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The Combination Assay with Circulating Vascular Endothelial Growth Factor (VEGF)-C, Matrix Metalloproteinase-9, and VEGF for Diagnosing Lymph Node Metastasis in Patients With Non–Small Cell Lung Cancer

From the Department of General and Cardiothoracic Surgery (MT, MO, IM, YT, KK, GW), Kanazawa University School of Medicine; and Department of Thoracic Surgery (YO), Ishikawa Prefectural Central Hospital, Kanazawa, Japan.

ABSTRACT

Background: The aim of the present study was to evaluate the diagnostic utility of levels of circulating vascular endothelial growth factor (VEGF)-C, matrix metalloproteinase-9 (MMP-9), and VEGF and to verify that the combination assay of these circulating factors is a clinically useful indicator to predict the presence of lymph node metastasis in non–small cell lung cancer (NSCLC).

Methods: A series of 78 patients who underwent surgery for NSCLC was used in this study. Serum VEGF-C and VEGF and plasma MMP-9 levels were analyzed with enzyme-linked immunosorbent assay (ELISA) kits. Logistic regression models were used to analyze the influence of VEGF-C, MMP, and VEGF levels on the probability of presence or absence of lymph node metastasis.

Results: Patients with lymph node metastasis had higher serum VEGF- C, VEGF, and plasma MMP-9 concentrations than did those without metastasis (VEGF-C, P = .0004; VEGF, P = .001). Serum VEGF- C reached a sensitivity of 85% and specificity of 68% when a cutoff value of 1762.0 pg/mL was applied, while VEGF reached 80% sensitivity and 59% specificity at 316.8 pg/mL. MMP-9 reached a sensitivity of 63% and specificity of 75% when a cutoff value of 51.4 ng/mL was applied. In the ROC curve analysis, VEGF-C (0.761) had the biggest areas under the ROC curve, followed by MMP-9 (0.723) and VEGF (0.694). Combination assay of three markers had higher sensitivity and specificity for prediction than single-marker assays (AUC = 0.837).

Conclusions: This study has confirmed that combination assay of three markers to determine VEGF-C, MMP-9, and VEGF expression in circulation detects lymph node metastasis in NSCLC with higher accuracy than single-marker assays.

Key Words: Enzyme-linked immunosorbent assay • Lymph node metastasis • Matrix metalloproteinase-9 • Vascular endothelial growth factor • Vascular endothelial growth factor-C

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