The Experimental And Clinical Study Of Combined Percutaneous Transhepatic Portal Venous Linear Iodine-125 Strands And Stents Implantation With TACE In Treating Hepatocellular Carcinoma With Main Portal Venous Tumor Thrombosis

Part One:Basic ResearchTitle:Dosimetric characterization of consecutive linear Iodine-125 seeds:a basic researchAbstractObjectiveTo evaluate the dose distrubution of consecutive linear Iodine-125 seeds(model 6711), as well as design and verify the software for calculating its dosage.Methods1 A computer software was designed to calculate the dosage of consecutive linear Iodine-125 seeds baesd on the formula and the required data recommended by the American Association of Physicists in Medicine(AAPM) TG43(1995) and TG43 revised(2004).The isodose curves of 1000cGy,2500cGy,5000cGy,7500cGy and 10000cGy of 5,10,15,20 consecutive linear Iodine-125 seeds,respectively,were created by the designed software.2 Ten Iodine-125 seeds(0.7mCi/seed),were consecutively sealed in a 4F catheter to be a source strand.Dosimetry of the Iodine-125 seeds strand which planted in a tissue equipotent phantom(model SM-2) was measured by a image plate(IP) on lateral axis, and the results were compared with the one caculated by the designed software.3 The Iodine-125 seeds strand with four GD-300 radiophotoluminescent glass detectors(RPLGD) 50 centimetres away from it in four directions were hang in the air vertically for twelve hours.The absorbed dose rate of the air was measured by RPLGDs,and the energy dependence coefficient of the RPLGD was calculated by comparing it with the parameter provided by the manufacturer.4 The source strand was impalnted in the centre hole of the phantom with the RPLGDs around it in four directions on same axial direction.Forty RPLGDs were divided in four groups(10/each) and were arrayed consecutively in axial direction. The absorbed dose rates were detected by the RPLGDs for an hour at the distance of 0.5,1.0,1.5,2,3 and 4 centimeters away from the strand source respectively.The results were compared with the one calculated by the software.5 Single-photon emission computed tomography/computed tomography(SPECT/CT) was used to monitor the dose field distribution of Iodine-125 strand in the phantom.Results1 The software(vison 0.11) worked very well,and its calculated isodose curves showed a column dose field distribution of the consecutive linear arrayed Iodine-125 seeds..The dosage attenuated obviously one centimeter away from the strand source, and it is relatively adqulis when the Iodine seeds were more than 10.2 The dosage measured by the IP matched well with the results calculated by the softwell,except for some attenuation in the centre caused by the self-absorption.3 The energy dependence coefficient calculated is 3.1056 which coincided well with the previous reported data.4 The dosage measured by the RPLGDs matched well with the results calculated by the software in the distance ranging from 0.5cm to 1.5cm.The smaller measured dosage than the calculated one was observed in the distance less than 0.5cm for about 11.6%of self-absorption;and the larger measured dosage than the calculated one was observed in the distance exceeds 1.5cm,which may be due to the density difference between the phantom and the body tissue.5 SPECT/CT scanning showed the dose field distribution of 125～I strands was a column with a radius about one centimeterConclusion1 The designed software could caluate the dosage of the consecutive linear Iodine-125 seeds and draw the isodose curves,which was of potential in clinical aplication.2 The consecutive linear Iodine-125 seeds showed a good distribution of dose field which could be applicable in luminal branchytherapy.3 SPECT/CT scanning was a macroscopic and convenient way to monitor the dose field distribution of 125～I seeds after the implantation.Part Two:Animal ExperimentAnimal Experiment OneTitle:Establishment and evaluation of rabbit models of implanted main portal venous tumor thrombusAbstractObjective:To establish a stable animal model of implanted main portal vein tumor thrombus(MPVTT) in rabbit and use MDCT and 3D-MPR to monitor its growth.Materials and Methods:1.Tumor cell line VX2 was inoculated subcutaneously into rabbit to develop a parent tumor for 2 weeks,which was cut into small slice(Φ1.0mm×4.0mm) and threaded into a 18G needle with a suture seamed on the head of it.2.Twenty-seven New Zealand white rabbits were randomly divided into 2 groups and numbered,including control group(Group A,n=10,A1-A10) and