血液和积液中的Fibulin-3可作为胸膜间皮瘤的生物标记物

文献 Fibulin-3 as a Blood and Effusion Biomarker for Pleural Mesothelioma 于 2012年 发表在 The New England Journal of Medicine 原文链接

Abstract

BACKGROUND:

New biomarkers are needed to detect pleural mesothelioma at an earlier stage and to individualize treatment strategies. We investigated whether fibulin-3 in plasma and pleural effusions could meet sensitivity and specificity criteria for a robust biomarker.


METHODS:

We measured fibulin-3 levels in plasma (from 92 patients with mesothelioma, 136 asbestos-exposed persons without cancer, 93 patients with effusions not due to mesothelioma, and 43 healthy controls), effusions (from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not due to mesothelioma), or both. A blinded validation was subsequently performed. Tumor tissue was examined for fibulin-3 by immunohistochemical analysis, and levels of fibulin-3 in plasma and effusions were measured with an enzyme-linked immunosorbent assay.


RESULTS:

Plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure, or degree of radiographic changes and were significantly higher in patients with pleural mesothelioma (105±7 ng per milliliter in the Detroit cohort and 113±8 ng per milliliter in the New York cohort) than in asbestos-exposed persons without mesothelioma (14±1 ng per milliliter and 24±1 ng per milliliter, respectively; P<0.001). Effusion fibulin-3 levels were significantly higher in patients with pleural mesothelioma (694±37 ng per milliliter in the Detroit cohort and 636±92 ng per milliliter in the New York cohort) than in patients with effusions not due to mesothelioma (212±25 and 151±23 ng per milliliter, respectively; P<0.001). Fibulin-3 preferentially stained tumor cells in 26 of 26 samples. In an overall comparison of patients with and those without mesothelioma, the receiver-operating-characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng of fibulin-3 per milliliter. In a comparison of patients with early-stage mesothelioma with asbestos-exposed persons, the sensitivity was 100% and the specificity was 94.1% at a cutoff value of 46.0 ng of fibulin-3 per milliliter. Blinded validation revealed an area under the curve of 0.87 for plasma specimens from 96 asbestos-exposed persons as compared with 48 patients with mesothelioma.


CONCLUSIONS:

Plasma fibulin-3 levels can distinguish healthy persons with exposure to asbestos from patients with mesothelioma. In conjunction with effusion fibulin-3 levels, plasma fibulin-3 levels can further differentiate mesothelioma effusions from other malignant and benign effusions.


摘要

研究背景:

胸膜间皮瘤的早期发现及个性化治疗方案的确定都需要新的生物标志物。我们研究了是否血浆和胸膜积液中的fibulin-3可作为既满足灵敏度标准又满足特异性标准的强生物标志物。


研究方法:

我们测量了血浆中(来自92名间皮瘤患者,136名石棉暴露的未患癌症的人员,93名非因间皮瘤而有渗出液的患者,43名健康对照者),渗出液中(来自74名间皮瘤患者,39名有良性渗出液患者,54名非因间皮瘤而有恶性渗出液的患者)及两者中的fibulin-3水平。随后进行了盲测,利用免疫组化分析了肿瘤组织的fibulin-3 ,并通过酶联免疫吸附测定法测定了血浆和渗出液中的fibulin-3含量。


研究结果:

血浆中fibulin-3的水平并不会随年龄,性别,石棉暴露持续的时间,或射线的强度而有所变化,但fibulin-3在间皮瘤患者血浆中的水平(底特律人群:105±7 ng/mL,纽约人群:113±8 ng/mL)显著高于在石棉暴露但未患间皮瘤人员血浆中的水平 (底特律人群:14±1 ng/mL,纽约人群:24±1 ng/mL,P<0.001)。Fibulin-3在间皮瘤患者渗出液中的水平(底特律人群:694±37 ng/mL,纽约人群:636±92 ng/mL)显著高于非因间皮瘤有渗出液患者渗出液中的水平 (底特律人群:212±25 ng/mL,纽约人群:151±23 ng/mL,P<0.001)。在26个样本中,Fibulin-3还会优先染肿瘤细胞。在对间皮瘤患者和无间皮瘤患者的总体比较中,血浆fibulin-3水平在临界值52.8 ng/mL时,血浆fibulin-3的受试者操作特征曲线的灵敏度为96.7%,特异性为 95.5%。在早期间皮瘤患者与石棉暴露者的比较中,血浆fibulin-3水平在临界值46.0 ng/mL时,灵敏度为100%,特异性为 94.1%。盲测结果显示,与48例间皮瘤患者相比,96例石棉暴露者血浆样本的曲线下面积为0.87。


总结:

血浆中fibulin-3 水平可以区分间皮瘤患者与石棉暴露者。血浆fibulin-3 水平与渗出液fibulin-3 水平结合分析可以进一步区分间皮瘤渗出液及其他恶性或良性渗出液。


使用试剂原文信息:Levels of fibulin-3 in plasma and pleural effusions were measured in duplicate wells and quantified in nanograms per milliliter with the use of the human fibulin-3 enzyme-linked immunosorbent assay (USCN Life Science).


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