肝癌化疗栓塞前后MR弥散和灌注成像的实验研究
|
摘要
研究背景
化疗栓塞病灶周边部的再血管化、存活癌细胞是肝癌TACE术后复发转移的主要病理基础。很长时期以来,CT扫描主要依靠肿瘤内部和周边的碘化油沉积情况来评价TACE的治疗效果。CT平扫可在某种程度上反映栓塞是否完全及栓塞后的瘤体变化,而CT双期增强扫描可反映存活瘤组织及新发病灶的血液供应情况。然而,碘化油与周围组织间较大的密度差所形成的放射状伪影与碘化油的高密度影响对栓塞病灶周边残余肿瘤的观察。
MR自旋回波序列(SE)T1WI、T2WI与动态增强扫描的应用,对HCC的TACE术后随访价值较大,特别是SE序列T2WI,多数存活肿瘤在T2WI上为高信号,而TACE术后肿瘤内部的凝固性坏死为低信号。肝癌TACE术后在T1WI和T2WI上的信号多种多样,特别是T2W上,存活肿瘤、出血、液化坏死和炎性细胞的浸润均可表现为高信号,因此T2WI对判断肿瘤的存活有一定困难,而对凝固性坏死的判断十分可靠。介入治疗后残存肿瘤的强化较肝实质早而持续时间短,动态增强MRI早期呈结节状、片状强化,可以鉴别瘤内坏死、纤维组织与肿瘤中央的残存肿瘤,但难以鉴别包膜与包膜内残存肿瘤结节。如果为乏血供的HCC,就难以使用这种技术发现存活肿瘤。部分肿瘤患者进行了经皮肝穿酒精注射联合TACE治疗,肿瘤由低信号变成高信号,即便用动态扫描也很难区分肿瘤增强,从而无法判断存活肿瘤。
原发性肝癌介入治疗术后的评价主要集中在CT和MR双期增强上,CT灌注成像定量分析组织灌注是评价肝癌动脉栓塞治疗后血流动力学变化的有效方法。但它的缺点也很突出,主要是需用大量的碘对比剂及具有潜在的过敏反应、中毒性肾损害等危险,同时病人也会受到较大剂量的辐射。
MRI灌注图在检测TACE术后残存肿瘤组织的灌注方面很有价值。TACE的疗效可以通过比较术前术后的灌注差异而评估。
DWI能够区分肿瘤中的坏死成分和存活成分,ADC值的改变早于T2WI上信号的改变,甚至早于组织学上的变化。因此,利用DWI对肿瘤组织不同时间平均ADC值的测量、对比,可以量化评价肝癌组织TACE术后的坏死、复发情况。
本研究利用兔VX2肝癌模型,通过MR DWI、PWI成像观察肝癌栓塞前后坏死及血流灌注情况的变化规律,判断MR DWI、PWI成像在观察肝癌栓塞后坏死及血流灌注的临床应用价值,从而为肝癌介入治疗的最佳方法的选择及疗效观察提供了更有价值的影像诊断依据。
第一章:兔VX2肝癌模型的制作及改进
目的:将穿刺器械进行改良,采用肿瘤组织块直接穿刺种植肿瘤,并与肿瘤细胞悬液植入法、肿瘤组织块悬液种植法对比,观察种植成功率及肿瘤异位种植的情况,筛选更为简便、有效的肿瘤模型的制作方法。
材料和方法:
1.1兔VX2肝癌模型制作
1.1.1实验动物新西兰大白兔30只,体重2.5～3.0kg,雌雄不限,由中山医科大学实验动物中心提供。随机分为3组,分别为肿瘤细胞悬液植入法组、肿瘤组织块悬液种植组、肿瘤组织块直接穿刺种植组(改进组),每组实验动物10只。
1.1.2 VX2细胞株制备
将瘤株接种于兔腹股沟区皮下或肌肉间,使之成瘤,三周后接种处可扪及一实质性包块。速眠新全麻后,无菌条件下剥离肿瘤,切取包块边缘生长旺盛的鱼肉样组织,置于盛有生理盐水的平皿中。1)配成2×10~6个细胞/ml浓度的VX2细胞悬液,用于第1组肿瘤的种植。2)取肿瘤组织用眼科剪将其剪成大小约1mm~3组织块。用于第2组肿瘤的种植。3)用眼科剪将肿瘤组织剪成约1mm×1mm×3mm大小瘤块用于第3组肿瘤的种植。
1.1.3兔肝VX2肿瘤种植穿刺针的改进:使用18G腰穿针。取出穿刺针芯,用油石打磨去掉尖端,以细沙纸抛光以去除毛刺,使顶端平整光滑,即成为推针,与常规尖头针芯及套管配合使用,成为改良的穿刺用具。
1.1.4兔肝VX2肿瘤的种植。
动物术前禁食12h,用速眠新全麻,仰卧位,固定四肢于兔手术板上,常规剑突左侧腹部剪毛。CT扫描兔肝脏,确定肝左叶待接种部位,选定穿刺点、角度、深度。常规消毒铺巾,刀尖挑开穿刺点皮肤,用带尖头穿刺针芯的18G穿刺针穿入肝脏预定位置,拨出针芯,用注射器抽吸无回血。第1组动物注入VX2细胞悬液1ml,第2组注入肿瘤组织块悬液1ml,两组在退针时注入少量明胶海绵颗粒。
第3组由助手固定好穿刺针,术者用眼科镊夹1块瘤块放入针鞘内,平头穿刺针芯将瘤块推入肝内,同理再分别放入2块组织块。如未成功,可再重复上述操作。将一小块明胶海绵用平头穿刺针芯推入肝内封堵针道。局部按压3分钟,并用创可帖封伤口。
1.2 CT扫描
种植后2周对新西兰白兔肝VX2瘤灶行CT扫描,四周再扫描一次,观察2周扫描是否有漏检病例。扫描条件:120kV,180mA,层厚3mm,间距3mm:延迟8～12s,30～40s行双期增强扫描。
1.3观察指标及统计学处理
分别观察不同种植方法的成功率,孤立病灶的成功率,异位种植情况。统计学处理采用SPSS13.0软件精确概率法进行统计分析,p＜0.05有统计学意义。
结果:
1、各组间种植成功率:瘤细胞悬液植入组30%,肿瘤组织块悬液种植组50%,肿瘤组织块直接种植组90%,经统计学分析p=0.036,可以认为不同种植方法成功率不同。
2、不同种植方法孤立肿瘤种植的成功率:肿瘤组织块直接种植组最高(80%),依次为肿瘤组织块悬液种植组(20%)和瘤细胞悬液植入组(10%)。统计学分析有显著性差异(p=0.003)。
3、不同种植方法异位种植发生数:瘤细胞悬液植入组1(3),肿瘤组织块悬液种植组1(5),肿瘤组织块直接种植组0(8),经统计学分析,无显著性差异(p=0.238)。
结论:1、经皮穿刺肿瘤组织块直接种植法制作兔肝癌模型,成功率尤其孤立瘤灶发生率高,方法简单、易行,模型性质稳定,并发症及异位种植低,在肝癌的基础及临床研究中将得到越来越广泛的应用。
2、兔VX2肝癌模型制备简单,是一种理想的肝癌研究动物模型。
第二章:MR弥散加权成像在肝癌诊断的应用价值
目的:研究兔肝癌不同时间在MR T1WI、T2WI及DWI的表现及ADC值的变化规律,从而探讨MR弥散加权成像在肝癌诊断中的作用。
材料和方法:
1.1动物分组及模型制作
1、新西兰大白兔30只,体重2.5～3.0kg,雌雄不限,由广东省实验动物中心提供。分别在肿瘤种植后4天、1周、2周、3周对30只动物肝VX2瘤灶行MR扫描。
2、采用“第一章:兔VX2肝癌模型的制作及改进”中“肿瘤组织块直接种植法”种植肿瘤。
1.2 MR检查
种植后4天、1周、2周、3周对兔肝VX2瘤灶行MR扫描,分别进行T1WI、T2WI、T2WI脂肪抑制序列和MR DWI成像。用Sense-Flex-M环形表面线圈。T2W_TSE_SENSE与T2W_TSE_SPIR序列扫描参数:TR 3544ms,TE 81ms,FOV150mm,层厚3mm,层间距-1mm,矩阵256×256,重建矩阵512×512,扫描时间1分14秒,NSA为2次。T1W_TSE SENSE序列扫描参数:TR407ms,TE 17ms,FOV 150mm,层厚3mm,层间距-1mm,矩阵256×256,重建矩阵512×512,扫描时间1分34秒,NSA为2次,EL=3。DWI采用单次激发平面回波成像(echo plannar imaging,EPI)序列,弥散因子b值取0 s/mm~2和300s/mm~2,TR 6000ms,TE 49ms,FOV 150mm,层厚3mm,层间距0mm,矩阵112×112,重建矩阵256×256,翻转角90°,扫描时间2分36秒,NSA为6次。
1.3观察指标及统计学处理
1、各种检查方法不同时间肿瘤检出率
分别观察不同时间兔肝癌在MR T1WI、T2WI、T2WI脂肪抑制序列和MRDWI检出率。统计学处理采用SPSS13.0软件,种植后第四天各序列的种瘤检出情况比较,采用多个相关样本的非参数检验中的Cochran's Q检验方法进行分析。各序列种植后四天和一周的检出率比较采用配对χ~2检验直接计算,p＜0.05有统计学意义。
2、不同时间ADC值的计算
在肿瘤种植后4天、1周、2周、3周ADC图上分别在中心区、边缘区随机选取感兴趣区,计算ADC值。用SPSS13.0的单个重复测量因素的方差分析(General Linear Model,repeated Measures)进行统计学分析,检验水准:α=0.05。
结果:
2.1不同MR序列的检出率
2.1 1种植成功率:30个实验动物,肿瘤种植成功25例,成功率81.25%。
2.1.2不同序列对兔肝VX2肿瘤的检出率
种植后第四天各种检查方法即可显示肿瘤灶,在T1W上表现为边缘不清的等或低信号灶,在T2WI和T2WI SPIR和DWI序列上表现为高信号,边界欠清晰。一周后肿瘤在各序列中显示清楚,边界清晰,在肿瘤灶中心出现在T2WI、DWI低信号的液化坏死区。在种植后第四天,DWI、T1W、T2WI、T2WI SPIR检出率分别为80%、60%、72%和72%。经统计学分析Cochran's Q=10.2,p=0.017,差异有统计学意义。种植后第一周各检查系列均检查出病变25例。种植后4天和一周的检出率比较:DWI组无显著性差异(χ~2=3.24,p＞0.05);而T1w、T2WI和T2WI SPIR组有统计学差异(p＜0.05)。
2.2肿瘤种植后不同时间ADC值的变化
周边区在种植后第4天、1周、2周、3周ADC值分别为1862.58±150.97、1636.70±5152.96、1273.43±173.59及1005.68±192.00,差异有显著性(F=153.997、p=0.000)。而中心区第4天、1周、2周、3周ADC值分别为1498.81±264.41、1078.92±153.58、662.751±174.27、1553.19±179.01(F=149.442、p=0.000)。随着时间的增加ADC值降低,但在第三周ADC值升高,甚至超过了第四天,表明病灶中央出现了坏死灶。
结论:
1、DWI是检查肝癌比较敏感技术,可较早期检出小肝癌,在肝脏肿瘤的诊断中将得到越来越广泛的应用。
2、MR弥散加权成像不但对肿瘤的定性诊断有很大帮助,通过ADC值,可大致判断肿瘤的坏死情况和发展趋势。
第三章:肝癌化疗栓塞前后MR弥散和灌注成像研究。
目的:通过MR DWI、PWI成像观察肝癌栓塞前、后肿瘤坏死及血流灌注情况的变化规律,并与病理和微血管密度对比,判断MR DWI、PWI成像在观察肝癌栓塞后坏死及血流灌注的临床应用价值。
材料和方法:
1.1实验动物分组及模型制备肝癌模型新西兰大白兔30只,体重2.5～3.0kg,雌雄不限,由广东省实验动物中心提供。实验动物随机分为3组,分别为TACE术前、术后三天、术后一周组,每组10只动物。采用“第一章:兔VX2肝癌模型的制作及改进”中,“肿瘤组织块直接种植法”制作肿瘤模型。
1.2兔肝癌的化疗栓塞
肿瘤种植3周,常规MR扫描发现病灶,进行肝动脉化疗栓塞。兔用速眠新全麻,取仰卧位固定于兔手术板上。常规消毒、铺巾。用手术刀切开腹股沟下皮肤,用止血钳分离出股动脉,用带有塑料套的穿刺针刺入到股动脉内。拔出针芯,见有血液喷出,送入黑泥鳅导丝,撤出塑料套,通过导丝引入4F超滑导管进入腹主动脉达腹腔动脉干开口处。用手推注造影剂造影,观察肿瘤血管和肿瘤染色。撤出导丝,引入3F微导管入腹腔干,越过胃动脉,将导管超选入肿瘤供血动脉,注射碘油、MMC(1mg)及表阿霉素(1mg)混合物1-3ml,至碘油沉积良好、肿瘤血管消失、动脉内碘油滞留停止。拨管,右侧股动脉结扎。局部皮肤缝合、消毒、包扎。
1.3 MR弥散和灌注加权成像
1.3.1扫描条件
各组在TACE术前、术后三天、术后一周分别进行MR弥散和灌注成像。应用Sense-Flex-M环形表面线圈。
DWI扫描条件:见第二章。
PWI成像:采用TFE序列,灌注成像参数:矩阵89×256,TR 4.3 ms,TE1.4 ms,激励次数1,视野355 mm×75 mm,层厚5mm,间距1mm,NSA为1次。扫描层面数4层,每层反复激励65次,总扫描时间为1分20秒。高压注射器经通过家兔耳缘静脉注射对比剂钆特酸葡胺注射液(多它灵,377mg/ml),剂量为0.2mmol/kg,注射流速为2ml/s。生理盐水3ml以同样速度注射冲管,团注开始即进行扫描。
1.3.2 MR灌注图像后处理
将原始图像输入到PHILIPS后处理工作站(VIEWFORUM),自动生成MR灌注图。分别在肿瘤中心区、边缘区设置感兴趣区,分别分析时间—信号强度曲线(time signal-intensity curve,TIC)及肿瘤中心区、边缘区最大增强斜率(maximum slop of increase,MSI)的变化规律。
1.4病理观察
3组动物MR弥散和灌注成像之后,用过量硫喷妥钠处死。根据MR图像引导切取肿块所在部位肝脏,进行大体病理观察,HE染色并进行免疫组化,计算其中心区、边缘区MVD值。
1.5观察指标及统计学处理
肿瘤中心区、边缘区在TACE前、后4天、后一周的ADC值、SMI值及MVD值。用SPSS13.0进行统计分析,采用计量资料的单因素的方差分析(One-Way ANOVA)。检查水准:a=0.05。MVD与ADC值相关分析、MVD与MSI值相关分析采用双变量相关分析(Bivariate)。
结果:
2.1化疗栓塞前后DWI结果
1、化疗栓塞前后DWI成像改变及与病理对照
化疗栓塞前MR成像在肝左叶可见T1低信号、T2高信号、DWI高信号的肿瘤。大体病理示肿瘤为白色,剖面呈鱼肉状,光镜下细胞体积大,胞浆丰富,淡红染色,核肥大,核分裂像多见,可见少量坏死,周边区和中央区未见明显区别。
栓塞后3d在DWI上出现斑片状低信号区,为凝固性坏死的表现。大体病理示肿瘤为白色,肿瘤中心可见豆腐渣样坏死组织,光镜下出现大量核碎裂、核溶解,肿瘤坏死较多。
栓塞后1w,病灶进一步进展,病灶中心在T2、DWI上出现了大面积低信号的坏死区。大体病理肿瘤中心坏死组织增多,光镜下肿瘤坏死增多。
2、化疗栓塞前后ADC值的改变
边缘区ADC值在栓塞前、栓塞后3d、栓塞后1w分别为1089.31±107.24、1865.38±157.28、1860.97±194.46,有显著性差异(F=80.875,p=0.000)。中心区ADC值在栓塞前、栓塞后3d、栓塞后1w分别为1595.92±197.51、1633.38±193.82、1848.14±183.01,有显著性差异(F=5.049,p=0.014)。
2.2 MR灌注结果
1、MR灌注图改变
栓塞前HBV图、HBF图清楚显出肿瘤灶,并可见病灶中央高灌注区。病灶中心区强化曲线,表现为速升速降;边缘区强化曲线强化峰值比病灶中心区高。
栓塞后3天强化曲线缓慢升高,缓慢下降。栓塞后1W表现与栓塞后3天相似,中心区伪彩进一步下降,甚至消失。边缘区强化曲线缓慢升高,缓慢下降。
2、栓塞前后不同时间MSI变化
边缘区在栓塞前、栓塞后3d、栓塞后1w的MSI值分别为7.35±1.20、8.70±0.96、2.85±0.96,有统计学差异(F=85.986,p=0.000)。术后第三天到一周组间变化较大。中心区在栓塞前、栓塞后3d、栓塞后1w的MSI值分别为2.41±0.59、1.50±0.38、1.33±0.46,统计学分析有显著性差异(F=14.414,p=0.000)。
2.3病理学观察
2.3.1光镜下病理表现
肿瘤组织在低倍镜下可见肝内浸润性癌巢,与肝实质无明显边界。肿瘤细胞分散排列,可见纤维间隔,新生毛细血管丰富。高倍镜下可见瘤细胞体积大,胞浆丰富,淡红染色,核肥大,核分裂像多见。化疗栓塞后瘤细胞团内可见大片坏死区及多个片状或灶性坏死,大部分瘤细胞核固缩及核碎裂。
2.3.2免疫组化病理
1、免疫组化表现
肿瘤血管被染成棕色、褐色,化疗栓塞前后肿瘤中心区、边缘区随着时间进展肿瘤血管减少。
2、化疗栓塞前后MVD改变
边缘区MVD值在栓塞前、栓塞后3d、栓塞后1w分别为51.14±19.71、26.88±12.76、11.07±6.52,经统计学分析:F=20.582,p=0.000,有显著性差异。中心区MVD值在栓塞前、栓塞后3d、栓塞后1w分别为13.49±5.17、8.52±3.64、8.32±5.11,有显著性差异(F=3.899,p=0.033)。
2.4 DWI、PWI与微血管密度相关性
