【作者】 张雯；

【导师】 颜志平； 石洪成； 罗剑钧； 刘清欣； 瞿旭东；

【作者基本信息】 复旦大学 ， 影像医学与核医学， 2010， 硕士

【摘要】 线状排列125I粒子条及金属内支架联合TACE治疗肝癌伴下腔静脉恶性梗阻的实验及临床研究第一部分动物实验动物实验一新西兰大白兔下腔静脉内植入不同剂量125I粒子条的实验研究目的：评估兔下腔静脉腔内植入线状排列125I粒子条的可行性及安全性；比较不同剂量125I粒子条对兔下腔静脉及周围组织的损伤情况。材料和方法：将14只新西兰大白兔随机分成两组并编号,包括两枚粒子组(A组)和四枚粒子组(B组),各7只。将两粒和四粒6711型初始活度为0.7mCi的125I粒子分别连续排列封装在4F透明导管内制成粒子条。兔开腹后在下腔静脉前壁做荷包缝合,将准备好的粒子条经荷包中央置入并悬挂固定在下腔静脉内壁。术后观察兔的生物学行为。比较125I粒子条植入前后血常规及肝功能的变化；比较两组兔术后1周、2周、4周、2个月、4个月的体重、血常规及肝功能变化。定期MDCT增强检查或DSA下腔静脉造影明确下腔静脉通畅情况。观察两组兔1周、2周、4周、2个月时下腔静脉,离粒子<10mm处肝组织,局部小肠及肝右叶外缘组织的病理变化。结果：手术成功率100%。A、B两组均未发现125I粒子辐射相关的呕吐、腹泻及死亡。125I粒子条植入前后血常规及肝功能无明显变化；两组间体重、血常规及肝功能无显著差异(P>0.05)。MDCT增强及DSA检查显示下腔静脉血流通畅。病理大体标本显示下腔静脉无穿孔、内壁光滑、无血栓形成,粒子条与管壁间无粘连。两组光镜下均见血管内皮细胞坏死、脱落,中膜及外膜无明显改变。两组临近125I粒子旁肝细胞坏死明显,B组较A组严重,但随时间延长均修复良好；远处肝脏及小肠组织无异常。结论：新西兰兔下腔静脉腔内植入线状排列125I粒子条是安全可行的。不同剂量125I粒子条对兔下腔静脉及周围组织的损伤情况无明显差异。动物实验二兔植入性下腔静脉癌栓模型的建立及评估目的：探讨建立稳定的兔移植性下腔静脉癌栓的动物模型并对其进行客观评估。材料与方法：VX2细胞株复苏后注入兔皮下成荷瘤,将母瘤取出制成瘤条,放于EMDM高糖培养液中备用。12只新西兰大白兔开腹后在下腔静脉肝下段前壁缝一荷包,将瘤条经荷包中央注入下腔静脉腔内,并通过预留缝线悬挂固定在下腔静脉内壁制成下腔静脉癌栓模型。术后观察兔的生物学行为、体重及生存时间。MDCT检查及3D-MPR重建观察术后1、2、3、4和5周瘤栓的生长及转移情况。所有兔自然死亡后,肉眼和光镜下观察下腔静脉癌栓及肝、肺、肾的转移情况。结果：术后第五周实验兔开始出现进食减少表现,术后第六周平均体重为2.02±0.20kg,平均生存时间为49.50±4.40天。MDCT和3D-MPR均见下腔静脉内充盈缺损。并可见下腔静脉阻塞后的侧枝血管和转移灶。病理显示下腔静脉管腔内癌栓的存在及转移病灶,下腔静脉腔内成瘤率达100%。结论：建立了稳定的、可供影像学评价的植入性下腔静脉癌栓的动物模型。MDCT和3D-MPR对诊断下腔静脉癌栓有很好的敏感性和特异性。此模型可用于评价不同治疗方法对下腔静脉癌栓疗效的进一步研究。动物实验三线状连续排列125I粒子条治疗兔植入性下腔静脉癌栓的实验研究目的：探讨线状连续排列125I粒子条治疗兔植入性下腔静脉癌栓的疗效。材料与方法：12只新西兰大白兔按照动物实验二方法建立兔植入性下腔静脉癌栓模型。2周后经MDCT确认下腔静脉癌栓模型建立后随机分成两组并编号：对照组(C组)和治疗组(D组)。将3粒6711型125I粒子封装在4F透明导管内制成粒子条。D组开腹后下腔静脉癌栓表面植入125I粒子条,对照组未作干预。术后观察兔的生物学行为、体重及生存期。MDCT每周观察癌栓生长情况并计算癌栓体积。自然死亡后,解剖观察下腔静脉癌栓及转移灶大体标本。光镜下观察比较两组癌栓坏死情况、PCNA指数(PI)及凋亡指数(AI)。两组间计量资料采用两独立样本的t检验,采用Wilcoxon秩和检验比较两组间癌栓的体积,采用Kaplan-Meier生存曲线分析比较动物的生存时间。结果：所有动物手术均顺利。对照组体重下降及恶液质出现较早,C组和D组三周时体重、生存时间、PI及AI分别为2.03±0.13kg、31.67±5.28d、(63.01±2.01)%、(6.02±2.93)%和2.23±0.12kg、45.83±8.68d、(16.73±5.18)%、(29.47±7.18)%,两组间差异有统计学意义(P<0.05)。C组和D组的癌栓体积有显著性差异(P<0.05)。结论：线状连续排列125I粒子条治疗兔植入性下腔静脉癌栓疗效明显,明显延长生存时间。第二部分临床研究连续线状排列125I粒子条及金属内支架下腔静脉内植入联合动脉化疗栓塞治疗原发性肝癌伴下腔静脉恶性梗阻的临床研究目的：评价连续线状排列125I粒子条及金属内支架下腔静脉内植入联合动TACE治疗原发性肝癌伴下腔静脉恶性梗阻的可行性、安全性及疗效。材料和方法：从2009.03至2010.01,共32例在我院行介入治疗的肝癌伴下腔静脉恶性梗阻的患者进入临床研究,所有病例行125I粒子条+IVC支架植入联合TACE术。所有病例术前行血常规、肝肾功能、凝血功能及上腹部增强CT检查。先行下腔静脉DSA明确梗阻位置及长度,确定所需125I粒子数目,将125I粒子制成粒子条,捆绑于Z型自膨式金属内支架上。将附有125I粒子条的腔静脉支架植入下腔静脉狭窄处,同时肝内病灶行经动脉化疗栓塞术。术后观察并发症,用SPECT/CT观察125I粒子条植入后的剂量分布。比较手术前后的IVC梗阻段直径、下腔静脉压力差变化、梗阻症状评分、肝肾功能及血常规等。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；多个协变量的Logistic回归分析分析影响预后的主要因素。结果：所有患者手术均成功,共植入36枚腔静脉支架。术后患者下腔静脉梗阻症状明显好转。术后仅1例出现急性肺栓塞、1例急性肾衰竭,经积极抢救治疗后均好转；余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,呈与支架伴行的、半径约1.0cm的圆柱体,塑型性良好。125I粒子条植入前后肝功能及血常规变化无明显差异(P>0.05)。125I粒子植入前和后梗阻段直径、下腔静脉压力差变化、梗阻症状评分分别为6.70±5.66mm.18.58±4.64cmH20.2.18±1.55和27.33±2.46mm、4.97±1.20cmH20.0.42±0.61。手术前后差异有统计学意义(P<0.05)。60,90,180,300天的累积支架通畅率和累积生存率分别为100%,93.5%,83.2%,83.2%和100%,96.6%,67.7%,51.7%。多个协变量的Logistic回归分析显示肿瘤生长方式(是否为浸润性)及Child-Pugh分级为影响预后的主要因素(P<0.05)。结论：连续线状排列125I粒子条及金属支架下腔静脉内植入联合动脉化疗栓塞治疗原发性肝癌伴下腔静脉恶性梗阻是安全可行的,可以提高支架通畅率,延长患者生存时间。远期效果尚需大量病例长期随机对照研究。更多还原

