恶性胸腔积液患者血管内皮生长因子表达水平与疗效相关性研究

doi:10.19983/j.issn.2096-8493.2024154

摘要/Abstract

摘要：

目的: 探讨恶性胸腔积液中血管内皮生长因子(vascular endothelial growth factor,VEGF)表达水平与顺铂联合恩度胸腔局部灌注疗效的相关性,以及其他潜在影响因素。方法: 将哈尔滨市胸科医院2022年1月6日至2024年1月18日收治的拒绝全身化疗仅同意胸腔局部治疗的恶性胸腔积液患者60例纳入研究组;采用随机数字表法按照2∶1的比例随机抽取同期收治的良性胸腔积液患者30例纳入对照组。研究组经胸腔闭式引流术充分引流后采用顺铂联合恩度局部灌注,根据胸腔积液控制情况分为有效组34例(56.67%)和无效组26例(43.33%),进行治疗前后胸腔积液中血管内皮生长因子、癌胚抗原和总蛋白检测,将胸腔积液中血管内皮生长因子和癌胚抗原值按照中位数进行高低表达的划分,同时搜集患者临床资料,以客观缓解率为应变量,对可能影响疗效的因素进行单因素分析,将差异有统计学意义的变量进行多因素logistic回归分析。结果: 采用顺铂联合恩度胸腔局部灌注可明显降低恶性胸腔积液中血管内皮生长因子和癌胚抗原值,治疗前血管内皮生长因子和癌胚抗原值分别为792.96(473.69,959.45)pg/ml和59.89(4.92,389.53)ng/ml,治疗后分别为454.46(353.97,558.40)pg/ml和11.94(3.64,46.47)ng/ml,两者比较差异均具有统计学意义(Z=5.703,P<0.001;Z=3.290,P<0.001);对患者年龄、性别、原发肿瘤、病理类型、治疗分类、远处转移、腔内治疗史、血性积液、卡氏(KPS)评分、胸腔积液中血管内皮生长因子值、胸腔积液中癌胚抗原值、胸腔积液中总蛋白值,进行影响恶性胸腔积液疗效的单因素分析;结果显示:原发肿瘤(Fisher精确概率法,P=0.023)、病理类型(Fisher精确概率法,P=0.034)、治疗分类(χ²=8.688,P=0.003)、远处转移(χ²=10.259,P<0.001)、腔内治疗史(χ²=7.330,P=0.007)、血性积液(χ²=5.831,P=0.016)、胸腔积液中血管内皮生长因子值(Z=5.057,P<0.001)、胸腔积液中癌胚抗原值(Z=4.446,P<0.001)均与疗效相关;多因素logistic回归分析显示:胸腔积液中血管内皮生长因子表达水平和癌胚抗原表达水平对疗效有影响(OR=8.15,95%CI:1.588~41.840;OR=25.67,95%CI 3.713~177.394)。结论: 恶性胸腔积液患者胸腔积液中血管内皮生长因子和癌胚抗原表达水平可作为预测治疗响应及疾病控制的生物标志物。

关键词: 胸腔积液,恶性, 药物疗法,联合, 血管内皮生长因子, 癌胚抗原, 因素分析,统计学

Abstract:

Objective: To investigate the correlation between the expression level of VEGF in malignant pleural effusion and the therapeutic effect of local cisplatin combined with endostar perfusion in the thoracic cavity, as well as to explore other potential influencing factors. Methods: From January 6, 2022, to January 18, 2024, 60 patients with malignant pleural effusion who declined systemic chemotherapy and consented only to local thoracic treatment were included in the study group. Additionally, 30 patients with benign pleural effusion treated during the same period were randomly selected using a 2∶1 ratio via a random number table to form the control group. After complete drainage via closed thoracic drainage, the study group was categorized into an effective group (34 cases, 56.67%) and an ineffective group (26 cases, 43.33%) based on pleural effusion control. Levels of VEGF, carcinoembryonic antigen (CEA), and total protein in pleural effusion were measured before and after treatment. The VEGF and CEA levels in pleural effusion were stratified into high and low expression groups according to the median values. Concurrently, clinical data were collected, with the objective response rate serving as the dependent variable. Univariate analysis was conducted to identify factors potentially influencing treatment efficacy, followed by multivariate logistic regression analysis on variables found to be statistically significant. Results: The use of cisplatin combined with endostar for local thoracic perfusion significantly reduced the levels of VEGF and CEA in malignant pleural effusion. Pre-treatment median levels of VEGF and CEA were 792.96 (473.69, 959.45) pg/ml and 59.89 (4.92, 389.53) ng/ml, respectively. Post-treatment levels were 454.46 (353.97, 558.40) pg/ml for VEGF and 11.94 (3.64, 46.47) ng/ml for CEA. The differences were statistically significant (Z=5.703, P<0.001; Z=3.29, P<0.001). Univariate analysis of factors such as patient age, gender, primary tumor, pathological type, history of systemic treatment, distant metastasis, endovascular treatment history, presence of hemothorax, KPS score, VEGF levels in pleural effusion, CEA levels in pleural effusion, and total protein levels in pleural effusion indicated the following correlations with treatment efficacy: primary tumor (fisher exact probability method, P=0.023), pathological type (fisher exact probability method, P=0.034), treatment classification (χ²=8.688, P=0.003), distant metastasis (χ²=10.259, P<0.001), history of endovascular treatment (χ²=7.330, P=0.007), presence of hemothorax (χ²=5.831, P=0.016), VEGF levels in pleural effusion (Z=5.057, P<0.001), and CEA levels in pleural effusion (Z=4.446, P<0.001). Multivariate logistic regression analysis revealed that the expression levels of VEGF and CEA in pleural effusion significantly impacted the therapeutic response (OR=8.15, 95%CI: 1.588-41.840; OR=25.67, 95%CI: 3.713-177.394). Conclusion: The expression levels of VEGF and CEA in the pleural effusion of patients with malignant pleural effusion can serve as predictive biomarkers for treatment response and disease control.

Key words: Pleural effusion, malignant, Drug therapy, combination, Vascular endothelial growth factor, Carcinoembryonic antigen, Factor analysis, statistics

中图分类号:

常丽, 任宏, 关雪晴, 庞有铨, 甄春英, 边楠楠, 孙素芹. 恶性胸腔积液患者血管内皮生长因子表达水平与疗效相关性研究[J]. 结核与肺部疾病杂志, 2024, 5(6): 533-539. doi: 10.19983/j.issn.2096-8493.2024154

Chang Li, Ren Hong, Guan Xueqing, Pang Youquan, Zhen Chunying, Bian Nannan, Sun Suqin. Correlation between vascular endothelial growth factor (VEGF) expression levels and therapeutic outcomes in patients with malignant pleural effusion[J]. Journal of Tuberculosis and Lung Disease, 2024, 5(6): 533-539. doi: 10.19983/j.issn.2096-8493.2024154

图/表 6

表1

表2

表3

表4

表5

表6

影响恶性胸腔积液疗效的多因素logistic回归分析

变量	β值	$s x ˉ$ 值	Wald χ²值	P值	OR(95%CI)值
胸腔积液中血管内皮生长因子表达水平	2.098	0.835	6.32	0.012	8.15(1.588~41.840)
胸腔积液中癌胚抗原表达水平	3.245	0.968	10.823	<0.001	25.67(3.713~177.394)