MVD与ADC值间存在负相关(r=-0.534,p=0.000);MVD与MSI值间存在正相关(r=0.694,p=0.000)。
结论:
1、栓塞前病灶中心区和边缘区强化曲线,表现为速升速降,边缘区强化峰值比病灶中心区高。栓塞后强化曲线缓慢升高,缓慢下降,随着时间发展,上升幅度降低。
2、肿瘤中心区、边缘区MVD值在栓塞前、栓塞后3d、栓塞后1w的比较,均有统计学差异,化疗栓塞后肿瘤的微血管明显减少。
3、肿瘤中心区、边缘区MSI值在栓塞前、栓塞后3d、栓塞后1w的比较中有统计学差异,随着时间发展MSI降低。MVD与MSI值呈正相关,MVD的减少使单位时间、单位组织内肝血流量增加,是MSI降低的病理基础。
4、MRI灌注成像能在活体判断肝癌的血管生成程度及血供情况,MR灌注值改变可揭示肿瘤新生血管的血流动力学变化,为研究肝癌的血流动力学改变提供了一种新的方法,对判断栓塞后肝癌的灌注水平变化及疗效评估也很有价值。
5、中心区和边缘区ADC值在栓塞前、栓塞后3d、栓塞后1w有显著性差异,说明TACE治疗3天后组织弥散增加。MVD与ADC呈负相关。ADC值作为可靠的动态监测治疗前后肿瘤坏死情况的方法,可较好地反应TACE后肿瘤的转归。
Background
Transcatheter arterial chemoembolization(TACE) is considered to be an effective treatment for hepatocellular carcinoma.However,angiogenesis,the process leading to the formation of new blood vessels from preexisting vessels,plays a central role in the survival of tumor cells,in local tumor growth,and in the development of distant metastasis and reduces therapeutic effectiveness.Early detection of residual tumor and vascularity after interventional treatments is critical before TACE and during follow up.
Generally,computed tomographic(CT) images could be considered as a routine modality to judge the efficacy of TACE.The pattern and distribution of iodized oil in the tumor are useful for assessing the therapeutic effects of TACE.A greater amount of accumulation of iodized oil within tumor indicates a greater area of necrosis.During follow-up,the focal defect or washout of iodized oil in the mass with the contrast-enhanced area suggests the presence of a viable tumor and that additional treatment is needed.The contrast-enhanced CT is a reliable method for the assessment of therapeutic efficacy.On contrast-enhanced CT,necrotic tissues were unenhanced and viable tumors were enhanced.But it was difficult to judge the viability and necrosis of the tumors correctly due to the inhomogeneous deposition,because lipiodol negative areas could not actually represent the viability of the tumors.It can also be difficult to evaluate contrast enhancement in a tumor with partial retention of iodized oil on contrast-enhanced CT because of the beam-hardening artifacts produced by the high attenuation of iodized oil.
MR imaging was valuable in the evaluation of therapeutic efficiency of TACE, especially on T_2WI,most of viable tumors were hyperintense and the coagulative necrosis within the tumors considered as a positive response to TACE was hypointense. But a signal intensity of the tumors after TACE was variable on SE T_1WI and T_2WI,all of viable tumors,hemorrhage,liquefied necrosis and inflammatory infiltration could also result in hyperintensity on the T_2WI.Therefore,it was difficult to assess the viable tumors of HCC after TACE by conventional SE imaging.Dynamic contrast scanning also has a great value in the evaluation of therapeutic efficacy of TACE.The residual viable tumors were shown as rapidly enhanced portions within the lesions,when necrotic portions had no enhancement at the contrast early phase scanning.At the late phase scanning,the enhancement of the most lesions became hypointense,and just a few lesions showed a persistent enhancement.Both viable tumors and inflammatory infiltration could present such changes,so the contrast early phase scanning was not more reliable in the evaluation of viable tumors.
Existing diagnostic imaging techniques provide limited evaluation of tissue characteristics beyond morphology.Perfusion imaging ultimately may have a role in the earlier identification of tumor recurrence if subtle differences in enhancement of benign versus malignant tissue can be captured earlier.CT perfusion imaging has the potential to provide both high-temporal-resolution and high-spatial-resolution imaging of the entire liver for the detection of HCC,however,the radiation doses must be considered.A whole-liver CT perfusion study would result in radiation doses that are approximately three to six times greater than those of a routine diagnostic CT examination.Perfusion MR imaging represents a promising technique for HCC surveillance.T1 weighted perfusion MRI has been used to assess tumor angiogenesis of uterine cervical carcinoma, and has a good correlation with microvessel density(MVD).
Diffusion-weighted imaging can provide an insight about water composition within a tumor and the degree of tumor viability.The apparent diffusion coefficients of malignant masses were significantly lower than those of benign masses.A study of an animal model of hepatocellular carcinoma showed that:diffusion-weighted imaging clearly distinguished the regions of tumor necrosis from viable tumor.So,DWI may offer significant utility in the longitudinal assessment of novel liver tumor treatments.
The purpose of this study was to observe angiogenesis and necrosis of HCC before and after TACE by MR perfusion Imaging and diffusion imaging,compared with microvessel density and histological evaluation,and to find out their feasibility and value in assessing therapeutic effectiveness of HCC during follow up.
Chapter One:The establishment and improvement of VX2 Carcinoma model
Objective To establish suitable metastatic rabbit vx2 hepatic carcinoma model,to compare the success rate of different tumor implantation methods.
Methods Thirty New Zealand white rabbits were randomly divided into three groups,10 rabbits in each group.Group 1:Solution of the VX2 carcinoma cells were injected into left liver by syringe needle.Group 2:Solution of the tumor tissue masses was transplanted into liver.Group 3(improvement group):VX2 carcinoma masses were injected into the liver using percutaneous puncture inoculation method.The operation was guided by CT scanner in each group.CT scanning was performed in all experimental animals 2 week after implantation.
Results The success rates of transplanted carcinoma were 30%,50%and 90%in group 1,group2 and group3 respectively,and the statistical difference was found.The respective ectopic implantation incidence at group 1,group2 and group3 were 1(3),1(5) and 0(8),no statistical difference was observed.The success rates of single nodule implanted tumor were the highest in group 3(80%) than in group 1(10%) and group 2 (20%).The difference was statistically different(p=0.003).
Conclusion It is successful to improve the rabbit modes bearing VX2 metastatic hepatic carcinoma.And the method of percutaneous puncture carcinoma masses implanation guided by CT was a good method to establish the hepatic carcinoma models with a high success rates,especial rates of single nodule implanted tumor,low ectopic implantation rates and little damage of animals.
Chapter Two:Observation of the value of MR Diffusion Weight Imaging in diagnosis of hepatocellular carcinoma
Objective To investigate the value of MR DWI in diagnosing hepatic carcinoma by studying the appearances of rabbit vx2 hepatic carcinoma in MR T1 WI,T2WI and DWI series at different times after the tumors were transplanted.