【Abstract】 Part One:Animal ExperimentAnimal Experiment One:Experimental study on the implantation of iodine-125 seeds strand with two different doses into inferior vena cava in rabbitObjective:To evaluate the safty and feasibility of the treatment that the iodine-125 seeds strand implantation into inferior vena cava(IVC) in rabbit.Materials and Methods:Fourteen New Zealand white rabbits were randomly divided into two groups, including two seeds group (GroupA) and four seeds group(Group B) 7 rabbits respectively. Two or four 125I seeds(model 6711, Ao=0.7mCi) were sealed into a transparent catheter as a seed strand, Purse-string suture was done on the anterior wall of IVC after the laparotomy, and the iodine-125 seeds strand was inserted into IVC through the purse and suspensory fixed on the inner wall of IVC. The general conditions were monitored after operation. The post-operation body weight, routine blood and liver function were compared with those of pre-operation respectively. DS A or MDCT examinations of IVC were performed at 1st,2nd,4th,8th and 16th week after operation, respectively. MDCT examinations were performed with plain scan, arterial phase, portal phase and venous phase enhancement for all animals and 3D MPR were acquired. Rabbits were killed at 1st,2nd,4th,8th and 16th week post-operation respectively. IVC, the liver tissue less and more than 10mm away from the seeds strand and the intestine were examined with the gross and histological pathology.Results:The success rate of operations was 100%. No vomiting, diarrhea and death related to irradiation were observed in both groups. No significant changes was observed in the body weight, routine blood and liver function between two groups (P>0.05). IVC was patent in DSA, MDCT and 3D-MPR images. In gross examination, the target IVC is smooth, there are no perforation or mural thrombosis. No adherence was observed between the seeds strand and blood vessel. The histological examination showed necrosis and exfoliation of endothelial cells in IVC in both groups, but no obvious pathological changes in media and adventitia tunicae. Swelling and distension, cytolysis and necrosis of liver cells were seen near the seeds strand in both groups, and is more severe in Group B.Conclusion:Linear iodine-125 seeds strand intraluminal implantation into the inferior vena cava is safe and feasible. There are no significant different about radiation injuries in different dose.Animal Experiment Two:Establishment and evaluation study of implanted inferior vena cava tumor thrombus in rabbit modelsObjective:To establish an animal model of implanted inferior vena cava tumor thrombus (IVCTT) and to evaluate