Evaluation of cellular water exchange in a mouse glioma model using dynamic contrast-enhanced MRI with two flip angles

Abstract

This manuscript aims to evaluate the robustness and significance of the water efflux rate constant (kio) parameter estimated using the two flip-angle Dynamic Contrast-Enhanced (DCE) MRI approach with a murine glioblastoma model at 7 T. The repeatability of contrast kinetic parameters and kio measurement was assessed by a test–retest experiment (n = 7). The association of kio with cellular metabolism was investigated through DCE-MRI and FDG-PET experiments (n = 7). Tumor response to a combination therapy of bevacizumab and fluorouracil (5FU) monitored by contrast kinetic parameters and kio (n = 10). Test–retest experiments demonstrated compartmental volume fractions (ve and vp) remained consistent between scans while the vascular functional measures (Fp and PS) and kio showed noticeable changes, most likely due to physiological changes of the tumor. The standardized uptake value (SUV) of tumors has a linear correlation with kio (R2 = 0.547), a positive correlation with Fp (R2 = 0.504), and weak correlations with ve (R2 = 0.150), vp (R2 = 0.077), PS (R2 = 0.117), Ktrans (R2 = 0.088) and whole tumor volume (R2 = 0.174). In the treatment study, the kio of the treated group was significantly lower than the control group one day after bevacizumab treatment and decreased significantly after 5FU treatment compared to the baseline. This study results support the feasibility of measuring kio using the two flip-angle DCE-MRI approach in cancer imaging.

Review of tracer kinetic models in evaluation of gliomas using dynamic contrast-enhanced imaging

“…The advantages of a DP model over the Tofts model have been demonstrated in the assessment of the IDH mutation status in glioma ( 105 ). Recent test-retest experiments using Brix ( 36 ) showed that only the median K trans was significantly different between scans, which might justify the separate modeling of intravascular transport and exchange between intra- and extra-vascular space in Brix, instead of mixed modeling using one transport rate parameter (K trans ). HIF-1α expression is significantly associated with HGGs ( 110 ) and is an excellent biomarker for glioma grading ( 111 ).…”

“…Tofts model was also named as generalized kinetic (GK) model in ( 18 ). The model developed by Brix and coauthors ( 24 , 25 ) has been denoted as two-compartment exchange model (2CXM) in some literature ( 19 , 35 , 36 ). However, this notation reflects also the fundamental features of other models such as TH and DP, likely leading to confusion in understanding the connection and the difference among these TKMs.…”

“…Kiser et al. ( 36 ) applied the Brix model of DCE MRI to evaluate test-retest repeatability and tumor response of a murine glioblastoma model at 7 T to a combination therapy of bevacizumab and fluorouracil. Test-retest experiments demonstrated that there was no significant difference between the scans in terms of the median values of parameters, except for K trans .…”