Methods The metastatic rabbit vx2 hepatic carcinoma models were presented in 30 New Zealand white rabbits.VX2 carcinoma masses were injected into the liver using percutaneous puncture inoculation method in guiding by CT scanner in each group.MR T1WI,T2WI,T2WI SiP and DWI were performed in all experimental animals at 4day,1, 2 and 3 weeks after implantation with a Sense-Flex-M.T2W_TSE_SENSE and T2W TSE_SPIR parameters:TR 3544ms,TE 81ms,FOV 150mm,slice thickness 4mm, intersection gap of-1 mm,matrix 256×256,restruction matrix 512×512,scan time 74s, NSA 2.The MR image parameters with T1WI SENSE were as follows:TR 407ms,TE 17ms,FOV 150mm,slice thickness 3mm,intersection gap of- 1 mm,matrix 256×256,restruction matrix 512×512,scan time 94s,NSA 2,EL=3.
Diffusion-weighted images of the liver were acquired using an SE-EPI sequence with the following imaging parameters:b-values of 0,300/mm~2,TR 6000ms,TE 49ms, FOV 150mm,slice thickness 3mm,intersection gap of 0mm,matrix 112×112,restruction matrix 256×256,flip angle 90°,scan time 156s,NSA 6.The diagnosis rates of different methods in different time were observed.The ADC values in cores and peri-areas were analyzed.
Results Of 30 rabbits,25 were transplanted vx2 hepatic carcinoma.The success rate of carcinoma transplanted was 81.25%.The tumor lesion could be found in every examination series at 4 days after the implantation.The diagnosis rates of DWI,T1WI, T2WI and T2WI SPIR were 80%,60%,72%and 72%respectively.Statistical difference was found(p=0.007).The diagnosis rates were 100%in all MR series at 1,2 and 3 week after implantation.In comparison of diagnosis rates between 4days and 1 to 3 week after the tumor implantation in different series,no significant difference was only observed on DWI series(p＞0.05) and significant difference on other series(p＜0.05).
The ADC values of peri-areas were 1862.58±150.97,1636.70±152.96, 1273.43±173.59,1005.68±192.00 respectively,at 4day,1,2 and 3 weeks after implantation.The significant difference was observed(F= 153.997,p=0.000).The values decreased with the times developing from 4 days to 3 weeks after the implantation.The ADC values of cores were 1498.81±264.41,1078.92±153.58,662.751±174.27, 1553.19±179.01 respectively at 4day,1,2 and 3 weeks.There were statistical difference in each group ADC values(F=149.442,p=0.000),which decreased with the times developing before 2 weeks,but increased at 3 weeks.
Conclusion MR DWI is a sensitive series in examination of liver tumor,,and will be used in diagnosis of liver tumor more and more.The values of ADC may help discriminate between the necrosis areas and normal areas,will play a important role in surgical operation and puncture biopsy.
Chapter Three:MR diffusion and perfusion imaging of the liver before and after transcatheter hapatic chemoembolization for hepatocellular carcinoma
Objective To observe angiogenesis and necrosis of HCC before and after TACE by MR perfusion imaging and diffusion imaging,compared with microvessei density and histological evaluation,and to find out their feasibility and value in assessing therapeutic effectiveness of HCC during follow up.
Methods
1.Animals and tumor models
30 New Zealand white rabbits(weight:2.5-3.0kg) with VX2 liver tumors were randomly divided into three groups,10 rabbits in each group(group 1,pre-TACE;group2, 3 day post- TACE;group 3,1 week post- TACE).The MR scan was performed before chemoembolization,at 3 day and 1 week after chemoembolization,respectively at group 1,2 and 3.The technique for tumor implantation was basically similar to that described in Group 3 of Chapter One.All three groups received interventional therapy after three weeks of the VX2 tumor was implanted.The laboratory animal center of Guangdong province provided all animals.
2.Chemoembolization
Each rabbit was successfully catheterized with DSA.Conventional DSA was performed by using a C-arm unit guidance.Rabbits were initially anesthetized by using sumianxin(0.1-.02mg/kg).Vascular access was achieved in the femoral artery through transfixion using a transfixion pin with plastic sleeve.A 4-F catheter was advanced over a guidewire into the celiac trunk.DSA of arteries was performed by using 2-3 ml manual injections of contrast agent.The 3-F catheter was advanced into the left hepatic artery.1-3 ml lipiodol emulsion(lipiodol mixed with 1mg MMC and 1mg pharmorubicin) were superselectively delivered into tumor vessel by manual injection.Follow-up angiography was performed and confirmed the complete stasis of antegrade blood flow to the liver tumors.After chemoembolization,the catheter was removed and the femoral artery was ligated.Then skin closure was finished.
3.MR imaging
MR perfusion and diffusion imaging examination were performed in the supine position by using a clinical Sense-Flex-M coil.The scans were done before chemoembolization,at 3 day and 1 week after chemoembolization,at group 1,2 and 3 respectively.MR diffusion imaging parameters has been described in Chapter Two. The MR perfusion imaging protocol consisted of T1-weighted fast field echo(FFE) sequences with a field of view of 355 mm×75 ram,matrix 89×256,TR/TE of 4.3/1.4 milliseconds,slice thickness of 5 mm,intersection gap of 1 mm,NSA of 1.This sequence was repeated 65 times,in4 slice(in total,80 seconds),a dose of 0.2 mmool/kg of Gadoteric Acid contrast medium was injected after the start of the scan.Injection of Gadodiamide was performed through a 22-gauge needle via ear vein at a flow rate of 2 ml/sec followed by injection of 3ml bolus of saline(NaCl 0.9%).
4.Histological evaluation
Each animal was then sacrificed with overdose penthiobarbital sodium intravenous injection for pathology observation after MR examination.The livers were removed and fixed in 10%acetic formalin.A slice was cut at the same level as the slice imaged in MR and the general pathology was observed.Each VX2 tumor was divided into the periphery area and center area.The specimens of both areas were embedded in paraffin,and thinner sections of 3mm were cut and stained with hematoxylin-eosin-safran.These slices were examined with an optical microscope at 20 magnifications.Immumohistochemical staining was performed using the SP method.The specimens were observed under a low power microscope(×40),then the sections with most dense area of microvessels were selected and observed under a high power(×400).Microvessels were evaluated under a microscope,microvessel density in the center and rim of the lesion were calculated.
5.Statistical analysis
The values of ADC,MSI and MVD in the center and rim of the lesion were calculated.All data were expressed as mean±SD,the statistical differences between different groups were analyzed by ANOVA,and the correlation between MSI and MVD, ADC and MVD was assessed by Spearman correlation analysis.Significance was accepted when p＜0.05.
Results
1.Lesion signal intensity characteristics in DWI images before and after TACE
The lesions assessed before TACE were hypo- intense relative to the surrounding liver parenchyma on T1-weighted images,and the most portion of tumors was hyperintense relative to the surrounding liver parenchyma on T2-weighted images and DWI images,and the heterogeneous signal intensity was observed when liquefied necrosis or fat degeneration occurred.At 3d after TACE,on DWI images,the heterogeneous hypo-intense was observed,which was coagulative necrosis confirmed by morphological observation.At 1w after TACE,the heterogeneous hypo-intense areas became larger.The coagulative necrosis progressed with the development of times.
2.Changes of ADC values
The ADC values of peri-areas were 1089.31±107.24,1865.38±157.28 and 1860.97±194.46 respectively,at pre-TACE group,3 days post-TACE group and 1week post-TACE group.The significant difference was observed(F=80.875,p=0.000).The ADC values of cores in each group were 1595.92±197.51,1633.38±193.82, 1848.14±183.01 respectively.Significant difference was found between pre-TACE and after TACE(F=5.049,p = 0.014)
3.Characteristics on PWI images before and after TACE
All tumors lesions were depicted on HBF,HBV images.Time intensity curves derived from ROIs drawn in the peri-areas and cores of the tumor showed a rapid initial increase in signal intensity,representing hypervascularity before and after TACE.The peak values in peri-areas were higher than cores.The intensity curves in post-TACE groups showed less steep than pre-TACE group.
4.Changes of MSI values
The MSI values of peri-areas were 7.35±1.20,8.70±0.96and 2.85±0.96 respectively at pre-TACE group,3 days post-TACE group and lweek post-TACE group.The significant difference was observed(F=85.986,p= 0.000).The MSI values of cores in each group were 2.41±0.59,1.50±0.38 and 1.33±0.46 respectively.Significant difference was found between pre-TACE and after TACE(F= 14.414,p= 0.000)
5.Results of morphological observation
Under low magnification,HCC was seen as invasive carcinoma in the liver,there was no clear margin between neoplasm and the hepatic parenchyma,neoplastic cells distributed straggly,there was separating fibre with abundant capillary of newly developed;under high magnification,the volume of neoplasm was large with irregular morphology,cells distributed irregularly with abundant cytoplasm.Nucleus was hypertrophic with different size and shape,staining was non-uniform,phase of nucleous mitosis showed in many cells,a great number of lymphocytes and plasma cells could be seen infiltrating in the mesenchyma.After TACE lesions underwent un-complete necrosis,karyopycnosis and nuclear fragmentation was seen at the center of the lesions.
6.Results of immunohistochemistry
CD34 was expressed in HCC and various degree of yellow stain could be seen in the epithelial cells of hepatic sinusoid in the HCC section.But MVD of HCC tissues were lower significantly after TACE than before TACE.The MVD values of peri-areas were 51.14±19.71,26.88±12.76 and 11.07±6.52 respectively at pre-TACE group,3 days post-TACE group and lweek post- TACE group.The significant difference was observed(F=20.582,p=0.000).The MVD values of cores in every group were 13.49±5.17,8.52±3.64,8.32±5.11 respectively.Significant difference was found between pre-TACE and after TACE(F=3.899,p=0.033)
7.Correlate analysis
The values were analyzed by Pearson's correlation coefficient.The results showed that there was negative correlation between ADC and MVD(r=-0.534,p=0.000),positive correlation between MSI and MVD(r=0.694,p=0.000).
Conclusion
1.Time intensity curves derived from ROIs drawn in the peri-areas and cores of the tumor showed a rapid initial increase in signal intensity.The peak values in peri-areas were higher than cores.The intensity curves in post-TACE groups showed less steep than pre-TACE group.
2.Significant difference in MVD values of peri-areas and cores was found at pre-TACE group,3 days post-TACE group and 1 week post-TACE.That indicated capillary vessels decrease obviously after TACE.
3.MVD values of peri-areas and cores decreased along the times of TACE developing. The statistical significant was found.There was a positive correlation between MSI and MVD.The hepatic blood flow decreased along with the MVD,which was the pathological basis of MSI values decreasing.
4.MR perfusion imaging has a potential to evaluate the angiogenesis of liver tumors in vivo,and could demonstrate the haemodynamics variation of new vessels.It provides a new,valuable technology for hemodynamics study of HCC and evaluation of perfusion level and therapeutic effect after TACE.
5.Significant difference of ADC values in peri-areas and cores was found between pre-TACE and after TACE,which demonstrated that the diffusion of tumor tissues increased after TACE.There was negative correlation between MVD and ADC values. Values of ADC could reflect the changes of tumor after TACE,was a reliable index to monitor the tumor necrosis.
