血管内皮生长因子在黑色素瘤疗效监测和预后判断中的价值

doi:10.3969/j.issn.1673-8640.2022.09.004

摘要/Abstract

摘要：

目的探讨血清血管内皮生长因子（VEGF）在黑色素瘤疗效监测和预后评估中的应用价值。方法选取黑色素瘤患者49例（黑色素瘤组）、健康体检者182名（正常对照组）,检测所有对象血清VEGF水平。收集所有患者的临床资料（性别、年龄、临床分期、化疗方案、疗效评价、肿瘤发病部位、是否发生溃疡和是否有肿瘤驱动基因突变）。对所有患者随访24个月,记录疾病无进展生存期（PFS）和总生存期（OS）。采用Kaplan-Meier生存曲线分析不同VEGF水平患者PFS和OS的差异。采用Cox回归分析评估黑色素瘤患者PFS和OS的影响因素。结果黑色素瘤组VEGF阳性率（48.98%）显著高于正常对照组（3.85%）（P<0.001）。根据血清VEGF水平是否升高将黑色素瘤患者分为VEGF正常组（25例）和VEGF升高组（24例）。血清VEGF水平升高与黑色素瘤患者疗效有关（P=0.001）,与患者性别、年龄、肿瘤发病部位、是否发生溃疡、临床分期及是否有肿瘤驱动基因突变均无关（P>0.05）。VEGF升高组PFS（3个月）显著短于VEGF正常组（9个月）（P=0.02）;OS稍短于VEGF正常组,但差异无统计学意义（P>0.05）。血清VEGF水平升高和临床分期Ⅳ期是黑色素瘤患者出现疾病进展的危险因素[风险比（HR）分别为2.55、4.64,95%可信区间（CI）分别为1.07~6.10、1.40~15.43],临床分期Ⅳ期是黑色素瘤患者OS缩短的危险因素（HR=14.52,95%CI为2.67~79.08）。结论血清VEGF在黑色素瘤疗效监测和预后评估方面具有潜在的临床应用价值。

关键词: 血管内皮生长因子, 黑色素瘤, 标志物, 血清, 预后

Abstract:

Objective To investigate the application role of serum vascular endothelial growth factor（VEGF） in monitoring treatment outcome and predicting the prognosis of patients with melanoma. Methods A total of 182 healthy subjects and 49 melanoma patients were enrolled. Serum samples were collected for analyzing the levels of serum VEGF. Clinical data,including sex,age,clinical stage,chemotherapy,treatment outcome,primary site,ulcer,mutations of driver genes,were collected. All the patients were followed up for 24 months,and the progression-free survival time（PFS） and overall survival time（OS） were recorded. The PFS and OS were analyzed by Kaplan-Meier survival curve. The factors for PFS and OS in melanoma patients were analyzed by Cox regression analysis. Results Melanoma patients（48.98%）have a higher VEGF positive rate than healthy subjects（3.85%）（P<0.001）. The melanoma patients were classified into 2 groups,VEGF normal group（25 cases） and VEGF increased group（24 cases）. Increased VEGF level was related to poor treatment outcome（P=0.001）,but it was not related to sex,age,tumor location,ulcer,clinical stage or driver gene mutation（P>0.05）. For patients with increased VEGF level（3 months）,PFS was shorter than that of patients with normal VEGF（9 months）（P=0.02）,and OS was shorter without statistical significance（P>0.05）. Patients with increased VEGF and advanced stage（Ⅳ）had increased risk of disease progression [hazard ratio（HR）=2.55 and 4.64,95% confidence intervals（CI） were 1.07-6.10 and 1.40-15.43]. Advanced stage（Ⅳ） was a risk factor for short OS in melanoma patients（HR=14.52,95%CI 2.67-79.08）. Conclusions VEGF in serum may be a circulating biomarker to predict treatment outcome in patients with advanced melanoma.

Key words: Vascular endothelial growth factor, Melanoma, Marker, Serum, Prognosis

中图分类号:

R446.1

张濛, 李莎, 常艳丽, 王鲁, 徐建军, 张青云. 血管内皮生长因子在黑色素瘤疗效监测和预后判断中的价值[J]. 检验医学, 2022, 37(9): 821-825.

ZHANG Meng, LI Sha, CHANG Yanli, WANG Lu, XU Jianjun, ZHANG Qingyun. Role of vascular endothelial growth factor in monitoring treatment outcome and evaluating the prognosis of patients with advanced melanoma[J]. Laboratory Medicine, 2022, 37(9): 821-825.

