱预测非小细胞肺癌患者放射性肺纤维化的临床意义

武军霞¹, 霍刚¹^,^†(

), 李姣姣¹, 杨会会¹, 马铭², 张王峰³

¹719000　榆林，西安交通大学第一附属医院榆林医院检验科
²719000　榆林，西安交通大学第一附属医院榆林医院肿瘤科
³719000　榆林，西安交通大学附属第一医院榆林医院呼吸科

收稿日期:2025-02-13 出版日期:2025-08-25
通信作者: 霍刚
基金资助:
陕西省自然科学基础研究计划项目(2022JQ-941)

Clinical significance of circulating cytokine profiles in predicting radioactive pulmonary fibrosis in patients with non-small cell lung cancer

Junxia Wu¹, Gang Huo¹^,^†(), Jiaojiao Li¹, Huihui Yang¹, Ming Ma², Wangfeng Zhang³

¹Department of Clinical Laboratory, The First Affiliated Hospital of Xi′an Jiaotong University Yulin Hospital, Yulin 719000, China
²Department of Oncology, The First Affiliated Hospital of Xi′an Jiaotong University Yulin Hospital, Yulin 719000, China
³Department of Respiratory, The First Affiliated Hospital of Xi′an Jiaotong University Yulin Hospital, Yulin 719000, China

Received:2025-02-13 Published:2025-08-25
Corresponding author: Gang Huo

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引用本文：

武军霞, 霍刚, 李姣姣, 杨会会, 马铭, 张王峰. 循环细胞因子谱预测非小细胞肺癌患者放射性肺纤维化的临床意义[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(04): 603-608.

Junxia Wu, Gang Huo, Jiaojiao Li, Huihui Yang, Ming Ma, Wangfeng Zhang. Clinical significance of circulating cytokine profiles in predicting radioactive pulmonary fibrosis in patients with non-small cell lung cancer[J/OL]. Chinese Journal of Lung Diseases(Electronic Edition), 2025, 18(04): 603-608.

目的

分析循环细胞因子谱预测非小细胞肺癌(non-small cell lung cancer, NSCLC)患者放射性肺纤维化(radiation-induced pulmonary fibrosis, RILF)的临床意义。

方法

选择2021年1月至2024年12月我院收治的根治性胸部放疗Ⅰ~Ⅲ期NSCLC患者86例，按7︰3分为训练集63例及验证集23例。收集患者临床资料，通过人细胞因子/趋化磁珠面板试剂盒、酶联免疫吸附测定试剂盒检测循环细胞因子，记录患者RILF≥2级(RILF2)发生情况。

结果

训练集RILF2 11例(17.46%)，验证集RILF2 4例(17.39%)(χ²＝0.001，P＝0.994)。患者RILF2中位发病时间4.90个月，Logistic、LASSO回归分析显示，平均肺剂量(mean lung dose, MLD)(HR：3.674，95%CI：1.240~10.887)、白细胞介素-8(interleukin-8, IL-8)(HR：0.231，95%CI：0.060~0.887)、C-C趋化因子配体4(C-C chemokine ligand 4, CCL4)(HR：0.204，95%CI：0.053~0.777)、转化生长因子-β1(transforming growth factor-β1, TGF-β1)(HR：21.831，95%CI：1.609~296.240)为NSCLC患者RILF2的影响因素。列线图预测训练集及验证集的RILF2，受试者工作特征曲线下面积分别为0.884(95%CI：0.779~0.989)和0.841(95%CI：0.672~0.990)。Hosmer-Lemeshow检验结果显示拟合良好(P>0.05)，高风险阈值分别为0.05~0.73及0.09~0.68。

结论

细胞因子MLD、IL-8、CCL4、TGF-β1及剂量学因素RILF2列线图预测NSCLC患者RILF具有临床意义。

关键词: 非小细胞肺癌, 循环细胞因子, 放射性肺纤维化

Objective

To analyze the clinical significance of circulating cytokine profiling in predicting radiation-induced pulmonary fibrosis (RILF) in patients with non-small cell lung cancer (NSCLC).

Methods

A total of 86 patients with stage Ⅰ-Ⅲ NSCLC who underwent radical thoracic radiotherapy in the First Affiliated Hospital of Xi'an Jiaotong University Yulin Hospital from January 2021 to December 2024 were selected and divided into a training set of 63 cases and a validation set of 23 cases in a ratio of 7︰3. The clinical data of the patients were collected. Circulating cytokines were detected by the human cytokine/chemotactic magnetic bead panel kit and the enzyme-linked immunosorbent assay kit. The occurrence of RILF≥ grade 2 (RILF2) in the patients was recorded.