化疗栓塞病灶周边部的再血管化、存活癌细胞是肝癌TACE术后复发转移的主要病理基础。很长时期以来,CT扫描主要依靠肿瘤内部和周边的碘化油沉积情况来评价TACE的治疗效果。CT平扫可在某种程度上反映栓塞是否完全及栓塞后的瘤体变化,而CT双期增强扫描可反映存活瘤组织及新发病灶的血液供应情况。然而,碘化油与周围组织间较大的密度差所形成的放射状伪影与碘化油的高密度影响对栓塞病灶周边残余肿瘤的观察。
MR自旋回波序列(SE)T1WI、T2WI与动态增强扫描的应用,对HCC的TACE术后随访价值较大,特别是SE序列T2WI,多数存活肿瘤在T2WI上为高信号,而TACE术后肿瘤内部的凝固性坏死为低信号。肝癌TACE术后在T1WI和T2WI上的信号多种多样,特别是T2W上,存活肿瘤、出血、液化坏死和炎性细胞的浸润均可表现为高信号,因此T2WI对判断肿瘤的存活有一定困难,而对凝固性坏死的判断十分可靠。介入治疗后残存肿瘤的强化较肝实质早而持续时间短,动态增强MRI早期呈结节状、片状强化,可以鉴别瘤内坏死、纤维组织与肿瘤中央的残存肿瘤,但难以鉴别包膜与包膜内残存肿瘤结节。如果为乏血供的HCC,就难以使用这种技术发现存活肿瘤。部分肿瘤患者进行了经皮肝穿酒精注射联合TACE治疗,肿瘤由低信号变成高信号,即便用动态扫描也很难区分肿瘤增强,从而无法判断存活肿瘤。
原发性肝癌介入治疗术后的评价主要集中在CT和MR双期增强上,CT灌注成像定量分析组织灌注是评价肝癌动脉栓塞治疗后血流动力学变化的有效方法。但它的缺点也很突出,主要是需用大量的碘对比剂及具有潜在的过敏反应、中毒性肾损害等危险,同时病人也会受到较大剂量的辐射。
MRI灌注图在检测TACE术后残存肿瘤组织的灌注方面很有价值。TACE的疗效可以通过比较术前术后的灌注差异而评估。
DWI能够区分肿瘤中的坏死成分和存活成分,ADC值的改变早于T2WI上信号的改变,甚至早于组织学上的变化。因此,利用DWI对肿瘤组织不同时间平均ADC值的测量、对比,可以量化评价肝癌组织TACE术后的坏死、复发情况。
本研究利用兔VX2肝癌模型,通过MR DWI、PWI成像观察肝癌栓塞前后坏死及血流灌注情况的变化规律,判断MR DWI、PWI成像在观察肝癌栓塞后坏死及血流灌注的临床应用价值,从而为肝癌介入治疗的最佳方法的选择及疗效观察提供了更有价值的影像诊断依据。
第一章:兔VX2肝癌模型的制作及改进
目的:将穿刺器械进行改良,采用肿瘤组织块直接穿刺种植肿瘤,并与肿瘤细胞悬液植入法、肿瘤组织块悬液种植法对比,观察种植成功率及肿瘤异位种植的情况,筛选更为简便、有效的肿瘤模型的制作方法。
材料和方法:
1.1兔VX2肝癌模型制作
1.1.1实验动物新西兰大白兔30只,体重2.5～3.0kg,雌雄不限,由中山医科大学实验动物中心提供。随机分为3组,分别为肿瘤细胞悬液植入法组、肿瘤组织块悬液种植组、肿瘤组织块直接穿刺种植组(改进组),每组实验动物10只。
1.1.2 VX2细胞株制备
将瘤株接种于兔腹股沟区皮下或肌肉间,使之成瘤,三周后接种处可扪及一实质性包块。速眠新全麻后,无菌条件下剥离肿瘤,切取包块边缘生长旺盛的鱼肉样组织,置于盛有生理盐水的平皿中。1)配成2×10~6个细胞/ml浓度的VX2细胞悬液,用于第1组肿瘤的种植。2)取肿瘤组织用眼科剪将其剪成大小约1mm~3组织块。用于第2组肿瘤的种植。3)用眼科剪将肿瘤组织剪成约1mm×1mm×3mm大小瘤块用于第3组肿瘤的种植。
1.1.3兔肝VX2肿瘤种植穿刺针的改进:使用18G腰穿针。取出穿刺针芯,用油石打磨去掉尖端,以细沙纸抛光以去除毛刺,使顶端平整光滑,即成为推针,与常规尖头针芯及套管配合使用,成为改良的穿刺用具。
1.1.4兔肝VX2肿瘤的种植。
动物术前禁食12h,用速眠新全麻,仰卧位,固定四肢于兔手术板上,常规剑突左侧腹部剪毛。CT扫描兔肝脏,确定肝左叶待接种部位,选定穿刺点、角度、深度。常规消毒铺巾,刀尖挑开穿刺点皮肤,用带尖头穿刺针芯的18G穿刺针穿入肝脏预定位置,拨出针芯,用注射器抽吸无回血。第1组动物注入VX2细胞悬液1ml,第2组注入肿瘤组织块悬液1ml,两组在退针时注入少量明胶海绵颗粒。
第3组由助手固定好穿刺针,术者用眼科镊夹1块瘤块放入针鞘内,平头穿刺针芯将瘤块推入肝内,同理再分别放入2块组织块。如未成功,可再重复上述操作。将一小块明胶海绵用平头穿刺针芯推入肝内封堵针道。局部按压3分钟,并用创可帖封伤口。
1.2 CT扫描
种植后2周对新西兰白兔肝VX2瘤灶行CT扫描,四周再扫描一次,观察2周扫描是否有漏检病例。扫描条件:120kV,180mA,层厚3mm,间距3mm:延迟8～12s,30～40s行双期增强扫描。
1.3观察指标及统计学处理
分别观察不同种植方法的成功率,孤立病灶的成功率,异位种植情况。统计学处理采用SPSS13.0软件精确概率法进行统计分析,p＜0.05有统计学意义。
结果:
1、各组间种植成功率:瘤细胞悬液植入组30%,肿瘤组织块悬液种植组50%,肿瘤组织块直接种植组90%,经统计学分析p=0.036,可以认为不同种植方法成功率不同。
2、不同种植方法孤立肿瘤种植的成功率:肿瘤组织块直接种植组最高(80%),依次为肿瘤组织块悬液种植组(20%)和瘤细胞悬液植入组(10%)。统计学分析有显著性差异(p=0.003)。
3、不同种植方法异位种植发生数:瘤细胞悬液植入组1(3),肿瘤组织块悬液种植组1(5),肿瘤组织块直接种植组0(8),经统计学分析,无显著性差异(p=0.238)。
结论:1、经皮穿刺肿瘤组织块直接种植法制作兔肝癌模型,成功率尤其孤立瘤灶发生率高,方法简单、易行,模型性质稳定,并发症及异位种植低,在肝癌的基础及临床研究中将得到越来越广泛的应用。
2、兔VX2肝癌模型制备简单,是一种理想的肝癌研究动物模型。
第二章:MR弥散加权成像在肝癌诊断的应用价值
目的:研究兔肝癌不同时间在MR T1WI、T2WI及DWI的表现及ADC值的变化规律,从而探讨MR弥散加权成像在肝癌诊断中的作用。
材料和方法:
1.1动物分组及模型制作
1、新西兰大白兔30只,体重2.5～3.0kg,雌雄不限,由广东省实验动物中心提供。分别在肿瘤种植后4天、1周、2周、3周对30只动物肝VX2瘤灶行MR扫描。
2、采用“第一章:兔VX2肝癌模型的制作及改进”中“肿瘤组织块直接种植法”种植肿瘤。
1.2 MR检查
种植后4天、1周、2周、3周对兔肝VX2瘤灶行MR扫描,分别进行T1WI、T2WI、T2WI脂肪抑制序列和MR DWI成像。用Sense-Flex-M环形表面线圈。T2W_TSE_SENSE与T2W_TSE_SPIR序列扫描参数:TR 3544ms,TE 81ms,FOV150mm,层厚3mm,层间距-1mm,矩阵256×256,重建矩阵512×512,扫描时间1分14秒,NSA为2次。T1W_TSE SENSE序列扫描参数:TR407ms,TE 17ms,FOV 150mm,层厚3mm,层间距-1mm,矩阵256×256,重建矩阵512×512,扫描时间1分34秒,NSA为2次,EL=3。DWI采用单次激发平面回波成像(echo plannar imaging,EPI)序列,弥散因子b值取0 s/mm~2和300s/mm~2,TR 6000ms,TE 49ms,FOV 150mm,层厚3mm,层间距0mm,矩阵112×112,重建矩阵256×256,翻转角90°,扫描时间2分36秒,NSA为6次。
1.3观察指标及统计学处理
1、各种检查方法不同时间肿瘤检出率
分别观察不同时间兔肝癌在MR T1WI、T2WI、T2WI脂肪抑制序列和MRDWI检出率。统计学处理采用SPSS13.0软件,种植后第四天各序列的种瘤检出情况比较,采用多个相关样本的非参数检验中的Cochran's Q检验方法进行分析。各序列种植后四天和一周的检出率比较采用配对χ~2检验直接计算,p＜0.05有统计学意义。
2、不同时间ADC值的计算
在肿瘤种植后4天、1周、2周、3周ADC图上分别在中心区、边缘区随机选取感兴趣区,计算ADC值。用SPSS13.0的单个重复测量因素的方差分析(General Linear Model,repeated Measures)进行统计学分析,检验水准:α=0.05。
结果:
2.1不同MR序列的检出率
2.1 1种植成功率:30个实验动物,肿瘤种植成功25例,成功率81.25%。
2.1.2不同序列对兔肝VX2肿瘤的检出率
种植后第四天各种检查方法即可显示肿瘤灶,在T1W上表现为边缘不清的等或低信号灶,在T2WI和T2WI SPIR和DWI序列上表现为高信号,边界欠清晰。一周后肿瘤在各序列中显示清楚,边界清晰,在肿瘤灶中心出现在T2WI、DWI低信号的液化坏死区。在种植后第四天,DWI、T1W、T2WI、T2WI SPIR检出率分别为80%、60%、72%和72%。经统计学分析Cochran's Q=10.2,p=0.017,差异有统计学意义。种植后第一周各检查系列均检查出病变25例。种植后4天和一周的检出率比较:DWI组无显著性差异(χ~2=3.24,p＞0.05);而T1w、T2WI和T2WI SPIR组有统计学差异(p＜0.05)。
2.2肿瘤种植后不同时间ADC值的变化
周边区在种植后第4天、1周、2周、3周ADC值分别为1862.58±150.97、1636.70±5152.96、1273.43±173.59及1005.68±192.00,差异有显著性(F=153.997、p=0.000)。而中心区第4天、1周、2周、3周ADC值分别为1498.81±264.41、1078.92±153.58、662.751±174.27、1553.19±179.01(F=149.442、p=0.000)。随着时间的增加ADC值降低,但在第三周ADC值升高,甚至超过了第四天,表明病灶中央出现了坏死灶。
结论:
1、DWI是检查肝癌比较敏感技术,可较早期检出小肝癌,在肝脏肿瘤的诊断中将得到越来越广泛的应用。
2、MR弥散加权成像不但对肿瘤的定性诊断有很大帮助,通过ADC值,可大致判断肿瘤的坏死情况和发展趋势。
第三章:肝癌化疗栓塞前后MR弥散和灌注成像研究。
目的:通过MR DWI、PWI成像观察肝癌栓塞前、后肿瘤坏死及血流灌注情况的变化规律,并与病理和微血管密度对比,判断MR DWI、PWI成像在观察肝癌栓塞后坏死及血流灌注的临床应用价值。
材料和方法:
1.1实验动物分组及模型制备肝癌模型新西兰大白兔30只,体重2.5～3.0kg,雌雄不限,由广东省实验动物中心提供。实验动物随机分为3组,分别为TACE术前、术后三天、术后一周组,每组10只动物。采用“第一章:兔VX2肝癌模型的制作及改进”中,“肿瘤组织块直接种植法”制作肿瘤模型。
1.2兔肝癌的化疗栓塞
肿瘤种植3周,常规MR扫描发现病灶,进行肝动脉化疗栓塞。兔用速眠新全麻,取仰卧位固定于兔手术板上。常规消毒、铺巾。用手术刀切开腹股沟下皮肤,用止血钳分离出股动脉,用带有塑料套的穿刺针刺入到股动脉内。拔出针芯,见有血液喷出,送入黑泥鳅导丝,撤出塑料套,通过导丝引入4F超滑导管进入腹主动脉达腹腔动脉干开口处。用手推注造影剂造影,观察肿瘤血管和肿瘤染色。撤出导丝,引入3F微导管入腹腔干,越过胃动脉,将导管超选入肿瘤供血动脉,注射碘油、MMC(1mg)及表阿霉素(1mg)混合物1-3ml,至碘油沉积良好、肿瘤血管消失、动脉内碘油滞留停止。拨管,右侧股动脉结扎。局部皮肤缝合、消毒、包扎。
1.3 MR弥散和灌注加权成像
1.3.1扫描条件
各组在TACE术前、术后三天、术后一周分别进行MR弥散和灌注成像。应用Sense-Flex-M环形表面线圈。
DWI扫描条件:见第二章。
PWI成像:采用TFE序列,灌注成像参数:矩阵89×256,TR 4.3 ms,TE1.4 ms,激励次数1,视野355 mm×75 mm,层厚5mm,间距1mm,NSA为1次。扫描层面数4层,每层反复激励65次,总扫描时间为1分20秒。高压注射器经通过家兔耳缘静脉注射对比剂钆特酸葡胺注射液(多它灵,377mg/ml),剂量为0.2mmol/kg,注射流速为2ml/s。生理盐水3ml以同样速度注射冲管,团注开始即进行扫描。
1.3.2 MR灌注图像后处理
将原始图像输入到PHILIPS后处理工作站(VIEWFORUM),自动生成MR灌注图。分别在肿瘤中心区、边缘区设置感兴趣区,分别分析时间—信号强度曲线(time signal-intensity curve,TIC)及肿瘤中心区、边缘区最大增强斜率(maximum slop of increase,MSI)的变化规律。
1.4病理观察
3组动物MR弥散和灌注成像之后,用过量硫喷妥钠处死。根据MR图像引导切取肿块所在部位肝脏,进行大体病理观察,HE染色并进行免疫组化,计算其中心区、边缘区MVD值。
1.5观察指标及统计学处理
肿瘤中心区、边缘区在TACE前、后4天、后一周的ADC值、SMI值及MVD值。用SPSS13.0进行统计分析,采用计量资料的单因素的方差分析(One-Way ANOVA)。检查水准:a=0.05。MVD与ADC值相关分析、MVD与MSI值相关分析采用双变量相关分析(Bivariate)。
结果:
2.1化疗栓塞前后DWI结果
1、化疗栓塞前后DWI成像改变及与病理对照
化疗栓塞前MR成像在肝左叶可见T1低信号、T2高信号、DWI高信号的肿瘤。大体病理示肿瘤为白色,剖面呈鱼肉状,光镜下细胞体积大,胞浆丰富,淡红染色,核肥大,核分裂像多见,可见少量坏死,周边区和中央区未见明显区别。
栓塞后3d在DWI上出现斑片状低信号区,为凝固性坏死的表现。大体病理示肿瘤为白色,肿瘤中心可见豆腐渣样坏死组织,光镜下出现大量核碎裂、核溶解,肿瘤坏死较多。
栓塞后1w,病灶进一步进展,病灶中心在T2、DWI上出现了大面积低信号的坏死区。大体病理肿瘤中心坏死组织增多,光镜下肿瘤坏死增多。
2、化疗栓塞前后ADC值的改变
边缘区ADC值在栓塞前、栓塞后3d、栓塞后1w分别为1089.31±107.24、1865.38±157.28、1860.97±194.46,有显著性差异(F=80.875,p=0.000)。中心区ADC值在栓塞前、栓塞后3d、栓塞后1w分别为1595.92±197.51、1633.38±193.82、1848.14±183.01,有显著性差异(F=5.049,p=0.014)。
2.2 MR灌注结果
1、MR灌注图改变
栓塞前HBV图、HBF图清楚显出肿瘤灶,并可见病灶中央高灌注区。病灶中心区强化曲线,表现为速升速降;边缘区强化曲线强化峰值比病灶中心区高。
栓塞后3天强化曲线缓慢升高,缓慢下降。栓塞后1W表现与栓塞后3天相似,中心区伪彩进一步下降,甚至消失。边缘区强化曲线缓慢升高,缓慢下降。
2、栓塞前后不同时间MSI变化
边缘区在栓塞前、栓塞后3d、栓塞后1w的MSI值分别为7.35±1.20、8.70±0.96、2.85±0.96,有统计学差异(F=85.986,p=0.000)。术后第三天到一周组间变化较大。中心区在栓塞前、栓塞后3d、栓塞后1w的MSI值分别为2.41±0.59、1.50±0.38、1.33±0.46,统计学分析有显著性差异(F=14.414,p=0.000)。
2.3病理学观察
2.3.1光镜下病理表现
肿瘤组织在低倍镜下可见肝内浸润性癌巢,与肝实质无明显边界。肿瘤细胞分散排列,可见纤维间隔,新生毛细血管丰富。高倍镜下可见瘤细胞体积大,胞浆丰富,淡红染色,核肥大,核分裂像多见。化疗栓塞后瘤细胞团内可见大片坏死区及多个片状或灶性坏死,大部分瘤细胞核固缩及核碎裂。
2.3.2免疫组化病理
1、免疫组化表现
肿瘤血管被染成棕色、褐色,化疗栓塞前后肿瘤中心区、边缘区随着时间进展肿瘤血管减少。
2、化疗栓塞前后MVD改变
边缘区MVD值在栓塞前、栓塞后3d、栓塞后1w分别为51.14±19.71、26.88±12.76、11.07±6.52,经统计学分析:F=20.582,p=0.000,有显著性差异。中心区MVD值在栓塞前、栓塞后3d、栓塞后1w分别为13.49±5.17、8.52±3.64、8.32±5.11,有显著性差异(F=3.899,p=0.033)。
2.4 DWI、PWI与微血管密度相关性
MVD与ADC值间存在负相关(r=-0.534,p=0.000);MVD与MSI值间存在正相关(r=0.694,p=0.000)。
结论:
1、栓塞前病灶中心区和边缘区强化曲线,表现为速升速降,边缘区强化峰值比病灶中心区高。栓塞后强化曲线缓慢升高,缓慢下降,随着时间发展,上升幅度降低。
2、肿瘤中心区、边缘区MVD值在栓塞前、栓塞后3d、栓塞后1w的比较,均有统计学差异,化疗栓塞后肿瘤的微血管明显减少。
3、肿瘤中心区、边缘区MSI值在栓塞前、栓塞后3d、栓塞后1w的比较中有统计学差异,随着时间发展MSI降低。MVD与MSI值呈正相关,MVD的减少使单位时间、单位组织内肝血流量增加,是MSI降低的病理基础。
4、MRI灌注成像能在活体判断肝癌的血管生成程度及血供情况,MR灌注值改变可揭示肿瘤新生血管的血流动力学变化,为研究肝癌的血流动力学改变提供了一种新的方法,对判断栓塞后肝癌的灌注水平变化及疗效评估也很有价值。
5、中心区和边缘区ADC值在栓塞前、栓塞后3d、栓塞后1w有显著性差异,说明TACE治疗3天后组织弥散增加。MVD与ADC呈负相关。ADC值作为可靠的动态监测治疗前后肿瘤坏死情况的方法,可较好地反应TACE后肿瘤的转归。
Background