表6

参考文献 26

[1]	赵艺涵, 翟怡然, 唐玉君, 等. 基于“血不利则为水”理论探究恶性胸腔积液病机及治法. 辽宁中医药大学学报, 2024, 26(8):132-137. doi:10.13194/j.issn.1673-842x.2024.08.027.
[2]	赵哲, 穆培娟, 张冬. 恩度联合顺铂胸腔灌注治疗肺癌合并恶性胸腔积液疗效的meta分析. 临床荟萃, 2023, 38(5):399-404. doi:10.3969/j.issn.1004-583x.2023.05.002.
[3]	林凯栓, 罗迪, 陈海龙, 等. 恩度联合顺铂腔内注射治疗恶性胸腹水的临床应用研究. 哈尔滨医药, 2023, 43(1):81-83. doi:10.3969/j.issn.1001-8131.2023.01.032.
[4]	汪博, 朱飞, 宋巍. 恩度联合顺铂用于恶性腹腔积液灌注治疗的临床疗效分析. 实用癌症杂志, 2021, 36(10):1726-1732. doi:10.3969/j.issn.1001-5930.2021.10.042.
[5]	Numnum TM, Rocconi RP, Whitworth J, et al. The use of bevacizumab to palliate symptomatic ascites in patients with refractory ovarian carcinoma. Gynecol Oncol, 2006, 102:425-428. doi:10.1016/j.ygyno.2006.05.018. pmid: 16797681
[6]	王雪, 张璐璐, 薛庆亮. 恶性胸腔积液预后评分系统的研究进展. 中国现代医生, 2023, 61(7): 108-116.
[7]	Prado-Garcia H, Romero-Garcia S, Rumbo-Nava U, et al. Predominance of Th117over regulatory Tcells in pleural effusions of patienes with lung cacer implicates a proinflammatory profile. Anticancer Res, 2015, 35(3): 1529-1535. pmid: 25750307
[8]	Marquez-Medina D, Popat S. Closingfaucets:the role of anti-an-giogenic therapies in malignant pleural diseases. Clin Trans Oncol, 2016, 18(8):760-768. doi:10.1007/s12094-015-1464-y.
[9]	朱敏, 张予辉. 血管内皮生长因子与恶性胸腔积液的研究进展. 临床内科杂志, 2015, 32(10):663-666. doi:10.3969/j.issn.1001-9057.2015.10.004.
[10]	王娟, 李翠荣, 刘伟, 等. 重组人血管内皮抑制素治疗晚期非小细胞肺癌的效果及对血清促红细胞生成素及其受体表达情况的影响. 癌症进展, 2021, 19(3):248-251. doi:10.11877/j.issn.1672-1535.2021.19.03.09.
[11]	黄萍, 邱伊莲, 陈海龙, 等. 重组人血管内皮抑制素联合紫杉醇脂质体和卡铂治疗老年晚期肺鳞癌的临床疗效观察. 中国现代医生, 2020, 58(33):111-114.
[12]	王武龙, 汪艾曼, 江振宇, 等. 重组人血管内皮抑素对恶性腹水瘤小鼠腹膜组织 MMP-2、VEGF 及 Survivin 表达的影响. 中国老年学杂志, 2020, 40(19):4185-4189. doi:10.3969/j.issn.1005-9202.2020.19.049.
[13]	董燕. 重组人血管内皮抑制素持续静脉泵入联合吉西他滨联合顺铂方案化疗治疗晚期肺鳞癌患者的疗效评价. 中国药物与临床, 2020, 20(13):2219-2221. doi:10.11655/zgywylc2020.13.054.
[14]	林卫佳, 张亚平, 李峰, 等. 重组人血管内皮抑制素注射液联合顺铂胸腔内灌注治疗肺癌恶性胸腔积液患者的临床研究. 中国临床药理学杂志, 2023, 39(13):1836-1840. doi:10.13699/j.cnki.1001-6821.2023.13.003.
[15]	李斌. 高剂量恩度单药胸腔灌注抑制非小细胞肺癌恶性胸腔积液的临床研究. 衡阳:南华大学, 2021.
[16]	曾灏, 田攀文, 李为民. 液体活检在肺癌伴恶性胸腔积液诊疗中的研究进展. 中国肺癌杂志, 2021, 24(9):653-659. doi:10.3779/j.issn.1009-3419.2021.101.24.
[17]	王悦. 重组人血管内皮抑制素注射液联合顺铂胸腔灌注治疗肺癌恶性胸腔积液的效果及对免疫球蛋白的影响. 中国医学创新, 2023, 20(12):5-9. doi:10.3969/j.issn.1674-4985.2023.12.002.
[18]	郑静娴, 王晓杰, 余家密, 等. 贝伐珠单抗或重组人血管内皮抑制素联合顺铂胸腔灌注治疗肺腺癌恶性胸腔积液患者的临床研究. 中国临床药理学杂志, 2021, 37(24): 3311-3314. doi:10.13699/j.cnki.1001-6821.2021.24.002.
[19]	杨海湾, 党新臣, 赵宝生. 奈达铂与顺铂胸腔热灌注疗法治疗老年肺癌合并恶性胸腔积液的疗效评价及风险评估. 医学综述, 2020, 26(18): 3734-3738,3744.
[20]	邹俊韬, 胡珍珍, 陈颖兰. 顺铂联合恩度胸腔灌注治疗肺癌恶性胸腔积液的临床效果和不良反应观察. 中国当代医药, 2016, 23(24):22-24.
[21]	常丽, 林红, 孙素芹, 等. 核苷酸切除修复交叉互补基因组1和肺耐药蛋白不同表达水平对顺铂治疗恶性胸腔积液的影响. 结核病与肺部健康杂志, 2019, 8(3):178-182. doi:10.3969/j.issn.2095-3755.2019.03.006.
[22]	刘雪梅, 常丽, 庞有铨, 等. ERCC1和LRP表达水平指导恶性胸腔积液的精准医疗. 黑龙江医学 2019, 43(12):1431-1434. doi:10.3969/j.issn.1004-5775.2019.12.01.
[23]	Zuo liang dong, Li Ren, Li Lin, et al. Effect of microRNA-21 on multidrug resistance reversal in A549/DDP human lung cancer cells. Mol Med Rep, 2015, 11(1):682-690. doi:10.3892/mmr.2014.2662. pmid: 25323306
[24]	王孝锦, 徐湛翔. 抗肿瘤药物多药耐药机制的研究进展. 牡丹江医学院学报, 2021, 41(3):164-167. doi:10.13799/j.cnki.mdjyxyxb.2021.03.043.
[25]	张玉敏, 高秀娟, 鞠思敏, 等. 胸水中HE4、MIC-1、CEA、P53在肺癌恶性胸腔积液诊断中的价值. 标记免疫分析与临床, 2021, 28(9):1485-1488. doi:10.11748/bjmy.issn.1006-1703.2021.09.009.
[26]	陈志平, 王岚枫. 良恶性胸腔积液患者VEGF、EGFR和MMP-9水平及相关因素分析. 中国医学创新, 2019, 16(28):40-43. doi:10.3969/j.issn.1674-4985.2019.28.010.

