The Experimental And Clinical Trial Of The Treatment With Sorafenib In Liver Cancer On Multi-slice Computed Tomography Perfusion Imaging

Part one:Establishment of the rabbit VX2 liver tumor model and evaluation of the characteristics in different growth period on MSCT perfusion imagingPurpose:To establish experimental rabbit VX2 liver model by implanting VX2 tumor cells into the rabbit liver, and to evaluate their perfusion parameter changes during different growth period.Methods:The VX2 tumor was passaged through successive subcutaneous injection into the hind limb of the New Zealand white rabbits. Tumor cells were implanted in the left lobe of the rabbit liver (n=10). The MSCT perfusion scan was performed before and 7th day 14th day and 21th day after VX2 tumor cells implantation. The perfusion parametes including HBF, HBV, MTT, PS and HAF were measured in the tumor and non-tumorous regions. All the rabbits were executed for pathological examination after MSCT examnination at the third bearing-tumor week. The data were statistically analyzed.Results:The rabbit VX2 liver tumor model was established successfully in this study. The tumors were demonstrated as low density with well-defined margin on the precontrast MSCT and were enhanced slightly on the postcontrast MSCT. The significant differences of the parameters of HBF, PS, HAF and HBV during the 1st-3rd week were found (P<0.01). There wre significant differences between the tumor area and non-tumorous area at the second week after tumor implantation The HBF, HBV, PS and HAF in the tumor area were increased after 2 weeks of tumor implantation and had stastistical differences as compared with non-tumorous area(P<0.01), while the MTT in the tumor area was decreased and had stastistical difference as compared with non-tumorous area(P<0.01). Ten solitary tumors, of which there was central cystic necrosis in 8 in pathological examination, were consistent with the imaging findings revealed by MSCT. Light microscope with low power revealed that the tumor was nest-like with newly-formed abundant capillary without clear margin between the tumor and liver parenchyma, and it revealed with high power that the tumor cells with abundant caryokinesis were bigger than those in normal liver cells, and they were distributed irregularly.Conclusion:Tumor-implanting method was a satisfactory method in animal liver tumor model construction with easy-going, short-growing and high-successful and stabling features. MSCT perfusion imaging could well evaluate the hemodynamics changes of the rabbit liver VX2 tumor.. MSCT could provide more quantification information while combined with its histology examination.Part two:Pre-and post-therapy of sorafenib for rabbit VX2 liver tumor:experimental study of neovascularization and cell apoptosisPurpose:To study the changes of MSCT perfusion imaging parameters and histology of pre-and post-therapy of sorafenib for rabbit VX2 liver tumor. To explore the feasibility of MSCT perfusion imaging in monitoring neovascularization, and to provide experimental basis to evaluate the effect of sorafenib on the inhibition of tumor angiogenesis and promotion of tumor cell apoptosis.Methods:The MSCT perfusion image was obtained in 12 New Zealand white rabbits at the second week after VX2 liver tumor implantation. Two of them were executed and served as the control group (for pathological examination), and the rest 10 rabbits were served as study group receiving oral administration of sorafenibat (20 m g/kg/d for one week) at 7-th day after tumor implantation. MSCT scans were performed respectively at 14-th and 21-th day after tumor implantation, and perfusion parameters (HBF, HBV, MTT, PS and HAF) in both groups were measured and compared in the tumor regions. Finally, all the rabbits were executed for Caspase-3 staining for detection of cell apoptosis.Results:Twelve (100%) rabbits were successfully implanted with VX2 tumor in the liver. The values of HBF, PS and HAF in tumor of the two groups of MSCT perfusions images were significant different (P<0.01). There were no significant difference in HBV and MTT between the two groups (P> 0.05). The positive cells of the Caspase-3 were observed around central vein and necrosis area of hepatocyte. The intensity expression of the Caspase-3 in tumor tissue was significantly higher than that of normal control group (P<0.05).Conclusion:MSCT combined with the histological examination could elucidate the therapeutic effects of sorafenib on the tumor angiogenesis inhibition and cell apoptosis promotion.Part three:MSCT perfusion imaging and pathological study on rabbit VX2 liver tumor treated with combinaion therapy of transcatheter arterial chemoembolization(TACE) and sorafenibPurpose:To study the changes of MSCT perfusion imaging and histology of rabbit VX2 liver tumor treated with combination therapy of TACE and sorafenib, and to explore the feasibility of improving the therapeutic effect of TACE by way of inhibition of tumor angiogenesis.Methods:Licer tumor modle was establised in 30 New Zealand white rabbits. They were randomly divided into three groups based on therapy stratigies:(A) 0.9% Sodium Chloride group; (B) TACE group; (C) TACE Plus sorafenib group. The MSCT scan was performed at 1st week to 3th week after post-therapy in order to measure the volume changes of tumor. Tumor growing situations were observed by MSCT at pre-therapy and post-therapy (at the 1st,2nd and 3th week). MSCT perfusion parameters of HBF, HBV, MTT, PS and HAF in the tumor regions were measured at pre-theraspy and the 3th week of post-therapy. All the rabbits with VX2 tumor were executed for routine pathological examination and VEGF and CD34 staining after 3 weeks of treatment. Expression of VEGF and CD34 was detected, and the percentage of positive tumor cells and micro vessel density (MVD) were calculated and comapred at high power field (400×magnification).Results:The size and growth rate of tumor were significant different between different groups. (P＜0.01). VEGF positive staining was mostly displayed homogeneous or inhomogeneous granule and clot with brown-yellow color in cytoplasm. The more tumor cells actively proliferated, the more abundant and strong staining positive tumor cells expressed. CD34 staining was expressed in tumor tissue, On light microscope, liver sinusoidal endothelial cells in the liver tissue were seen in varyied degrees of yellow dye. Individual vessel staining can be observed in adjacent cancer tissue.Conclusion:Sorafenib could inhibit tumor angiogenesis and improve the therapeutic effect of the TACE. Measurement of MSCT perfusion parameters and comparson with liver tumor immunohistochemistry findings reflected that sonafenib could prevent tumor growth and inhibition of tumor angiogenesis.Part four:Clinical application study of MSCT perfusion imaging in primary hepatic carcinomas treated with sorafenibPurpose:To study the changes of MSCT perfusion parameter and clinical indexes on primary hepatic carcinomas treated with sorafenib and evaluate the therapeutic effect of sorafenib.Methods:The MSCT perfusion and routine laboratory examination were performed on six patients with primary hepatic carcinomas before therapy and three months after treatment of sorafenib. All statistical data were done respectively.Results:There was significant decrease in HBF, PS and HAF post-treatment with sorafenib (P＜0.01). There was no significant difference in blood test, hepatic function and renal function (P>0.05)Conclusion:MSCT could evaluate the hemodynamic changes in patients with primary hepatic carcinomas after treatment with sorafenib. Sorafenb was the choice of treatment of primary hepatic carcinomas because of few side-effects.