Transcatheter arterial chemoembolization(TACE) is considered to be an effective treatment for hepatocellular carcinoma.However,angiogenesis,the process leading to the formation of new blood vessels from preexisting vessels,plays a central role in the survival of tumor cells,in local tumor growth,and in the development of distant metastasis and reduces therapeutic effectiveness.Early detection of residual tumor and vascularity after interventional treatments is critical before TACE and during follow up.
Generally,computed tomographic(CT) images could be considered as a routine modality to judge the efficacy of TACE.The pattern and distribution of iodized oil in the tumor are useful for assessing the therapeutic effects of TACE.A greater amount of accumulation of iodized oil within tumor indicates a greater area of necrosis.During follow-up,the focal defect or washout of iodized oil in the mass with the contrast-enhanced area suggests the presence of a viable tumor and that additional treatment is needed.The contrast-enhanced CT is a reliable method for the assessment of therapeutic efficacy.On contrast-enhanced CT,necrotic tissues were unenhanced and viable tumors were enhanced.But it was difficult to judge the viability and necrosis of the tumors correctly due to the inhomogeneous deposition,because lipiodol negative areas could not actually represent the viability of the tumors.It can also be difficult to evaluate contrast enhancement in a tumor with partial retention of iodized oil on contrast-enhanced CT because of the beam-hardening artifacts produced by the high attenuation of iodized oil.
MR imaging was valuable in the evaluation of therapeutic efficiency of TACE, especially on T_2WI,most of viable tumors were hyperintense and the coagulative necrosis within the tumors considered as a positive response to TACE was hypointense. But a signal intensity of the tumors after TACE was variable on SE T_1WI and T_2WI,all of viable tumors,hemorrhage,liquefied necrosis and inflammatory infiltration could also result in hyperintensity on the T_2WI.Therefore,it was difficult to assess the viable tumors of HCC after TACE by conventional SE imaging.Dynamic contrast scanning also has a great value in the evaluation of therapeutic efficacy of TACE.The residual viable tumors were shown as rapidly enhanced portions within the lesions,when necrotic portions had no enhancement at the contrast early phase scanning.At the late phase scanning,the enhancement of the most lesions became hypointense,and just a few lesions showed a persistent enhancement.Both viable tumors and inflammatory infiltration could present such changes,so the contrast early phase scanning was not more reliable in the evaluation of viable tumors.
Existing diagnostic imaging techniques provide limited evaluation of tissue characteristics beyond morphology.Perfusion imaging ultimately may have a role in the earlier identification of tumor recurrence if subtle differences in enhancement of benign versus malignant tissue can be captured earlier.CT perfusion imaging has the potential to provide both high-temporal-resolution and high-spatial-resolution imaging of the entire liver for the detection of HCC,however,the radiation doses must be considered.A whole-liver CT perfusion study would result in radiation doses that are approximately three to six times greater than those of a routine diagnostic CT examination.Perfusion MR imaging represents a promising technique for HCC surveillance.T1 weighted perfusion MRI has been used to assess tumor angiogenesis of uterine cervical carcinoma, and has a good correlation with microvessel density(MVD).
Diffusion-weighted imaging can provide an insight about water composition within a tumor and the degree of tumor viability.The apparent diffusion coefficients of malignant masses were significantly lower than those of benign masses.A study of an animal model of hepatocellular carcinoma showed that:diffusion-weighted imaging clearly distinguished the regions of tumor necrosis from viable tumor.So,DWI may offer significant utility in the longitudinal assessment of novel liver tumor treatments.
The purpose of this study was to observe angiogenesis and necrosis of HCC before and after TACE by MR perfusion Imaging and diffusion imaging,compared with microvessel density and histological evaluation,and to find out their feasibility and value in assessing therapeutic effectiveness of HCC during follow up.
Chapter One:The establishment and improvement of VX2 Carcinoma model
Objective To establish suitable metastatic rabbit vx2 hepatic carcinoma model,to compare the success rate of different tumor implantation methods.
Methods Thirty New Zealand white rabbits were randomly divided into three groups,10 rabbits in each group.Group 1:Solution of the VX2 carcinoma cells were injected into left liver by syringe needle.Group 2:Solution of the tumor tissue masses was transplanted into liver.Group 3(improvement group):VX2 carcinoma masses were injected into the liver using percutaneous puncture inoculation method.The operation was guided by CT scanner in each group.CT scanning was performed in all experimental animals 2 week after implantation.
Results The success rates of transplanted carcinoma were 30%,50%and 90%in group 1,group2 and group3 respectively,and the statistical difference was found.The respective ectopic implantation incidence at group 1,group2 and group3 were 1(3),1(5) and 0(8),no statistical difference was observed.The success rates of single nodule implanted tumor were the highest in group 3(80%) than in group 1(10%) and group 2 (20%).The difference was statistically different(p=0.003).
Conclusion It is successful to improve the rabbit modes bearing VX2 metastatic hepatic carcinoma.And the method of percutaneous puncture carcinoma masses implanation guided by CT was a good method to establish the hepatic carcinoma models with a high success rates,especial rates of single nodule implanted tumor,low ectopic implantation rates and little damage of animals.
Chapter Two:Observation of the value of MR Diffusion Weight Imaging in diagnosis of hepatocellular carcinoma
Objective To investigate the value of MR DWI in diagnosing hepatic carcinoma by studying the appearances of rabbit vx2 hepatic carcinoma in MR T1 WI,T2WI and DWI series at different times after the tumors were transplanted.
Methods The metastatic rabbit vx2 hepatic carcinoma models were presented in 30 New Zealand white rabbits.VX2 carcinoma masses were injected into the liver using percutaneous puncture inoculation method in guiding by CT scanner in each group.MR T1WI,T2WI,T2WI SiP and DWI were performed in all experimental animals at 4day,1, 2 and 3 weeks after implantation with a Sense-Flex-M.T2W_TSE_SENSE and T2W TSE_SPIR parameters:TR 3544ms,TE 81ms,FOV 150mm,slice thickness 4mm, intersection gap of-1 mm,matrix 256×256,restruction matrix 512×512,scan time 74s, NSA 2.The MR image parameters with T1WI SENSE were as follows:TR 407ms,TE 17ms,FOV 150mm,slice thickness 3mm,intersection gap of- 1 mm,matrix 256×256,restruction matrix 512×512,scan time 94s,NSA 2,EL=3.
Diffusion-weighted images of the liver were acquired using an SE-EPI sequence with the following imaging parameters:b-values of 0,300/mm~2,TR 6000ms,TE 49ms, FOV 150mm,slice thickness 3mm,intersection gap of 0mm,matrix 112×112,restruction matrix 256×256,flip angle 90°,scan time 156s,NSA 6.The diagnosis rates of different methods in different time were observed.The ADC values in cores and peri-areas were analyzed.