its growth with MDCT and 3D-MPR.Materials and Methods:Tumor cell line VX2 was inoculated subcutaneously into rabbit to develop parent tumor, which was cut into small strip. Purse-string suture was done on the anterior wall of IVC after the laparotomy in twelve New Zealand white rabbits, the tumor strip was injected into IVC through the purse and suspensory fixed on the inner wall of IVC. The general conditions, body weight and the survival time were monitored after operations. MDCT examinations were performed with plain scan, arterial phase, portal phase and venous phase enhancement every week for all animals and 3D MPR were acquired. The volumes of IVCTT were calculated. IVC, IVCTT and metastasis were examined with gross and histological pathology.Results:The mean body weight of rabbits at the 6th week was 2.02±0.20kg. The mean survival time was 49.50±4.40 days. The IVCTT was confirmed by MDCT and 3D-MPR images. Collateral varicose veins caused by IVC obstruction and metastasis were also showed in images. IVCTT and metastasis were confirmed by pathology. The success rate of IVCTT was 100%.Conclusions:Injecting and suspensory fixing VX2 tumor strip into IVC is a reliable method to establish IVCTT animal model. MDCT and 3D MPR are valuable method for monitoring the growth and metastasis of IVCTT in animal models. The model of implanted IVCTT of rabbit provides useful tool for the research of treatment of IVCTT.Animal Experiment Three:Experimental study on the treatment of the implanted inferior vena cava tumor thrombus in rabbit models with linear iodine-125 seeds strandObjective:To evaluate the effect of linear iodine-125 seeds strand on the implanted inferior vena cava tumor thrombus in rabbit model.Materials and Methods:Twelve New Zealand white rabbits with IVCTT were randomly divided into two groups and numbered, including control group(Group C) and treatment group(Group D). Three iodine-125 seeds(model 6711) were sealed in a transparent catheter to form a seeds strand. The general condition, body weight and survival time were monitored. MDCT examinations were performed every week for all animals and 3D MPR were acquired. The volumes of IVCTT were calculated. IVC, IVCTT and metastasis were examined with gross and histological pathology for both groups. The proliferating cell nuclear antigen (PCNA) index (PI) and apoptosis index(AI) of IVCTT were compared between two groups. T-test, Wilcoxon rank test and Kaplan-Meier survival curve analysis were used.Results:The success rate of operation was 100%. The body weight loss and the cachexia of Group C appeared earlier than Group D. At the third week, the body weight, the mean survival time, PI,AI in Group C and D were 2.03±0.13kg、31.67±5.28d、(63.01±2.01)%、(6.02±2.93)% and 2.23±0.12kg、45.83±8.68d、(16.73±5.18)%、(29.47±7.18)%, respectively. There were statistically significant