Results

There were 11 cases (17.46%) of RILF2 in the training set and 4 cases (17.39%) of RILF2 in the validation set (χ²=0.001, P=0.994). The median onset time of RILF2 in patients was 4.90 months. Logistic and LASSO regression analyses showed that the mean lung dose(MLD) (HR: 3.674, 95%CI: 1.240~10.887), interleukin-8 (IL-8) (HR: 0.231, 95%CI: 0.060~0.887), C-C chemokine ligand 4 (CCL4) (HR: 0.204, 95%CI: 0.053~0.777), transforming growth factor-β1 (TGF-β1) (HR: 21.831, 95%CI: 1.609~296.240) are the influencing factors of RILF2 in NSCLC patients. The nomogram predicted the RILF2 of the training set and the validation set, and the area under the receiver operating characteristic curve was 0.884 (95%CI: 0.779~0.989) and 0.841 (95%CI: 0.672~0.990), respectively. The Hosmer-Lemeshow test results showed a good fit (P>0.05), and the high-risk thresholds were 0.05-0.73 and 0.09-0.68, respectively.

Conclusion

The nomogram of cytokines MLD, IL-8, CCL4, TGF-β1 and the dosimetric factor RILF2 has clinical significance in predicting RILF in NSCLC patients.

Key words: Non-small cell lung cancer, Circulating cytokines, Radiation-induced lung fibrosis, Nomogram

表1 NSCLC患者临床资料比较

临床资料	训练集(n＝63)	验证集(n＝23)	Z/t/χ²	P值
吸烟史[n(%)]			0.207	0.902
从未吸烟	7(11.11)	3(13.04)
既往吸烟	28(44.44)	9(39.13)
吸烟	28(44.44)	11(40.74)
KPS[分，(±s)]	84.13±9.44	81.48±9.49	1.218	0.226
化疗[n(%)]	46(73.02)	19(82.61)	0.840	0.359
组织学亚型[n(%)]			0.249	0.618
鳞状细胞癌	42(66.67)	14(60.87)
非鳞状细胞癌	21(33.33)	9(39.13)
临床分期[n(%)]			0.236	0.889
Ⅰ期	11(17.46)	5(18.52)
Ⅱ期	5(7.94)	2(7.41)
Ⅲ期	47(74.60)	16(69.57)
T分期[n(%)]			2.546	0.467
T1	12(19.05)	6(22.22)
T2	13(20.63)	7(25.93)
T3	17(26.98)	3(13.04)
T4	21(33.33)	7(25.93)
N分期[n(%)]			3.981	0.264
N0	18(28.57)	4(17.39)
N1	5(7.94)	2(7.41)
N2	30(47.62)	9(39.13)
N3	10(15.87)	8(29.63)
GTV[cm³，M₅₀(P₂₅，P₇₅)]	139.29(53.16，294.36)	100.10(37.04，221.97)	－1.290	0.197
总辐射剂量[Gy，(±s)]	67.77±7.36	69.96±6.89	1.318	0.191
MLD[Gy，M₅₀(P₂₅，P₇₅)]	14.46(11.91，17.23)	14.99(12.43，17.55)	－0.392	0.695
V20[%，M₅₀(P₂₅，P₇₅)]	24.09(17.51，29.81)	25.42(22.07，29.33)	－0.691	0.489

表1 NSCLC患者临床资料比较

临床资料	训练集(n＝63)	验证集(n＝23)	Z/t/χ²	P值
吸烟史[n(%)]			0.207	0.902
从未吸烟	7(11.11)	3(13.04)
既往吸烟	28(44.44)	9(39.13)
吸烟	28(44.44)	11(40.74)
KPS[分，(±s)]	84.13±9.44	81.48±9.49	1.218	0.226
化疗[n(%)]	46(73.02)	19(82.61)	0.840	0.359
组织学亚型[n(%)]			0.249	0.618
鳞状细胞癌	42(66.67)	14(60.87)
非鳞状细胞癌	21(33.33)	9(39.13)
临床分期[n(%)]			0.236	0.889
Ⅰ期	11(17.46)	5(18.52)
Ⅱ期	5(7.94)	2(7.41)
Ⅲ期	47(74.60)	16(69.57)
T分期[n(%)]			2.546	0.467
T1	12(19.05)	6(22.22)
T2	13(20.63)	7(25.93)
T3	17(26.98)	3(13.04)
T4	21(33.33)	7(25.93)
N分期[n(%)]			3.981	0.264
N0	18(28.57)	4(17.39)
N1	5(7.94)	2(7.41)
N2	30(47.62)	9(39.13)
N3	10(15.87)	8(29.63)
GTV[cm³，M₅₀(P₂₅，P₇₅)]	139.29(53.16，294.36)	100.10(37.04，221.97)	－1.290	0.197
总辐射剂量[Gy，(±s)]	67.77±7.36	69.96±6.89	1.318	0.191
MLD[Gy，M₅₀(P₂₅，P₇₅)]	14.46(11.91，17.23)	14.99(12.43，17.55)	－0.392	0.695
V20[%，M₅₀(P₂₅，P₇₅)]	24.09(17.51，29.81)	25.42(22.07，29.33)	－0.691	0.489

