【作者】 李说；

【导师】 王建华； 颜志平； 石洪成； 卓维海； 刘清欣； 罗剑钧；

【作者基本信息】 复旦大学 ， 影像医学与核医学， 2009， 博士

【摘要】 第一部分基础研究题目:连续线状排列¹²⁵I粒子条剂量分布测量体外研究摘要目的:研究连续排列的¹²⁵I粒子条的剂量分布,设计并验证相关剂量分布的计算软件。材料及方法:1.根据美国医学物理学家协会AAPM TG43（1995年）及TG43修改版（2004年）推荐的放射籽源剂量计算公式编制连续排列¹²⁵I籽源的剂量计算软件。并绘制5、10、15和20例连续排列¹⁵²I粒子的1000cGy,2500cGy,5000cGy,7500cGy和10000cGy等剂量曲线。2.将10粒¹²⁵I粒子（0.7mCi/粒）连续排列封装在4F透明导管内制成粒子条,利用IP板测量粒子条在等效体模内横轴向剂量分布,并将其与设计软件的计算结果比较。3.将粒子条垂直悬挂在空中,四周距离50cm处各悬挂一枚GD300型辐射光致发光玻璃计量器,照射12小时后,读取玻璃计量器读数,利用空气实际测得的粒子条的剂量率和厂家提供的数据,获得玻璃剂量器的能量修正系数。4.等效体模块钻孔,在距离粒子条轴心0.5、1.0、1.5、2.0、3.0、4.0cm处连续放入GD300型玻璃计量器（每个距离4孔,相互错开,每孔放入连续10枚玻璃计量器）,中心植入¹²⁵I粒子条照射1小时后,读取玻璃计量器计数,计算吸收剂量并与设计软件的计算结果比较。5.应用SPECT/CT扫描观察连续排列的¹²⁵I粒子条在等效体模内辐射分布。结果:1.软件运行良好,计算获得的等剂量曲线显示连续排列的¹²⁵I粒子条辐射分布呈圆柱状,距离粒子条1cm外剂量明显衰减,随粒子长度增加（＞10枚）,粒子条周围剂量分布均匀。2.除了中心区域有部分自吸收发生,IP板测得的数据与软件计算结果匹配良好。3.根据空气中测得数据计算获得的GD300型玻璃计量器的能量修正系数为3.1056,与文献报道相符。4.在距离粒子轴心0.5cm到1.5cm处,体模内GD300型玻璃计量器测得数据与软件计算结果匹配良好;小于0.5cm范围内,由于存在约为11.6%的自吸收率,实测数据低于软件数据;大于1.5cm范围内,由于体模密度低于组织密度,实测数据高于软件计算结果,增大趋势随距离增加而放大。5.SPECT/CT扫描连续排列的¹²⁵I粒子条在等效体模内辐射分布,提示其为与粒子条等长,半径约1.0cm的圆柱体。结论:1.设计软件《¹²⁵I辐射场分布version 0.11》能够计算连续线状排列的¹²⁵I粒子条组织内的剂量分布并绘制等剂量曲线,可被应用于临床。2.连续线状排列的¹²⁵I粒子条组织内剂量分布呈圆柱形,塑形性良好,可以用于临床腔内近距离治疗。3.SPECT/CT可方便、直观监测连续线状排列的¹²⁵I粒子条组织内植入剂量分布。第二部分动物实验动物实验一题目:兔植入性门静脉主干癌栓模型建立及评估摘要目的:探讨建立稳定的兔移植性门静脉主干癌栓动物模型。材料与方法:1.VX2细胞株注入兔皮下成瘤2周,将母瘤切成小条（Φ1.0mm×4.0mm）,头端缝线固定穿入18G针头中备用。2.27只新西兰大白兔随机分成2组并编号:对照组（A组,n=10,A1～A10）和实验组（B组,n=17,B1～B10）。实验组开腹后在门静脉主干前壁缝一荷包,将准备好的瘤条经荷包中央注入门静脉腔内,并通过预留缝线悬挂固定在门静脉内壁。