experimental group (Group B,n=17,B1-B17),respectively.Purse-string suture was done on the anterior wall of the portal venous trunk after the laparotomy in both groups,and only in group B,the tumor slice was injected into the portal vein through the purse and suspensory fixed on the inner wall of portal vein.3.The body weight and the survival time were monitored after operations.MDCT examinations were performed at the 7^th,14^th,21^th,28^th and 35^th day and 3D-MPRs were aquired.A1,A2 and B1-B4 were sacrifaced at the 14^th day and A3,A4,B5～B8, B10 and B11 were sacrificed at the 28^th day for pathologic examination,respectively. The volumes of PVTT were calculated and metastasis were examined.Results:1.The successful rate of MPVTT establishment was 100%except for one rabbit(B9) died of opertaion.The body weight at the 35^th day were 2.08±0.17kg and 1.48±0.19kg(P=) for Group A and Group B(B12～B17),respectively.The survival time of Group B(B12～B17) was 41.7±4.72 days.and Group A had no death.2.Both MDCT and 3D-MPR confirmed the PVTT presentation.MDCT and 3D-MPR also depicted collateral vessels caused by obstruction of PV and metastasis.3.PVTT and metastasis were conformed pathologically.The volumes of PVTT at the 14^th day was 42.45±9.66 mm³ and 2269.94±437.04 mm³ at the 28^th day.Conclusions:1.The MPVTT animal model could be established by injection and suspensory fixation of VX2 tumor slice in the portal venous trunk.2.MDCT and 3D-MPR could monitor the growth and metastasis of PVTT in animal models. Animal Experiment TwoTitle:Implantation of the iodine-125 seed strand into portal venous trunk in rabbit modelsAbstractObjective:To evaluate the safty of implantation of the iodine-125 seed strand into portal vein.Materials and Methods:1.Twenty New Zealand white rabbits were randomly divided into two groups and numbered,including experimental group(Group I,10 rabbits,I1-I10) and control group(Group A,10 rabbits,A1-A10) respectively.Three linear iodine-125 seeds(model 6711,(?)₀=0.7mCi) were sealed in a transparent catheter to form a seed strand,which deliver a absorbed dose of 15.95,23.00,53.35 and 79.92Gy in 14,28, 60 and 120 days respectively.Purse-string suture was done on the anterior wall of the portal venous trunk after the laparotomy in both groups,and the iodine-125 seed strand was inserted into the portal vein through the purse and suspensory fixed on the inner wall of portal vein in group I.2.The general condition and body weight were monitored after operation.MDCT and portal venous DSA were performed at 14^th,28^th,60^th and 120^th day respectively.Blood samples were collected before the CT scan for the test of routine blood and liver function.2,2,2 and 4 animals of each group were sacrificed at 14^th,28^th,60^thand 120^th day,respectively,after the DSA examination.Portal venous trunk,the liver tissue 10mm away from the seed strand,the right inferior liver lobe and the duodenum were harvested for pathologic examination..Results:1.The operations were successfully completed in all 20 animals.No irradiation related diarrhea,vomiting,body weight loss and death were observed in Group I.2.MDCT and DSA results showed the patency of the portal vein.The target blood vessel segments had no perforation,deformation,stricture or mural thrombosis in general examination.No adherence was observed between the seed strand and blood vessel.Necrosis and exfoliation of endothelial cells were seen under microscope in Group I,and no obvious pathological changes of tunicae media and adventitia were detected in all time range.3.The obvious liver necrosis was seen near the seed strand in Group I,but except for the right inferior liver lobe and duodenum.No significent change in the blood count and liver function was observed between two groups(P＞0.05).Conclusion:Intraluminal implantation of linear iodine-125 seed strand into portal venous trunk is safe and available..Animal Experiment ThreeTitle:Treating the implanted main portal venous thrombus in rabbit models with linear iodine-125 seed strandAbstractObjective:To evaluate the therapeutic effect of linear iodine-125 seeds in treating main portal vein tumor thrombus on rabbit model.Materials and Methods:1.Twenty-four rabbit models with MPVTT were established in the aforementioned method.After confirmation the existence of MPVTT by CT scanning 14 days after tumor implantation,the rabbits were then randomly devided into two groups and numbered,including treatment group(Group T,12 rabbits,T1-T12) and control group(Group C,12 rabbits,C1-C12 ).Three linear iodine-125 seeds(model 6711, (?)