表2 单因素Logistic回归分析NSCLC患者RILF2影响因素

影响因素	β	SE	Walds值	HR(95%CI)	P值
年龄(0＝<60岁，1＝≥60岁)	0.015	0.035	0.190	1.015(0.948~1.087)	0.663
性别(0＝女，1＝男)	－0.201	0.871	0.053	0.818(0.148~4.512)	0.818
吸烟史(0＝从未吸烟，1＝既往吸烟/吸烟)	0.636	0.556	1.310	1.890(0.636~5.617)	0.252
KPS(0＝<90分，1＝≥90分)	0.006	0.036	0.027	1.006(0.937~1.080)	0.870
化疗(0＝否，1＝是)	0.601	0.840	0.513	1.824(0.352~9.456)	0.474
组织学亚型(0＝鳞状细胞癌，1＝非鳞状细胞癌)	－0.491	1.206	0.166	0.612(0.058~6.505)	0.684
临床分期(0＝Ⅰ，1＝Ⅱ/Ⅲ)	0.667	0.600	1.237	1.949(0.601~6.314)	0.266
T分期(0＝T1/T2，1＝T3/T4)	0.471	0.337	1.949	1.602(0.827~3.103)	0.163
N分期(0＝N0/N1，1＝N2/N3)	0.352	0.336	1.097	1.422(0.736~2.749)	0.295
GTV(0＝<139.29 cm³，1＝≥139.29 cm³)	0.001	0.002	0.530	1.001(0.998~1.005)	0.467
总辐射剂量(0＝<67.80 Gy，1＝≥67.80 Gy)	0.020	0.046	0.185	1.020(0.932~1.116)	0.667
MLD(0＝<14.46 Gy，1＝≥14.46 Gy)	0.750	0.231	10.553	2.116(1.346~3.327)	0.000
V20(0＝<24.09%，1＝≥24.09%)	0.105	0.051	4.193	1.111(1.005~1.228)	0.041
IL-8(0＝<2.50，1＝≥2.50)	－0.817	0.330	6.142	0.442(0.231~0.843)	0.013
CCL4(0＝<3.90，1＝≥3.90)	－0.853	0.267	10.211	0.426(0.253~0.719)	0.001
TGF-β1(0＝<1.70，1＝≥1.70)	1.931	0.610	10.036	6.898(2.088~22.781)	0.002

表2 单因素Logistic回归分析NSCLC患者RILF2影响因素

影响因素	β	SE	Walds值	HR(95%CI)	P值
年龄(0＝<60岁，1＝≥60岁)	0.015	0.035	0.190	1.015(0.948~1.087)	0.663
性别(0＝女，1＝男)	－0.201	0.871	0.053	0.818(0.148~4.512)	0.818
吸烟史(0＝从未吸烟，1＝既往吸烟/吸烟)	0.636	0.556	1.310	1.890(0.636~5.617)	0.252
KPS(0＝<90分，1＝≥90分)	0.006	0.036	0.027	1.006(0.937~1.080)	0.870
化疗(0＝否，1＝是)	0.601	0.840	0.513	1.824(0.352~9.456)	0.474
组织学亚型(0＝鳞状细胞癌，1＝非鳞状细胞癌)	－0.491	1.206	0.166	0.612(0.058~6.505)	0.684
临床分期(0＝Ⅰ，1＝Ⅱ/Ⅲ)	0.667	0.600	1.237	1.949(0.601~6.314)	0.266
T分期(0＝T1/T2，1＝T3/T4)	0.471	0.337	1.949	1.602(0.827~3.103)	0.163
N分期(0＝N0/N1，1＝N2/N3)	0.352	0.336	1.097	1.422(0.736~2.749)	0.295
GTV(0＝<139.29 cm³，1＝≥139.29 cm³)	0.001	0.002	0.530	1.001(0.998~1.005)	0.467
总辐射剂量(0＝<67.80 Gy，1＝≥67.80 Gy)	0.020	0.046	0.185	1.020(0.932~1.116)	0.667
MLD(0＝<14.46 Gy，1＝≥14.46 Gy)	0.750	0.231	10.553	2.116(1.346~3.327)	0.000
V20(0＝<24.09%，1＝≥24.09%)	0.105	0.051	4.193	1.111(1.005~1.228)	0.041
IL-8(0＝<2.50，1＝≥2.50)	－0.817	0.330	6.142	0.442(0.231~0.843)	0.013
CCL4(0＝<3.90，1＝≥3.90)	－0.853	0.267	10.211	0.426(0.253~0.719)	0.001
TGF-β1(0＝<1.70，1＝≥1.70)	1.931	0.610	10.036	6.898(2.088~22.781)	0.002

图1 RILF2列线图预测模型注：MLD为平均肺剂量；IL-8为白细胞介素-8；CCL4为C-C趋化因子配体4；TGF-β1为转化生长因子-β1；RILF2为放射性肺纤维化≥2级

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Clinical significance of circulating cytokine profiles in predicting radioactive pulmonary fibrosis in patients with non-small cell lung cancer

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Clinical significance of circulating cytokine profiles in predicting radioactive pulmonary fibrosis in patients with non-small cell lung cancer