对照组仅门静脉壁作荷包缝合。3.术后观察动物一般情况,体重及生存时间。术后7、14、21、28和35天行MDCT检查及3D-MPR重建,观察瘤栓生长及转移。术后14天处死A1、A2及B1～B4号兔,28天处死A3、A4、B5～B8、B10和B11号兔,行病理检查,观察门静脉癌栓体积和转移情况。结果:1.除了B9号兔死于手术中,实验组门静脉主干成瘤率达100%。实验组（B12～B17号兔）及对照组术后第35天平均体重分别为1.48±0.19公斤和2.08±0.17公斤,实验组（B12～B17号兔）平均生存时间为41.7±4.72天。2.MDCT和3D-MPR都显示了门静脉癌栓。同时MDCT可以显示门静脉阻塞后的侧枝循环和转移灶。3.病理所见证实了门静脉管腔内的癌栓的存在及转移病灶。14天和28天时PVTT的平均体积分别为42.45±9.66 mm³和2269.94±437.04 mm³结论:1.通过开腹向门静脉主干内注入VX2瘤条,并将其悬挂固定在门静脉内壁可以建立稳定的兔门静脉主干癌栓的动物模型。2.MDCT和3D-MPR可以观察动物模型门静脉癌栓的生长及转移。动物实验二题目:兔门静脉主干内植入¹²⁵I粒子条实验研究摘要目的:评价兔门静脉管腔内植入连续排列¹²⁵I粒子条的安全性。材料和方法:1.20只新西兰大白兔随机分成两组并编号,包括治疗组（I组,10只,I1～I10）和对照组（B组,10只,B1～B10）。将三粒6711型¹²⁵I粒子（初始活度为0.7mCi/粒）连续排列封装在4F透明导管内制成粒子条备用,粒子条14、28、60和120天组织内的平均吸收剂量分别为15.95、23.00、53.35和79.92Gy。所有动物剖腹后在门静脉主干前壁做荷包缝合,治疗组将一枚准备好的粒子条经荷包中央插入并悬挂固定在门静脉内壁。2.术后观察动物的生物学行为和体重。术后14、28、60和120天分别行CT检查和直接门静脉造影。CT检查前取血标本行血常规及肝功能检查。治疗组、对照组在14、28和60天造影后分别处死2只动物;120天时处死剩余动物。收取门静脉主干,离粒子10mm处肝组织,十二指肠起始部,肝右叶下角组织标本行病理检查。结果:1.所有动物均手术成功。治疗组未发现¹²⁵I粒子辐射相关的呕吐、腹泻,体重下降等症状及死亡。2.MDCT及DSA均显示门静脉血流通畅。病理大体标本显示门静脉无穿孔,狭窄及血栓形成,植入粒子条与管壁无粘连。治疗组镜下见血管内皮细胞坏死、脱落,中膜及外膜无改变。3.治疗组临近¹²⁵I粒子旁肝细胞坏死明显,肝右叶下角及十二指肠组织无异常。两组间血常规及肝功能无显著差异（P＞0.05）。结论:连续排列¹²⁵I粒子条兔门静脉管腔内植入是安全可行的。动物实验三题目:连续排列¹²⁵I粒子条治疗兔植入性门静脉主干癌栓实验研究摘要目的:探讨连续排列¹²⁵I粒子条治疗兔植入性门静脉癌栓的疗效。材料与方法:1.24只新西兰大白兔按照动物实验一方法建立兔植入性门静脉癌栓模型,2周MDCT确认模型建立后随机分成两组并编号:治疗组（T组,T1～T12号）和对照组（C组,C1～C12号）。将3粒6711型¹²⁵I粒子（初始活度0.7mCi/粒）封装在4F透明导管内制成粒子条备用。粒子条组织内14天和28天的平均吸收剂量分别为15.95Gy和23.00 Gy。治疗组经开腹门静脉癌栓表面植入¹²⁵I粒子粒子条,对照组未作干预。2.术后观察动物一般状况及体重。14天时行MDCT检查,MDCT检查后处死T1～T6及C1～C6行病理检查,剩余动物观察生存期。