Results Of 30 rabbits,25 were transplanted vx2 hepatic carcinoma.The success rate of carcinoma transplanted was 81.25%.The tumor lesion could be found in every examination series at 4 days after the implantation.The diagnosis rates of DWI,T1WI, T2WI and T2WI SPIR were 80%,60%,72%and 72%respectively.Statistical difference was found(p=0.007).The diagnosis rates were 100%in all MR series at 1,2 and 3 week after implantation.In comparison of diagnosis rates between 4days and 1 to 3 week after the tumor implantation in different series,no significant difference was only observed on DWI series(p＞0.05) and significant difference on other series(p＜0.05).
The ADC values of peri-areas were 1862.58±150.97,1636.70±152.96, 1273.43±173.59,1005.68±192.00 respectively,at 4day,1,2 and 3 weeks after implantation.The significant difference was observed(F= 153.997,p=0.000).The values decreased with the times developing from 4 days to 3 weeks after the implantation.The ADC values of cores were 1498.81±264.41,1078.92±153.58,662.751±174.27, 1553.19±179.01 respectively at 4day,1,2 and 3 weeks.There were statistical difference in each group ADC values(F=149.442,p=0.000),which decreased with the times developing before 2 weeks,but increased at 3 weeks.
Conclusion MR DWI is a sensitive series in examination of liver tumor,,and will be used in diagnosis of liver tumor more and more.The values of ADC may help discriminate between the necrosis areas and normal areas,will play a important role in surgical operation and puncture biopsy.
Chapter Three:MR diffusion and perfusion imaging of the liver before and after transcatheter hapatic chemoembolization for hepatocellular carcinoma
Objective To observe angiogenesis and necrosis of HCC before and after TACE by MR perfusion imaging and diffusion imaging,compared with microvessei density and histological evaluation,and to find out their feasibility and value in assessing therapeutic effectiveness of HCC during follow up.
Methods
1.Animals and tumor models
30 New Zealand white rabbits(weight:2.5-3.0kg) with VX2 liver tumors were randomly divided into three groups,10 rabbits in each group(group 1,pre-TACE;group2, 3 day post- TACE;group 3,1 week post- TACE).The MR scan was performed before chemoembolization,at 3 day and 1 week after chemoembolization,respectively at group 1,2 and 3.The technique for tumor implantation was basically similar to that described in Group 3 of Chapter One.All three groups received interventional therapy after three weeks of the VX2 tumor was implanted.The laboratory animal center of Guangdong province provided all animals.
2.Chemoembolization
Each rabbit was successfully catheterized with DSA.Conventional DSA was performed by using a C-arm unit guidance.Rabbits were initially anesthetized by using sumianxin(0.1-.02mg/kg).Vascular access was achieved in the femoral artery through transfixion using a transfixion pin with plastic sleeve.A 4-F catheter was advanced over a guidewire into the celiac trunk.DSA of arteries was performed by using 2-3 ml manual injections of contrast agent.The 3-F catheter was advanced into the left hepatic artery.1-3 ml lipiodol emulsion(lipiodol mixed with 1mg MMC and 1mg pharmorubicin) were superselectively delivered into tumor vessel by manual injection.Follow-up angiography was performed and confirmed the complete stasis of antegrade blood flow to the liver tumors.After chemoembolization,the catheter was removed and the femoral artery was ligated.Then skin closure was finished.
3.MR imaging
MR perfusion and diffusion imaging examination were performed in the supine position by using a clinical Sense-Flex-M coil.The scans were done before chemoembolization,at 3 day and 1 week after chemoembolization,at group 1,2 and 3 respectively.MR diffusion imaging parameters has been described in Chapter Two. The MR perfusion imaging protocol consisted of T1-weighted fast field echo(FFE) sequences with a field of view of 355 mm×75 ram,matrix 89×256,TR/TE of 4.3/1.4 milliseconds,slice thickness of 5 mm,intersection gap of 1 mm,NSA of 1.This sequence was repeated 65 times,in4 slice(in total,80 seconds),a dose of 0.2 mmool/kg of Gadoteric Acid contrast medium was injected after the start of the scan.Injection of Gadodiamide was performed through a 22-gauge needle via ear vein at a flow rate of 2 ml/sec followed by injection of 3ml bolus of saline(NaCl 0.9%).
4.Histological evaluation
Each animal was then sacrificed with overdose penthiobarbital sodium intravenous injection for pathology observation after MR examination.The livers were removed and fixed in 10%acetic formalin.A slice was cut at the same level as the slice imaged in MR and the general pathology was observed.Each VX2 tumor was divided into the periphery area and center area.The specimens of both areas were embedded in paraffin,and thinner sections of 3mm were cut and stained with hematoxylin-eosin-safran.These slices were examined with an optical microscope at 20 magnifications.Immumohistochemical staining was performed using the SP method.The specimens were observed under a low power microscope(×40),then the sections with most dense area of microvessels were selected and observed under a high power(×400).Microvessels were evaluated under a microscope,microvessel density in the center and rim of the lesion were calculated.
5.Statistical analysis
The values of ADC,MSI and MVD in the center and rim of the lesion were calculated.All data were expressed as mean±SD,the statistical differences between different groups were analyzed by ANOVA,and the correlation between MSI and MVD, ADC and MVD was assessed by Spearman correlation analysis.Significance was accepted when p＜0.05.
Results
1.Lesion signal intensity characteristics in DWI images before and after TACE
The lesions assessed before TACE were hypo- intense relative to the surrounding liver parenchyma on T1-weighted images,and the most portion of tumors was hyperintense relative to the surrounding liver parenchyma on T2-weighted images and DWI images,and the heterogeneous signal intensity was observed when liquefied necrosis or fat degeneration occurred.At 3d after TACE,on DWI images,the heterogeneous hypo-intense was observed,which was coagulative necrosis confirmed by morphological observation.At 1w after TACE,the heterogeneous hypo-intense areas became larger.The coagulative necrosis progressed with the development of times.
2.Changes of ADC values
The ADC values of peri-areas were 1089.31±107.24,1865.38±157.28 and 1860.97±194.46 respectively,at pre-TACE group,3 days post-TACE group and 1week post-TACE group.The significant difference was observed(F=80.875,p=0.000).The ADC values of cores in each group were 1595.92±197.51,1633.38±193.82, 1848.14±183.01 respectively.Significant difference was found between pre-TACE and after TACE(F=5.049,p = 0.014)
3.Characteristics on PWI images before and after TACE
All tumors lesions were depicted on HBF,HBV images.Time intensity curves derived from ROIs drawn in the peri-areas and cores of the tumor showed a rapid initial increase in signal intensity,representing hypervascularity before and after TACE.The peak values in peri-areas were higher than cores.The intensity curves in post-TACE groups showed less steep than pre-TACE group.
4.Changes of MSI values
The MSI values of peri-areas were 7.35±1.20,8.70±0.96and 2.85±0.96 respectively at pre-TACE group,3 days post-TACE group and lweek post-TACE group.The significant difference was observed(F=85.986,p= 0.000).The MSI values of cores in each group were 2.41±0.59,1.50±0.38 and 1.33±0.46 respectively.Significant difference was found between pre-TACE and after TACE(F= 14.414,p= 0.000)
5.Results of morphological observation
Under low magnification,HCC was seen as invasive carcinoma in the liver,there was no clear margin between neoplasm and the hepatic parenchyma,neoplastic cells distributed straggly,there was separating fibre with abundant capillary of newly developed;under high magnification,the volume of neoplasm was large with irregular morphology,cells distributed irregularly with abundant cytoplasm.Nucleus was hypertrophic with different size and shape,staining was non-uniform,phase of nucleous mitosis showed in many cells,a great number of lymphocytes and plasma cells could be seen infiltrating in the mesenchyma.After TACE lesions underwent un-complete necrosis,karyopycnosis and nuclear fragmentation was seen at the center of the lesions.
6.Results of immunohistochemistry
CD34 was expressed in HCC and various degree of yellow stain could be seen in the epithelial cells of hepatic sinusoid in the HCC section.But MVD of HCC tissues were lower significantly after TACE than before TACE.The MVD values of peri-areas were 51.14±19.71,26.88±12.76 and 11.07±6.52 respectively at pre-TACE group,3 days post-TACE group and lweek post- TACE group.The significant difference was observed(F=20.582,p=0.000).The MVD values of cores in every group were 13.49±5.17,8.52±3.64,8.32±5.11 respectively.Significant difference was found between pre-TACE and after TACE(F=3.899,p=0.033)
7.Correlate analysis
The values were analyzed by Pearson's correlation coefficient.The results showed that there was negative correlation between ADC and MVD(r=-0.534,p=0.000),positive correlation between MSI and MVD(r=0.694,p=0.000).
Conclusion
1.Time intensity curves derived from ROIs drawn in the peri-areas and cores of the tumor showed a rapid initial increase in signal intensity.The peak values in peri-areas were higher than cores.The intensity curves in post-TACE groups showed less steep than pre-TACE group.
2.Significant difference in MVD values of peri-areas and cores was found at pre-TACE group,3 days post-TACE group and 1 week post-TACE.That indicated capillary vessels decrease obviously after TACE.
3.MVD values of peri-areas and cores decreased along the times of TACE developing. The statistical significant was found.There was a positive correlation between MSI and MVD.The hepatic blood flow decreased along with the MVD,which was the pathological basis of MSI values decreasing.
4.MR perfusion imaging has a potential to evaluate the angiogenesis of liver tumors in vivo,and could demonstrate the haemodynamics variation of new vessels.It provides a new,valuable technology for hemodynamics study of HCC and evaluation of perfusion level and therapeutic effect after TACE.
5.Significant difference of ADC values in peri-areas and cores was found between pre-TACE and after TACE,which demonstrated that the diffusion of tumor tissues increased after TACE.There was negative correlation between MVD and ADC values. Values of ADC could reflect the changes of tumor after TACE,was a reliable index to monitor the tumor necrosis.
引文
[1]李洪林,罗斗强,石木兰.MRI对评价肝癌Lp-TACE治疗的价值.临床放射学杂志,2000,19(10):629-632.
[2]Yoshioka H,Nakagawa K,Shindou H,et al.MR imaging of the liver before and after transcatheter hepatic chemo-embolization for hepatocellular carcinoma.Acta Radiologica, 1990, 31(1):63-67.
[3]Hsu HC, Wei TC, Tasang YM, et al.Histologic assessment of resected hepatocellular carcinoma after transcatheter hepatic carterial embolization.Cancer, 1986,57(6): 1184-1191.
[4]Yan FH, Zhou KR, Cheng JM, et al.Role andl imitation of FMPSP dynamic contrast scanning in the follow-up of patients with hepatocellcar carcinoma treated by TACE.World J Gastroenterol, 2002,8(4):658-662.
[5]Murakami T, Nakamura H, Tsuda K, et al.Treatment of hepatocellular carcinoma by chemoembolization: Evaluation with 3DFT MR imaging.AJR,1993,160(2):295-299.
[6]Numata K, Tanaka K, Kiba T, et al.Using contrast-enhanced sonography to assess the effectiveness of transcatheter arterial embolization for hepatocellular carcinoma.AJR, 2001,176(5): 1199-1205.
[7]Ippolito D, Sironi S, Pozzi M et al.Perfusion computed tomographic assessment of early hepatocellular carcinoma in cirrhotic liver disease: initial observations.J Comput Assist Tomogr, 2008;32(6):855-858.
[8]Kobayashi T, Hayashi T, Funabasama S et al.Three-dimensional perfusion imaging of hepatocellular carcinoma using 256-slice multidetector-row computed tomography.Radiat Med, 2008;26(9):557-561.
[9]Chen G, Ma DQ, He W, et al.Computed tomography perfusion in evaluating the therapeutic effect of transarterial chemoembolization for hepatocellular carcinoma.World J Gastroenterol, 2008;14(37):5738-5743
[10]Tsushima Y, Unno Y, Koizumi J, et al.Hepatic perfusion change after transcatheter arterial emlolization (TAE) of hepatocellular carcinoma measurement by dynamic computed tomography.Dig Dis Sci,1998, 43(2):317-322.
[11]Ito K, Honjo K, Fujita T, et al.Therapeutic efficacy of transcatheter arterial hemoembolization for hepatocellular carcinoma: MRI and pathology.Comput AssistTomogr, 1995, 19(2): 198-203.
[12]Svagzdys S, Lesauskaite V, Pavalkis D,et al.Microvessel density as a new prognostic marker after radiotherapy in rectal cancer.BMC Cancer, 2009,9(1):95-120
[13]White MJ, O'Gorman RL, Charles-Edwards EM,et al.Parametric mapping of the hepatic perfusion index with gadolinium-enhanced volumetric MRI.British Journal of Radiology, 2007,80(950): 113-120
[14]Ichikawa T, Haradome H, Hachiya J, et al.Characterization of hepatic lesions by perfusion-weighted MR imaging with echoplanar sequence.AmJ Roentgenol, 1998,170(4):1029-1034.