图/表 5

参考文献 21

[1]	SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. DOI URL
[2]	GUO J, QIN S, LIANG J, et al. Chinese guidelines on the diagnosis and treatment of melanoma(2015 edition)[J]. Ann Transl Med, 2015, 3(21):322.
[3]	唐智柳, 石建伟, 蔡美玉, 等. 中国皮肤黑色素瘤发病及其影响因素分析[J]. 中国肿瘤, 2014, 23(10):829-833.
[4]	ROBERT C, GROB J J, STROYAKOVSKIY D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma[J]. N Engl J Med, 2019, 381(7):626-636. DOI URL
[5]	ROBERT C, RIBAS A, SCHACHTER J, et al. Pembrolizumab versus ipilimumab in advanced melanoma(KEYNOTE-006):post-hoc 5-year results from an open-label,multicentre,randomised,controlled,phase 3 study[J]. Lancet Oncol, 2019, 20(9):1239-1251. DOI URL
[6]	National Comprehensive Cancer Network. Clinical practice guidelines in oncology-cutaneous melanoma[S]. Version 2.2022,NCCN, 2022.
[7]	YE X, GAUCHER J F, VIDAL M, et al. A structural overview of vascular endothelial growth factors pharmacological ligands:from macromolecules to designed peptidomimetics[J]. Molecules, 2021, 26(22):6759. DOI URL
[8]	GOEL H L, MERCURIO A M. VEGF targets the tumour cell[J]. Nat Rev Cancer, 2013, 13(12):871-882. DOI PMID
[9]	HOERES T, WILHELM M, SMETAK M, et al. Immune cells regulate VEGF signalling via release of VEGF and antagonistic soluble VEGF receptor-1[J]. Clin Exp Immunol, 2018, 192(1):54-67. DOI PMID
[10]	EDGE S B, COMPTON C C. The American Joint Committee on Cancer:the 7th edition of the AJCC cancer staging manual and the future of TNM[J]. Ann Surg Oncol, 2010, 17(6):1471-1474. DOI URL
[11]	EISENHAUER E A, THERASSE P, BOGAERTS J, et al. New response evaluation criteria in solid tumours:revised RECIST guideline(version 1.1)[J]. Eur J Cancer, 2009, 45(2):228-247. DOI URL
[12]	CHI Z, LI S, SHENG X, et al. Clinical presentation,histology,and prognoses of malignant melanoma in ethnic Chinese:a study of 522 consecutive cases[J]. BMC Cancer, 2011, 11:85. DOI URL
[13]	FUJISAWA Y, YOSHIKAWA S, MINAGAWA A, et al. Clinical and histopathological characteristics and survival analysis of 4 594 Japanese patients with melanoma[J]. Cancer Med, 2019, 8(5):2146-2156. DOI URL
[14]	REVYTHIS A, SHAH S, KUTKA M, et al. Unraveling the wide spectrum of melanoma biomarkers[J]. Diagnostics(Basel), 2021, 11(8):1341.
[15]	PROŠVICOVÁ J, GRIM J, KOPECKÝ J, et al. Non-specific immunotherapy inhibits angiogenesis-results of the monitoring of serum levels of vascular endothelial growth factor and matrix metalloproteinase 8 in patients with malignant melanoma receiving adjuvant high-dose interferon therapy[J]. Epidemiol Mikrobiol Imunol, 2017, 66(1):15-23.
[16]	TARHINI A A, FRANKEL P, RUEL C, et al. NCI 8628:a randomized phase 2 study of ziv-aflibercept and high-dose interleukin 2 or high-dose interleukin 2 alone for inoperable stage Ⅲ or Ⅳ melanoma[J]. Cancer, 2018, 124(22):4332-4341. DOI URL
[17]	CAPORALI S, AMARO A, LEVATI L, et al. MiR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A[J]. J Exp Clin Cancer Res, 2019, 38(1):272. DOI URL
[18]	WAN X, ZHU Y, ZHANG L, et al. Gefitinib inhibits malignant melanoma cells through the VEGF/AKT signaling pathway[J]. Mol Med Rep, 2018, 17(5):7351-7355. DOI PMID
[19]	LIANG B, HE Q, ZHONG L, et al. Circulating VEGF as a biomarker for diagnosis of ovarian cancer:a systematic review and a meta-analysis[J]. Onco Targets Ther, 2015, 8:1075-1082.
[20]	SHEN H, LIU Q, LI M, et al. The prognostic value of vascular endothelial growth factor in patients with renal cell carcinoma:a systematic review of the literature and meta-analysis[J]. Clin Invest Med, 2017, 40(2):E40-E48.
[21]	FURUE M, ITO T, WADA N, et al. Melanoma and immune checkpoint inhibitors[J]. Curr Oncol Rep, 2018, 20(3):29. DOI PMID