Fig. 2.
Correlation networks of circulating and imaging biomarkers. a Pearson’s correlation networks were constructed for circulating and imaging biomarkers measured at baseline. Clusters with median correlation coefficients above 0.5 are shown in thick black lines, while <0.5 but ≥ 0.35 are shown with dotted lines and correlations <0.35 are not displayed. b Compares PFS outcomes in two groups of patients defined by the ratio of pre-treatment VEGFR2:Ktrans, where the cut-off was selected as the 33rd percentile of the ratios. Thus 24 patients were included in the worse prognostic group (dashed black line) and 46 in the better prognostic group (solid black line). The median survival intervals of the two groups were 248 (range 58–423) and 348 (73–1750) days (p = 0.0008, Log rank test), respectively. Prognostic factors such as performance status and tumor volume were controlled for by using Cox proportional hazard analysis. The hazard ratio demonstrated that patients with high VEGFR2:Ktrans ratio have a significantly greater risk of progression than the other cohorts (HR 3.01, p = 0.00014, Wald test). This defines this cohort as the poor prognostic group, we compared the group’s WTV derived from DCE-MRI data with that of the other patient groups. c Pearson’s correlation networks were constructed for circulating and imaging biomarkers measured after two weeks of treatment with bevacizumab; tight correlations between circulating biomarkers were lost and some biomarkers were completely removed from the correlative relationship (arrows). In contrast bevacizumab induced a correlative relationship between Ktrans, Ang2, and Tie2 (gray line). Clusters with median correlation coefficients above 0.5 are shown in thick black lines, while <0.5 but ≥ 0.35 are shown with dotted lines and correlations <0.35 are not displayed. Ang1 and 2, angiopoietin 1 and 2; FGFb, fibroblast growth factor beta; HGF, hepatocyte growth factor, IL6 and 8, interleukins 6 and 8; KGF; keratinocyte growth factor, CK18; cytokeratin 18, PDGFbb; platelet-derived growth factor bb isoform, PlGF; placental growth factor, SDF1b; stromal-derived growth factor beta, VCAM1; vascular cell adhesion molecule 1; VEGFA, C, D, R1 and R2; vascular endothelial growth factor A, C and D and receptors 1 and 2, ADC; apparent diffusion coefficient, EF; ejection fraction, ETV; enhancing tumor volume, WTV; whole tumor volume, IAUC; initial area under the contrast agent concentration curve; Ktrans; endothelial transfer constant, Ve; extracellular extravascular space fractional volume, Vp; plasma fractional volume, DCE-MRI; dynamic contrast-enhanced magnetic resonance imaging