| ObjectiveThe researcher found that erlotinib change the vasculature in nude mice transplanted tumor. We also found the volume perfusion CT (VPCT) parameters will be changed before and after the Gefitinib therapy in patients with lung cancer. These evidences suggest EGFR-TKI not only act directly on the tumor cell, may also has an effect on the vascular perfusion in lung cancer. Based on these, this paper discussed the relationships between the VPCT and the vascular architecture in nude mice transplantation tumors and patients with lung cancer respectively. Then the changes of VPCT parameters in lung cancer patients before and after treatment of Gefitinib were observed to determine the response of EGFR-TKI therapy. This paper tried to seek a new index to evaluate the effect of EGFR-TKI therapy, and aimed to provide technical support and theoretical basis of this new index.Methods(1) Nude mice transplanted tumors were randomly divided into bevacizumab group and blank control group.6-8mice were randomly selected in the day0,2,4,6and10in each group. After VPCT perfusion parameters (PEI and BF) were acquired, the mice were sacrificed immediately, then the indexes of vascular architecture were detected to evaluate the level of "vascular normalization" and "vascular homeostasis". The indexex of "vascular normalization" include vascular structure (MPI), vascular function (electron microscopic) and vascular effects (Pimonidazole expression). The indexes of "vascular homeostasis" include vascular maturation index (VMI), the balance of angiogenesis regulation factor, the stability of tumor cell and the relationship between tumor and vascular. Then we observed the relationships between CT perfusion parameters and pathological indexes by using image-pathologic correlation method in mice.(2)48patients with lung cancer received CT perfusion scan (including VPCT and MS-CTP) and pathological biopsy, the indexes of vascular architecture (MPI, VMI, tumor proliferation and apoptosis) were detected. The CT perfusion parameters were compared with pathological indexes by using image-pathologic correlation method in lung cancer patient.(3)18patients received VPCT scan, then followed by Gefitinib therapy and follow-up observation. VPCT was repeated and the therapy effect was evaluated with RECIST criteria. The VPCT parameters of18patients were compared with their short term effect and middle term effect.Resluts:(1) The relationship between VPCT and micro vessel density/maturation in nude mice:Tumor blood flow (BF) and tumor microvascular maturity (MPI and VMI) were increased significantly in day4(P<0.01), and down to the preoperative level in day10(P>0.05), however, PEI and microvessel density were decreased(P<0.01).(2) The relationship between VPCT and the indexes of "vascular normalization" in nude mice:The "vascular normalization window" occurred in2-6days after bevacizumab treatment. In the window, tumor MPI were increased, Endothelial cells and pericytes were closely connected, the integrity of basement membranes were repaired, hypoxia in tumor microenvironment was improved, tumor blood flow(BF) were increased.(3) The relationship between VPCT and the indexes of "vascular homeostasis" in nude mice:the balance of angiogenesis regulation factor and the stability of tumor cell were improved in2-6days after bevacizumab treatment, tumor blood flow(BF) were increased.(4) The relationship between CT perfusion parameters and vascular architecture in patients with lung cancer:There was a positive correlation between BF and microvascular maturity (r=0.680, P=0.000), and there was a weakly positive correlation between BF and CD31-MVD(r=0.365, P=0.013). There was no correlation between PEI and microvascular maturity (P>0.05), and there was a weakly positive correlation between PEI and CD31-MVD (P<0.05). There was no correlation between CT perfusion parameters and the stability of tumor cell (P>0.05)(5) Evaluating the short term effect of Gefitinib in patients with advanced lung adenocarcinoma by VPCT:Short term effect was poor in the case which the BF increase after6weeks of targeted therapy. BF before therapy was a negative correlated with differentiation grade (r=-0.904, P=0.000).There was a negative correlation between rate of BF decline and the differentiation grade (r=-0.525, P=0.025); There was a negative correlation between the trend of BF and RECIST criteria (r=-0.636, P=0.005), but there was no significant correlation with the differentiation grade(P=0.151).The VPCT can predict the effect of RECIST criteria, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of VPCT is77.8%,66.7%,72.2%,70.0%and75.0%.(6) Evaluating the middle term effect of Gefitinib in advanced lung adenocarcinoma by VPCT:There was a positive correlation between RECIST-PFS and VPCT-PFS (r=0.761, P=0.004); The VPCT-PFS was shorter than RECIST-PFS(the median PFS12weeks vs30weeks), the median lead time was12weeks. There was no relationship between BF before therapy and the middle term effect. There was a positive correlation between rate of BF decline after6weeks of targeted therapy and VPCT-PFS (r=0.584, P=0.046).The VPCT can predict the progress of RECIST criteria, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of VPCT is92.3%,60.0%,83.3%,85.7%and75.0%.Conclusion:(1) VPCT can be used to evaluate dynamically the changes of vascular architecture, then to evulate the "vascular normalization" and "vascular homeostasis" in nude mice.(2) VPCT is a good technology to evaluate dynamically the changes of vascular architecture by using image-pathologic correlation method in nude-mice transplanted tumor model and patients with lung cancer. VPCT parameters, such as BF and PEI, have different pathological basis.(3) The changes of VPCT parameters is earlier than the change of tumor volume, and the changes of VPCT parameters are ideal indexes to evaluate the effect of EGFR-TKI therapy in lung cancer.
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