difference between Group C and Group D (P< 0.05).The IVCTT volume of Group D was remarkably smaller than that of Group C (P< 0.05). Conclusion:The implantation of linear iodine-125 seeds strand is an effective method for treatment of IVCTT in rabbit model. It can inhibit the growth, promote apoptosis of IVCTT, and prolong the survival time of the rabbit with IVCTT.Part Two:Clinical ResearchTreatment of hepatocellular carcinoma with malignant inferior vena cava obstruction by implantation of linear iodine-125 seeds strand attached to IVC-stent combined with TACE:a clinical researchObjective:To evaluate the safty, feasibility and clinical efficacy of treatment of hepatocellular carcinoma with malignant inferior vena cava obstruction by the implantation of linear iodine-125 seeds strand attached to IVC-stent combined with TACE.Methods:From Mar 2009 to Jan 2010,32 patients of irresectable HCC with IVC obstruction were enrolled into this study. All of them received the implantation of 125I seeds strand attached to IVC-stent combined with TACE therapy. The postoperative complications were monitored. SPECT/CT was used to monitor the dose field distribution of iodine-125 seeds. The routine blood and liver function, diameter of obstructive segment of IVC, pressure gradient and clinical symptoms related to obstruction were compared before and after therapy. The stent patency rate and survival rate were calculated with Kaplan-Meier survival curve analysis. Cox proportional hazards model were used to analyze independent prognostic factors.Results:Technical successful rate was 100% for the implantation of 125I seeds strand attached to IVC-stent in the obstructive segment of IVC. A total of 36 stents were placed in 32 cases. Clinical improvements were remarkable after therapy. No severe complications related to the operation were observed, except the episode of acute renal dysfunction after therapy in one case, and acute pulmonary embolism in another one. 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 diameter of obstructive segment of IVC, pressure gradient and clinical symptoms related to obstruction before and after operation were 6.70±5.66mm、18.58±4.64cmH2O、2.18±1.55 and 27.33±2.46mm、4.97±1.20cmH2O、0.42±0.61 respectively. There was statistically significant difference (P＜0.05). The cumulative stent patency rates and survival rates at 60,90,180,300 days were 100%,93.5%, 93.5%,83.2% and 100%,96.6%,67.7%,51.7%, respectively. Multinomial Logistic Regression revealed that tumor growth pattern and Child-Pugh classification were principal predictors of prognosis (P< 0.05).Conclusions:It is a safe and feasible therapeutic option for hepatocellular carcinoma with malignant IVC obstruction for the implantation of linear iodine-125 seeds strand attached to IVC-stent combined with TACE. And further study is needed for the long-term efficacy.更多还原