[15]Chan JH, Tsui EY, Luk SH,et al.Detection of hepatic tumor perfusion following transcatheter arterial chemoembolization with dynamic susceptibility contrast-enhanced echoplanar imaging.Clin Imaging, 1999, 23(3):190-194.
[16]Tsui EY, Chan JH, Cheung YK,et al.Evaluation of therapeutic effectiveness of transarterial chemoembolization for hepatocellular carcinoma: correlation of dynamic susceptibility contrast-enhanced echoplanar imaging and hepatic angiography.Journal of Clinical Imaging, 2000, 24(4):210-216.
[17]Herneth AM, GuccioneS, Bednarski M.Apparent diffusion coefficient: a quantitative parameter for in vivo tumor characterization.Eur J Radiol,2003,45(3):208-213.
[18]Kamel IR, Bluemke DA, Ramsey D, et al.Role of diffusion-weighted imaging in estimating tumor necrosis after chemoembolization of hepatocellular carcinoma.Am J Roentgenol, 2003, 181(3): 708-710.
[19]Kamel IR, Liapi E, Reyes DK, et al.Unresectable hepatocellular carcinoma: serial early vascular and cellular changes after transarterial chemoembolization as detected with MR imaging.Radiology, 2009,250(2):324-326.
[20]Okada M, Kudo S, Miyazaki 0,et al.Antitumoral efficacy and pharmacokinetic properties of pirarubicn upon hepatic intra-arterial injection in the rabbit VX2 tumor model.Br J Cancer, 1995, 71 (3):518-524.
[21]Ramirez LH, Julieron M, Bonnay M, et al.Stimulation of tumor growth in vitro and in vivo by suramin on the VX2 model.Invest New Drugs,1995,13(1):51-53.
[22]Geschwind JF,Artemov D,Abraham S,et al.Chemoembolization of liver tumor in a rabbit model:assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis.J Vasc Interv Radiol,2000,11(10):1245-1255.
[23]Lee KH,Liapi E,Buijs M et al.Considerations for implantation site of VX2carcinoma into rabbit liver.J Vasc Interv Radiol,2009;20(1):113-117.
[24]Prat F,Centarti M,Sibille A,et al.Extracorporea high-intensity focused ultrasound for VX2 liver tumors in the rabbit.Hepatology,1995,21(3):832-836.
[25]王晓东,任军,杨仁杰等.VX2活细胞数与兔肝癌模型成功率及成瘤时间的关系.现代肿瘤医学,2005,13(5):589-591.
[26]吴文娟,崔慧先,李海涛等.兔VX2肝癌模型的建立及超声观察.中华超声影像学杂志,2005,14(2):147-150
[27]曹玮,王执民,张洪新等.兔VX2肝癌模型的移植方式及生长特性的研究.实用放射学杂志,2003,19(2),97-99
[1]Colagrande S,Politi LS,Messerini L,et al.Solitary necrotic nodule of the liver:imaging and correlation with pathologic features.Abdom Imaging,2003,28(1):41-44.
[2]Murtz P,Flacke S,Traber F,et al.Abdomen:diffusion-weighted MR imaging with pulse triggered single-shot sequences.Radiology,2002,224(1):258-264.
[3]Chow LC,Bammer R,Moseley ME,et al.Single breathhold diffusion-weighted imaging of the abdomen.J Magn Reson Imaging,2003,18(3):377-382.
[4]Willatt JM,Hussain HK,Adusumilli S et al.MR Imaging of hepatocellular carcinoma in the cirrhotic liver:challenges and controversies.Radiology,2008,247(2):311-330.
[5]Lim JH,Kim CK,Lee WJ,et al.Detection of hepatocellular carcinomas and dysplastic nodules in cirrhotic livers:accuracy of helical CT in transplant patients.AJR Am J Roentgenol,2000,175(3):693-698.
[6]Semelka RC, Cance WQ Marcos HB, et al.Liver metastases: comparison of current MR techniques and spiral CT during arterial portography for detection in 20 surgically staged cases.Radiology, 1999,213(1 ):86—91.
[7]Krinsky GA, Lee VS, Theise ND, et al.Hepatocellular carcinoma and dysplastic nodules in patients with cirrhosis: prospective diagnosis with MR imaging and explanation correlation.Radiology, 2001, 219(2):445-454.
[1]Weidner N.Intratumor microvessel density as a prognostic factor in cancer.Am J Pathol,1995,147(1):9-19.
[2]Cha C,DeMatteo RP,Blumgart LH,et al.Surgery and ablative therapy for hepatocellular carcinoma.J Clin Gastroenterol,2002,35(5 Suppl 2):130-137.
[3]Tang ZY.Hepatocellular carcinoma-cause,treatment and metastasis.World J Gastroenterol,2001,7(4):445-454.
[4]Sturm JW,Keese MA,Bonninghoff RG,et al.Locally ablative therapies of hepatocellular carcinoma.Onkologie,2001,24(Suppl 5):35-45.
[5]Kinji I.Effect of repeated transcatheter arterial emolization on the survival time in patients with hepatocellular carcinoma.Cancer,1991,68(10):2150-2154.
[6]田建明,贾雨辰,张韵,等.肝动脉闭塞后的侧支循环通路的分析.中华放射学杂志,1992,26(5):344-346.
[7]Furui S,Otomo K,ltai Y,et al.Hepatocellular carcinoma treated by transcatheter arterial embolization:progress evaluated by computed tomography.Radiology,1984,150(3):773-778.
[8]Konno T.Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium.Cancer,1990,66(9):1897-1903.
[9]Hatanaka Y,Yamashits Y,Takahashi M,et al.Unresectable hepatocellular carcinoma:analysis of prognostic factors in tran-scatheter management.Radiology,1995,195(3):747-752.
[10]王瑛,王武.肝癌栓塞治疗前后彩色多普勒超声与血管造影对照观察疗效的研究.中国超声医学杂志,2000,16(1):15-18.
[11]Yoshioka H,Nakagawa K,Shindou H,et al.MR imaging of the liver before and after transcatheter hepatic chemoembolization for hepatocellular carcinoma.Acta Radiologica,1990,31(1):63-67.
[12]Honda H,Tajima T,Kajiyama K,et al.Vascular changes in hepatocellular carcinoma:correlation of radiologic and pathologic findings.AJR,1999,173(5):1213-1217.
[13]Barinaga M.Designing therapies that target tumor blood vessels.Science.1997,275(5299):482-484..
[14]Folkman J, Tumor rangiogenesis: therapeutic implication.N Engl J Med, 1971, 285(21):1182-1186.
[15]Luiten RM, Fleuren GJ, Warnaar SO, et al.Target-specific activation of mastcells by immunoglobulin E reactive with a renal cell carcinoma-Associated antigen.Lab Invest, 1996,74(2):467-475.
[16]Potgens AJ, Westphal HR,de waal RM, et al.The role of vascular Permeability factor and basic fibroblast growth factor in tumorangiogenesis.Biol Chem Hoppe Seyler,1995,376(2):57-70.
[17]Tseng PL, Tai MH, Huang CC, et al.Over expression of VEGF is associated with positive p53 immunostaining in hepatocellular carcinoma (HCC) and adverse outcome of HCC patients.Surg Oncol, 2008, 98(5):349-357J
[18]Li YJ, Wen G, Wang Q.Expression of vascular endothelial growth factor and its receptor Flk-1/KDR in benign and malignant breast neoplasms.Nan Fang Yi Ke Da Xue Xue Bao,2009,29(1):70-71
[19]Takahashi Y,Tucker SL,Kitadai Y,et al.Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer.Arch Surg, 1997,132(5): 541-546.
[20]Appleton MA, Attanoos RL, Jasani B.Thrombomodulin as a marker of vascular and lymphatic tumours.Histopathology, 1996,29(2): 153-157.
[21]Kimura H, Nakajima T, Kagawa K, et al.Angiogenesis in hepatocellular carcinoma as evaluated by CD34 immunohistochemistry.Liver, 1998,18(1): 14-19.
[22]Oxboel J, Binderup T, Knigge U, et al.Quantitative gene-expression of the tumor angiogenesis markers vascular endothelial growth factor, integrin alphaV and integrin beta3 in human neuroendocrine tumors.Oncol Rep.2009,21(3):769-775.
[23]Jain PK.Determinants of tumor blood flow: a review.Cancer Res,1988,48(10): 2641-2658.
[24]Lu JP, Wang J, Wang T, et al.Microvessel density of malignant and benign hepatic lesions and MRI evaluation.World J Gastroenterol,2004,10(12):1730-1734.
[25]Piao YF,He M,Shi Y,et al.Relationship between microvessel density and telomerase activity in hepatocellular carcinoma.World J Gastroenterol,2004,10(14):2147-2149.
[26]Pooh RT,Ng IO,Lau C,et al.Tumor microvessel density as a padictor of recurrnce after resection of hepatocellular carcinoma a prospective study.J Clin Oncol,2002,20(7) 1775-1785.
[27]Svagzdys S,Lesauskaite V,Pavalkis D,et a.Microvessel density as a new prognostic marker after radiotherapy in rectal cancer.BMC Cancer,2009,9(1):95-120.
[28]Tanigawa N,Lu C,MitsuiT,et al.Quantitation of sinusoid like vessels in hepatocellular carcinoma its clinical and prognostic significance.Hepatology,1997,26(5):1212-1216.
[29]陈永杰,付艳忠,赵志华等.原发性肝癌组织中血管内皮生长因子、微血管密度检测.郑州大学学报(医学版),2007,42(5):925-927.
[30]Brasch R,Pham C,Shames D,et al.Assessing tumor angiogenesis using macromolecular MR imaging contrast media.J Magn Resort Imaging,1997,7(1):68-74.
[31]陈雁,周纯武,刘玉清.肿瘤微血管生成和肺癌及其影像学的联系.中国医学影像技术,2000,16(10):913-915.
[32]向昕,刘志伟,顾万清等.TAE后肝癌微血管密度及VEGF表达与再手术治疗研究.肝胆外科杂志,2004,12(1):24-27.
[33]孙卫东,何维新,任普海.经导管肝动脉化疗栓塞后肝癌微血管密度、血管内皮生长因子表达的变化,现代实用医学,2007;19(7):547-548.
[34]林小军,张昌卿,张亚奇等.单纯切除与介入治疗后原发性肝癌肿瘤微血管密度变化研究.癌症,2000,19(10):919-922.
[35]Goldberg SN,Ahmed M.Minimally invasive image-guided therapies for hepatocellular carcinoma.J Clin Gastroenterol,2002;35[5 suppl2]:115-129.
[36]Ito K,Honjo K,Fujita T,et al.Therapeutic efficacy of transcatheter arterial chemoembolization for hepatocellular carcinoma:MRI and pathology.J Comput Assist Tomogr,1995,19(2):198-203.
[37]Hsu HC,Wei TC,Tasang YM,et al.Histologic assessment of resected hepatocellular carcinoma after transcatheter hepatic carteriai embolization.Cancer,1986,57(6):1184-1191.
[38]李洪林,罗斗强,石木兰.MRI对评价肝癌Lp-TACE治疗的价值.临床放射学杂志,2000,19(10):629-631.
[39]Yah FH,Zhou KR,Cheng JM,et al.Role and limitation of FMPSP dynamic contrast scanning in the follow-up of patients with hepatocellcar carcinoma treated by TACE.World J Gastroenterol,2002,8(4):658-662.
[40]Murakami T,Nakamura H,Hori S,et al.Detection of viable tumor cells in hepatocellula rcarcinoma following transcatheter arterial chemoembolization with Iodized Oil:Pathologic correlation with dynamic turbo-FLASH MR imaging with Gd-DT-PA.Acta Radiologica,1993,34(4):399-403.
[41]Castrucci M,Sironi S,De Cobelli F,et al.Plain and gadolinium-DTPA-enhanced MR imaging of hepatocellular carcinoma treated with transarterial chemoembolization.Abdominal Imaging,1996,21(6):488-494.
[42]Kubota K,Hisa N,Nishikawa T,et al.Evaluation of hepatoceilular carcinoma after treatment with transcatheter arterial chemoembolization:comparison of Lipiodol-CT,power Doppler sonography,and dynamic MRI.Abdom Imaging,2001;26(2):184-190.
[43]Murakami T,Nakamura H,Tsuda K,et al.Treatment of hepatocellular carcinoma by chemoembolization:Evaluation with 3DFT MR imaging.AJR,1993,160(2):295-299.
