Application of Intravoxel Incoherent Motion Diffusion-Weighted Imaging in Predicting and Monitoring Early Efficacy of Anti-Angiogenic Therapy in the C6 Glioma Rat Model.

Weishu Hou,Man Xu,Yangyang Xue,Yujun Shen,Xiaohu Li,Yinfeng Qian,Yongqiang Yu,Hongli Pan

doi:10.3389/fonc.2021.842169

Abstract

ObjectiveTo investigate the feasibility of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in evaluating early effects of anti-angiogenic therapy in the C6 glioma rat model.MethodsTwenty-six rats of the C6 glioma model were randomly divided into a treatment group (received bevacizumab) and a control group (physiological saline). IVIM-DWI was performed on days 0, 1, 3, 5, and 7 after anti-angiogenic therapy and tumor growth and IVIM-DWI parameters were dynamically observed. Hematoxylin and eosin, CD34 microvessel density (MVD), proliferation of cell nuclear antigen (PCNA), and Hif-α staining were performed on day 7. One-way ANOVA was used to compare intra-group differences and an independent-samples t-test was used to compare inter-group differences of MRI parameters. Correlations between IVIM-DWI parameters, tumor size, and pathological results were analyzed.ResultsThe relative change in tumor volume (ΔVolume) in the two groups differed significantly on days 5 and 7 (p = 0.038 and p < 0.001). The perfusion-related parameters D*- and f-values decreased in the treatment group and demonstrated significant differences compared with the control group on days 3, 5, and 7 (p = 0.033, p < 0.001, and p < 0.001, respectively). The diffusion-related parameters ADC and D-values increased in the treatment group and were found to be significantly differently different from the control group on days 5 and 7 (both p < 0.001). The initial D-value showed a negative correlation with ΔVolume (γ = −0.744, p < 0.001), whereas the initial D*-value and relative change of D-value had a positive correlation with ΔVolume (γ = 0.718, p < 0.001 and γ = 0.800, p < 0.001, respectively). MVD was strongly positively correlated with D*-value (r = 0.886, p = 0.019), PCNA was negatively correlated with ADC- and D-values (r = −0.848, p = 0.033; and r = −0.928 p = 0.008, respectively), and Hif-1α was strongly negatively correlated with D*-value (r = −0.879, p = 0.010).ConclusionIVIM-DWI was sensitive and accurate in predicting and monitoring the effects of early anti-angiogenesis therapy in a C6 glioma rat model.

Highlights

High-grade glioma is the most aggressive primary malignant tumor of the central nervous system in adults and has a high expression of vascular endothelial growth factor (VEGF) [1]
microvessel density (MVD) was strongly positively correlated with D*-value (r = 0.886, p = 0.019), proliferation of cell nuclear antigen (PCNA) was negatively correlated with apparent diffusion coefficient (ADC)- and D-values (r = −0.848, p = 0.033; and r = −0.928 p = 0.008, respectively), and Hif-1a was strongly negatively correlated with D*-value (r = −0.879, p = 0.010)
VEGF plays an essential role in regulating angiogenesis of glioma and, anti-angiogenesis therapy targeting the VEGF signaling pathway has been recognized as an effective targeted therapy method for malignant glioma [2, 3]

Summary

Introduction

High-grade glioma is the most aggressive primary malignant tumor of the central nervous system in adults and has a high expression of vascular endothelial growth factor (VEGF) [1]. The recombinant humanized monoclonal antibody bevacizumab (Avastin®, Bev), an anti-angiogenesis medicine, has been widely used as a treatment, either alone or in combination with traditional chemotherapy, for recurrent glioblastoma and newly diagnosed high-grade glioma [4–6]. To date, how to monitor the effects of antiangiogenesis therapy sensitively, dynamically, and noninvasively is still a major challenge of glioma therapy. Diffusion-weighted imaging (DWI) is a functional magnetic resonance imaging (MRI) sequence used to evaluate or predict treatment outcome of malignant tumors; the apparent diffusion coefficient (ADC) has been shown to be influenced by both the diffusion of water molecules and microcirculation due to the mono-exponential model of DWI [7, 8]. An intravoxel incoherent motion DWI (IVIM-DWI) has been developed that can separate microcirculation from restricted Brownian self-diffusion, and has been applied to evaluate the microcirculation of tumors after anti-angiogenic therapy several types of animal models [9–11]. Few studies have focused on the early and dynamic changes of IVIM-DWI parameters during therapy and the correlation between IVIMDWI parameters and histological assessment

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Conclusion