组别	年龄 (岁,$\bar{x}\pm s$)	性别[例,构成比(%)]
组别	年龄 (岁,$\bar{x}\pm s$)	男性	女性
研究组	61.58±10.76	32(53.33)	28(46.67)
对照组	57.00±13.55	15(50.00)	15(50.00)
统计检验值	t=1.744	χ²=0.089
P值	0.085	0.765

组别	胸腔积液中血管内皮生长因子值 [pg/ml, M(Q₁,Q₃)]	胸腔积液中癌胚抗原值 [ng/ml, M(Q₁,Q₃)])	胸腔积液中总蛋白值 (g/L,$\bar{x}\pm s$)
研究组(60例)	792.96(473.69,959.45)	59.89(4.92,389.53)	45.14±6.53
对照组(30例)	325.97(227.56,513.62)	3.46(2.37,4.06)	42.41±6.01
统计检验值	Z=3.363	Z=4.717	t=1.924
P值	<0.001	<0.001	0.058

临床特征	有效组(34例)	无效组(26例)	统计检验值	P值
年龄(岁,$\bar{x}\pm s$)	61.71±10.90	61.42±10.79	t=0.100	0.921
性别[例(构成比,%)]			χ²=2.677	0.102
男性	14(46.67)	18(60.00)
女性	16(53.33)	12(40.00)
原发肿瘤[例(构成比,%)]			-^a	0.023
肺癌	21(70.00)	16(53.33)
间皮瘤	3(10.00)	7(23.33)
卵巢癌	3(10.00)	2(6.67)
乳腺癌	2(6.67)	2(6.67)
胃癌	1(3.33)	3(10.00)
病理类型[例(构成比,%)]			-^a	0.034
腺癌	21(70.00)	15(50.00)
间皮瘤	3(10.00)	7(23.33)
神经内分泌癌	1(3.33)	4(13.33)
妇科肿瘤	5(16.67)	4(13.33)
治疗分类[例(构成比,%)]			χ²=8.688	0.003
初治	20(66.67)	20(66.67)
复治	10(33.33)	10(33.33)
远处转移[例(构成比,%)]			χ²=10.259	<0.001
有	15(50.00)	17(56.67)
无	15(50.00)	13(43.33)
腔内治疗史[例(构成比,%)]			χ²=7.330	0.007
有	21(83.33)	24(80.00)
无	9(16.67)	6(20.00)
血性积液[例(构成比,%)]			χ²=5.831	0.016
是	10(33.33)	12(40.00)
否	20(66.67)	18(60.00)
KPS评分[例(构成比,%)]			-^a	0.470
≥90分	5(16.67)	4(13.33)
80~89分	11(36.67)	14(46.67)
70~79分	11(36.67)	8(26.67)
60~69分	3(10.00)	4(13.33)
胸腔积液中血管内皮生长因子值[pg/ml, M(Q₁,Q₃)]	891.16(766.82,1121.07)	475.71(373.56,789.45)	-Z=5.057	<0.001
胸腔积液中癌胚抗原值[ng/ml, M(Q₁,Q₃)]	227.93(59.83,562.53)	7.58(3.89,37.29)	Z=4.446	<0.001
胸腔积液中总蛋白值(g/L,$\bar{x}\pm s$)	46.21±6.31	43.74±6.67	t=1.467	0.148