3.观察门静脉癌栓及转移灶大体标本,测量并计算癌栓体积。HE染色观察癌栓坏死;免疫组化法计算癌栓标本Ki-67标记指数;TUNEL法计算癌栓标本凋亡指数。结果:1.对照组较早出现体重下降及恶液质表现,平均生存时间为26.5±4.46天明显短于治疗组38.4±6.19天。两组间比较有统计学差异（x²=7.286,P=0.007）。2.术后14天治疗组癌栓体积明显小于对照组（565.4±220.85 mm³ VS 2269.93±437.04 mm³,P=0.000）。治疗组与对照组间Ki-67标记指数和凋亡指数有显著性差异（分别为4.14%±1.84%VS 33.82%±6.07%,P=0.000,和6.51%±1.92%VS0.91%±0.26%,P=0.001）结论:连续排列¹²⁵I粒子条植入治疗兔植入性门静脉癌栓可以减少肿瘤细胞的增殖,促进其凋亡,减少癌栓造成的转移,延长生存时间。第三部分临床研究题目:¹²⁵I粒子条联合支架门静脉内植入+化疗栓塞治疗原发性肝癌合并门静脉主干癌栓临床研究摘要目的:研究连续排列¹²⁵I粒子条联合金属支架门静脉内植入+动脉化疗栓塞治疗原发性肝癌合并门静脉主干癌栓的疗效。方法:随机选取同时期连续37例原发性肝癌伴门静脉主干癌栓患者,将其分成两组:对照组（B组,20例）行门静脉支架植入+TACE;治疗组（A组,17例）行¹²⁵I粒子条联合支架门静脉内+TACE。A组粒子植入数量17～23粒（6711型,0.7mCi/粒）,第一个半衰期组织内平均吸收剂量为73.51～76.22Gy,使用SPECT/CT观察粒子植入后剂量分布。疗效评价指标包括:术后并发症,术前术后的门静脉压力改变,肝肾功能及血常规改变等;Fisher精确概率法比较两组患者肝脏肿瘤治疗效果;采用Kaplan-Meier生存曲线分析患者的生存时间、支架通畅时间、累积生存率和累积支架通畅率,组间差异应用Log-rank检验;多因素回归分析用Cox风险比例模型。结果:所有患者门静脉支架和¹²⁵I粒子条均成功植入,两组均未发生手术相关重大并发症。SPECT/CT扫描显示植入¹²⁵I粒子条的辐射分布为与粒子条长度相当,与支架伴行的,半径约1.0cm的圆柱体,塑型性良好。治疗组和对照组肿瘤治疗有效率分别为41.2%VS 15%（x²=4.59,P=0.074）;60、180和360天的累积支架通畅率为94%、94%和94%VS 56.5%、37%和37%（t=7.998,P=0.005）;60、180和360天的累积生存率为87%、65%和53%VS 60%、36%和18%（t=4.018,P=0.045）。单因素分析提示肿瘤类型,肝外转移,Child-Pugh分级,支架通畅状况为影响总体生存的预后因素;Cox逐步回归分析提示肿瘤类型和支架通畅状况为影响总体生存的独立预后因素。支架通畅状况与¹²⁵I粒子条的植入密切相关（rr=4.81,P=0.003）。结论:1.连续排列¹²⁵I粒子条联合金属支架门静脉内植入+动脉化疗栓塞治疗原发性肝癌合并门静脉主干癌栓可以提高支架通畅率,延长生存时间。但远期效果尚需进一步研究。2.SPECT/CT扫描可以直观、方便地显示植入体内的¹²⁵I粒子条辐射范围,具有较好的临床应用价值。更多还原

【Abstract】 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.更多还原