| Objective Accurate monitoring of tumor blood vessel normalization progression is beneficial to accurate treatment of patients.At present,there is a lack of safe and non-invasive monitoring methods.To serial monitor the vascular normalization time window of tumor anti-angiogenesis treatment through intra-voxel incoherent motion diffusion-weighted imaging(IVIM-DWI)and histopathological methods,verify the feasibility of IVIM-DWI monitoring the vascular normalization time window of tumor.Methods A total of 60 rat C6 in situ Xenograft glioma models were established(50for magnetic resonance imaging(MRI)and 10 for electron microscope testing).In the first part,these 50 rats were randomly and equally divided into the five control groups and five bevacizumab treatment groups.Five rats in each group were randomly selected for MR scan at five different time points(days 0,2,4,6,and 8 after treatment),and the IVIM-DWI quantitative parameters(f,D,D*,and f D*)were obtained.The following sequences were scanned using Siemens 3T superconducting magnetic resonance imaging: T1 weighted imaging(T1WI),T2 WI with a fast spin echo sequence and IVIM-DWI with a spin-echo echo-planar imaging sequence.After MRI,the brain tumor tissues were monitored to assess the pathological indicators of microvessel density(MVD),pericyte coverage,and hypoxia-inducible factor-1α(HIF-1α).In the second part,10 rats were randomly divided into 5 control groups and5 bevacizumab treated groups.One rat in each group was randomly selected at 5different time points(days 0,2,4,6,and 8 after treatment)to obtain brain tissue for electron microscope observed changes in tumor vascular structure.One-way analysis of variance(ANOVA)and Student’s t-tests were used to compare differences within and between groups.Spearman’s correlation coefficient(r)assess the correlation between IVIM and pathological parameters.The intra-group correlation coefficient(ICC)was determined to assess the repeatability of each IVIM parameter.Results(1)There was no significant difference in tumor volume between the bevacizumab treatment group and the control group at baseline(day 0 after intervention)(P>0.05).The tumor volume in the control group was significantly larger than that in the treatment group on days 6-8(P<0.05).(2)The f value of the treatment group was higher than that of the control group on the day 2,day 4 and day6(P<0.05),and the difference was the largest on the day4;compared with the baseline,the f value of the treatment group increased on the day 2 and day 4(P<0.05).On the day 2,the D value of the treatment group was higher than that of the control group(P<0.05);the D value of the treatment group at other time points was not significantly different from the baseline(P>0.05).On the day 4,the D* value in the treatment group was significantly higher than that in the control group(P<0.05);there was no statistical difference between the D* value at other time points in the treatment group and the baseline(P>0.05).The f D* value of the treatment group was higher than that of the control group on days 2 and 4(P<0.05);compared with baseline,the f D* value of the treatment group was increased on day 4(P<0.05).(3)On the 2 days after the intervention,the microvessel density(MVD)of the treatment group was lower than that of the control group(P<0.05).On the 4 days after intervention,the pericyte coverage rate in the treatment group was significantly higher than that in the control group(P<0.05).No statistical difference was observed in hypoxia-inducible factor-1α(HIF-1α)between the treatment group and the control group(P>0.05).(4)In the control group,f had the highest correlation with MVD(r=0.689),followed by f D*(r=0.594);D* and D had no significant correlation with microvessel density.Pericyte coverage was slightly positively correlated with f D*(r=0.398),followed by f(r=0.338).D* and D had no significant correlation with pericyte coverage.There was no significant correlation between HIF-1α and IVIM parameters.Among the treatment groups,f had the highest correlation with MVD(r=0.602),followed by f D*(r=0.552)and D*(r=0.416);D had no significant correlation with MVD.Pericyte coverage was moderately correlated with f(r = 0.557),followed by f D*(r=0.394)and D*(r=0.318),and D had no significant correlation with pericyte coverage.HIF-1αwas moderately positively correlated with f(r=0.480)and f D*(r=0.447),followed by D*(r=0.335),but D had no significant correlation with it.(5)The repeatability of the D* value of the control group is general,and other parameters of the control group have good repeatability.All parameters of the treatment groups showed good reproducibility.(6)Electron microscope showed that the tight junctions between endothelial cells in the treatment group were prolonged and had no fissures on days2-4,the basement membrane was continuous and intact,the shape of endothelial cells was mostly flat,and there were few pinocytosis vesicles;other time points in the treatment group and control group were Time-point electron microscopy showed that the tight junctions between endothelial cells were incomplete and the number of fissures was increased,the basement membrane was discontinuous,some endothelial cells were plump in shape,and there were many pinocytosis vesicles.Conclusion The vascular normalization time window of bevacizumab treatment of glioma was days 2-4 after anti-angiogenesis treatment,which could be monitored non-invasively by IVIM-DWI.There was a correlation between IVIM-DWI parameters and pathological parameters. |
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