₀=0.7mCi) were sealed in a transparent catheter to form a seed strand,which deliver a absorbed dose of 15.95Gy and 23.00 Gy in 14 and 28 days respectively.The Group T was treated with implantation of iodine-125 seed strand on laparotomy.2.The general condition and body weight were monitored.MDCT examinations were performed at the 14^th day after the iodine-125 seed strand implantation and six rabbits of each group were sacrificaced for pathologic examination after CT scanning.The volumes of PVTT were calculated and metastasis were examined.The Ki-67 proteins were detected by immunohistochemical method and the apoptosis of the PVTT were measured by TUNEL.The Ki-67 labeling index(Ki-67 LI) and apoptosis index were calculated.The survival time of rest animals was recorded.Results: 1.The body weight loss and the cachexia of Group C appeared earlier than Group T. The mean survival time of Group T was longer than Group C((38.4±6.19 d v.s.26.5±4.46d,P=0.007).2.The PVTT volume of Group T at the 14^th day was remarkably smaller than it of Group B(565.4±220.85 mm³ v.s.2269.93±437.04 mm³,P=0.000).Both Ki-67 LI and apoptosis index were significent different between Group T and Group C(4.14%±1.84%VS 33.82%±6.07%,P=0.000,and 6.51%±1.92%VS 0.91%±0.26%,P= 0.001,respectively)Conclusion:The linear iodine-125 seeds implantation was effective in treating main portal vein tumor thrombus on rabbit model,by reducing PVTT related metastasis and prolong the overall survival.Part Three:Clinical ResearchTitle:Combined percutaneous transhepatic portal venous stent and linear iodine-125 strands implantation with transarterial chemoembolization in treating hepatocellular carcinoma with main portal venous tumor thrombosis:a clinical researchBackground/Aims To evaluate the clinical efficacy of percutaneous transhepatic portal vein stenting and transarterial chemoembolization(PTPVS-TACE) combined with or without portal venous consecutive linear iodine-125 seeds strands implantation in hepatocellular carcinoma(HCC).Methods The study population comprised 37 consecutive patients with advanced HCC accompanied by tumor thrombosis in the main portal vein,of whom,20(Group B) received PTPVS-TACE,and 17(Group A) received combined PTPVS-TACE and linear iodine-125 strands placement.17 to 23 model 6711 iodine-125 seeds ((?)₀=0.7mCi) with dosage of 73.51～76.22Gy on the first half-decay period were delivered to each patients(Group A).SPECT/CT was used to monitor the dose field distribution of iodine-125 seeds.The postoperative complications,tumor responses and stent patency rate,were evaluated,and the Kaplan-Meier method and Log-rank test were utilized for survival analysis.Cox proportional hazards model were used to analyze independent prognostic factors.Results Stents and iodine-125 strands were successfully placed in the portal veins in all patients.No severe operation related complications were observed.SPECT/CT scan showed the dose field distribution of iodine-125 strands was a column with a radius about one centimeter which accompanied the stent.The tumor response rate (CR+PR) was 41.2%in Group A and 15%in Group B(x²=4.59,P=0.074).The 60-, 180-,and 360-day cumulative stent patency rates were 94%,94%and 94%in Group A,and 56.5%,37%and 37%in group B,respectively,showing significant difference (t=7.998,P=0.005).The median patency time was 360 days and 160.73 days for Group A and Group B,respectively.The 60-,180-,and 360-day overall survival(OS) rates were 87%,65%and 53%,for Group A,and 60%,36%and 18%for Group B, respectively.Significant statistical differences were detected between the two groups (t=4.018,P=0.045).The median survival time were 360 days and 165.21 days, respectively.Tumor type,extrahepatic metastasis,Child-Pugh classification,stent patency status,were significant predictors of a poor prognosis on univariate analysis. Cox's proportional hazards model revealed the tumor type and stent patency status were the independent prognostic factors for OS(P＜0.01).Furthermore,the stent patency correlated significantly with the iodine-125 strands placement(rr=4.81,P= 0.003).Conclusions:1.Combined PTPVS-TACE and linear iodine-125 strands placement may benefit the survival and stent patency of the patients with HCC accompanied by MPVT,however long-term efficacy needs to be further confirmed.2.SPECT/CT scanning is a macroscopic and convenient way to monitor the dose field distribution of iodine-125 seed strand after the implantation.