[44]Numata K,Tanaka K,Kiba T,et al.Using contrast-enhanced sonography to assess the effectiveness of transcatheter arterial embolization for hepatocellular carcinoma.AJR,2001,176(5):1199-1205.
[45]Murakami T,KimT,Nakamura H.Hepatitis,cirrhosis,and hepatoma.J Magn Reson Imaging,1998,8(2):346-358.
[46]潘平,刘爱连,宋清伟等.动态增强磁共振在评价肝细胞癌微血管密度中的意义.中国医学计算机成像杂志,2001,7(5)326-330.
[47]Chenevert TL,Meyer CR,Moffat BA,et al.Diffusion MRI:a new strategy for assessment of cancer therapeutic efficacy.Molecular Imaging,2002,1(4):336-343.
[48]Hanahan D,Folkman J.Patterns and emergingmechanisms of the an- giogenic switch during tumorigenesis.Cell,1996,86(3):353-364.
[49]Park YN,Kim YB,Yang KM,et al.Increased expression of vascular endothelial growth factor and angiogenesis in early stage of multistep hepatocarcinogenesis.Arch Pathol Lab Med,2000,124(7):1061-1065.
[50]Vossen JA,Kamel IR,Buijs M et al.Role of functional magnetic resonance imaging in assessing metastatic leiomyosarcoma response to chemoembolization.J Comput Assist Tomogr,2008,32(3):347-352.
[51]Kamel IR,Bluemke DA,Ramsey D,et al.Role of diffusion-weighted imaging inestimating tumor necrosis after chemoembolization of hepatocellular carcinoma.Am J Roentgenol,2003,181(3):708-710.
[52]Geschwind JF,Artemov D,Abraham S,et al.Chemoembolization of liver tumor in a rabbit model:assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis.Journal of Vascular and Interventional Radiology,2000,11(10):1245-255.
[53]Herneth AM,Guccione S,Bednarski M.Apparent diffusion coefficient:a quantitative parameter for in vivo tumor characterization.Eur J Radiol,2003,45(3):208-213.
[54]尚全良,肖恩华,贺忠等.肝癌经导管动脉灌注化疗栓塞术疗效的MR扩散加权成像动态研究.中华放射学志,2006,40(3):235-240.
[55]Kamel IR,Liapi E,Reyes DK,et al.Unresectable hepatocellular carcinoma:serial early vascular and cellular changes after transarterial chemoembolization as detected with MR imaging.Radiology,2009,250(2):324-326.
[56]Suzuki K,Hayashi N,Miyamoto Y,et al.Expression of vascular permeability factor/vascular endothelial growth factor in humanhepatocellular carcinoma.Cancer Res,1996,56(13):3004-3009.
[57]Semela D,Dufour JF.Angiogenesis and hepatocellular carcinoma.J Hepatol,2004,41(5):864-880.
[58]Miles KA.Functional computed tomography in oncology.EurnJ Cancer,2002,38(16):2079-2084.
[59]Ippolito D,Sironi S,Pozzi Met al.Perfusion computed tomographic assessment of early hepatocellular carcinoma in cirrhotic liver disease:initial observations.J Comput Assist tomogr,2008,32(6):855-858.
[60]Kobayashi T,Hayashi T,Funabasama S et al.Three-dimensional perfusion imaging of hepatocellular carcinoma using 256-slice multidetector-row computed tomography.Radiat Med,2008,26(9):557-561.
[61]Chert G,Ma DQ,He W,et al.Computed tomography perfusion in evaluating the therapeutic effect of transarterial chemoembolization for hepatocellular carcinoma.World J Gastroenterol,2008,14(37):5738-5743.
[62]史丽静,田建明,王培军等.多层螺旋计算机X线体层扫描肝脏灌注成像的临床应用初步研究.中华肝脏病杂志,2003,11(9):522-525.
[63]葛英辉,谢晓东,宋彬等.肝脏螺旋CT血管造影一动脉系统三维成像初探.胃肠病学和肝病学杂志,1999,8(1):40-43.
[64]Tsushima Y,Unno Y,Koizumi J,et al.Hepatic perfusion change after transcatheter arterial emlolization(TAE) of hepatocellular carcinoma measurement by dynamic computed tomography.Dig Dis Sci,1998,43(2):317-322.
[65]Ichikawa T,Haradome H,Hachiya J,et al.Characterization of hepatic lesions by perfusion-weighted MR imaging with echoplanar sequence.Am J Roentgenol,1998, 170(4): 1029-1034
[66]Villringer A, Rosen BR, Beiliveau JW, et al.Dynamic imaging with lanthanide chelates in normal brainxontrast due to magnetic susceptibility effects.Magn Reson Med, 1988,6(2): 164-174.
[67]Chan JH, Tsui EY, Luk SH,et al.Detection of hepatic tumor perfusion following transcatheter arterial chemoembolization with dynamic susceptibility contrast-enhanced echoplanar imaging.Clin Imaging, 1999, 23(3): 190-194.
[68]Guan S, Zhao WD, Zhou KR, et al.Assessment of hemodynamics in precancerous lesion of hepatocellular carcinoma: evaluation with MR perfusion.World J Gastroenterol, 2007,13(8): 1182-1186.
[69]Materne R, Smith AM, Peeters F, et al.Assessment of hepatic perfusion parameters with dynamic MRI.Magn Reson Med, 2002,47(1): 135-142.
[70]Scharf J, Zapletal C, Hess T, et al.Assessment of hepatic perfusion in pigs by pharmacokinetic analysis of dynamic MR images.J Magn Reson Imaging, 1999,9(4):568-572.
[71]Zhao JG, Feng GS, Kong XQ, et al.Changes of tumor microcirculation after transcatheter arterial chemoembolization: first pass perfusion MR imaging andChinese ink casting in a rabbit model.World J Gastroenterol, 2004,10(10): 1415-1420.
[72]Kamel IR, Bluemke DA, Eng J, et al.The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma.J Vasc Interv Radiol, 2006,17(3):505—512.
[73]Li W, Brophy DP, Chen Q, et al.Semiquantitative assessment of uterine perfusion using first pass dynamic contrast-enhanced MR imaging for patients treated withuterine fibroid embolization.J Magn Reson Imaging, 2000,12(6): 1004-1008.
[74]Pandharipande PV, Krinsky GA, Rusinek H,et al.Perfusion imaging of the liver current challenges and future goals.Radiology,2005,234(3):661-673.
[75]Ostergaard L.Principles of cerebral perfusion imaging by bolus tracking.J Magn Reson Imaging,2005,22(6):710-717.
[76]el-Khalily H,Hoeffken H,yon Wichert P,et al.Hepatic perfusion scintigraphy.Relationship of liver perfusion and ascites in patients with liver cirrhosis.Clin Nuel Med,1996,21(2):132-135.
[77]Yoshioka H,Takahashi N,Yamaguchi M,et al.Double arterial phase dynamic MRI with sensitivity encoding(SENSE) for hyper-vascular hepatocellular carcinomas.J Magn Reson Imaging,2002,16(2):259-266.
[78]Bipat S,van Leeuwen MS,Ijzermans JN,et al.Imaging and treatment of patients with colorectal liver metastases in the Netherlands:a survey.Neth J Med,2006,64(5):147-151.
[79]Totman JJ,O'Gorman RL,Kane PA,et al.Comparison of the hepatic perfusion index measured with gadolinium-enhanced volumeric MRI in controls and in patients with colorectal cancer.BrRadiol,2005,78(926):105-109.
[80]Wang J,Zhang Y,Wolf RL,et al.Amplitude-modulated continuous arterial spin-labeling 3.0-T perfusion MR imaging with a single coil:feasibility study.Radiology,2005,235(1):218-228.
[81]Taouli B,Losada M,Holland A,et al.Magnetic resonance imaging of hepatocellular carcinoma.Gastroenterology,2004,127(5 Suppl 1):S144-152.
[82]连海英.磁共振灌注成像在肝硬化的临床应用.国外医学临床放射学分册.2006,29(1):36-39.
[83]White MJ,O'Gorman RL,Charles-Edwards EM,et al.Parametric mapping of the hepatic perfusion index with gadolinium-enhanced volumetric MRI.British Journal of Radiology,2007,80(950):113-120
[84]Breedis C,Young G.The blood supply of neoplasms in the liver.Am J Pathol.1954;30(5):969-977.
[85]Blomley M J,Coulden R,Dawson P,et al.Liver perfusion studied with Ultrafast CT.J Comput Assisted Tomogr,1995,19(3):424-433.
[86]Leggett DA, Kelley BB, Bunce IH, et al.Colorectal cancer: diagnostic potential of CT measurements of hepatic perfusion and implications for contrast enhancement protocols.Radiology, 1997,205(3):716-720.
[87]Harvey CJ, Blomley MJ, Eckersley RJ, et al.Developments in ultrasound media.Eur Radiol, 2001,11 (4):675-689
[88]Miles KA, Hayball MP, Dixon AK.Functional images of hepatic perfusion obtained with dynamic CT.Radiology, 1993,188(2):405-41 1.
[89]Tsushima Y, Blomley MJ, Kusano S, et al.Measuring portal venous perfusion with contrast- enhanced CT: comparison of direct and indirect methods.Acad Radiol.2002; 9(3):276-282.
[90]Cha S, Knopp EA, Johnson G, et al.Intracranial mass lesion: Dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging.Radiology, 2002, 223(1): 11-29.
[91]Sugahara T, Korogi Y, Kochi M, et al.Perfusion-sensitive MR imaging of gliomas: comparison between gradient-echo and spin-echo echo-planar imaging techniques.ANJR Am J Neumradiol, 2001, 22(7): 1306-1315.
[92]Tian JL,Zhang JS.Hepatic perfusion disorders: etiopathogenesis and related diseases.World J Gastroenterol,2006,12(20):3265-3270.
[93]Bhartia B,Ward J,Guthrie JA,et al.Hepatocellular carcinoma in cirrhotic livers double-contrast thin-section MR imaging with pathologic correlation of explanted tissue.AJR,2003,180(3):577-584.
[94]Peeters F, Annet L, Hermoye L, et al.Inflow correction of hepatic pefusion measurements using Tl-weighted, fast gradient-echo, contrast-enhanced MRI.Magn Reson Med, 2004, 51(4): 710-717.
[95]Yang ZH, Ye XH, Tan Y, et al.Evaluation of cirrhotic liver with perfusion-weighted magnetic resonance imaging: a preliminary experimental study in animal models with half-liver cirrhosis.Chin Med Sci J, 2006,21(4):252-257.
[96]张皓,顾爱华,缪竞陶等.晚期肝硬化肝脏MR灌注成像的灌注量化分析.放射学实践,2006,21(12)1236-1239.
[97]Shimizu A,ItoK,Koike S,et al.Cirrhosis or chronic hepatitis evaluation of small (＜or=2cm) early-enhancing hepatic lesions with serial contrast-enhanced dynamic MR imaging.Radiology,2003,226(2):550-555.
[98]Bipat S,van Leeuwen MS,Ijzermans JN,et al.lmaging and treatment of patients with colorectal liver metastases in the Netherlands a survey.Neth J Med,2006,64(5):147-151.
[99]Totman JJ,O'gorman RL,Kane PA,et al.Comparison of the hepatic perfusion index measured with gadolinium-enhanced volumetric MRI incontrols and in patients with colorectal cancer.British Journal of Radiology,2005,78(926):105-109.
[100]Kutara K,Asano K,Kito A,et al.Contrast harmonic imaging of canine hepatic tumors.J Vet Med Sci,2006,68(5):433-438.
[101]张铁宁,张皓,缪竟陶等.MR灌注成像在肝脏常见占位性病变诊断及鉴别诊断中的价值初探.中国医学影像技术,2006,22(12):1849-1852.
[102]Tsui EY,Chan JH,Cheung YK,et al.Evaluation of therapeutic effectiveness of transarterial chemoembolization for hepatocellular carcinoma:correlation of dynamic susceptibility contrast-enhanced echoplanar imaging and hepatic angiography.Journal of Clinical Imaging,2000,24(4):210-216.
[103]Ichikawa T,Araki T.Fast magnetic resonance imaging of liver.Eur J Radiol,1999,29(3):186-210.
[1]Cha C,DeMatteo RP,Blumgart LH,et al.Surgery and ablative therapy for hepatocellular carcinoma.J Clin Gastroenteroi,2002,35(5 Suppl 2):130-137.
[2]Tang ZY.Hepatocellular carcinoma-cause,treatment and metastasis.World J Gastroenterol,2001,7(4):445-454.
[3]Sturm JW,KeeseMA,Bonninghoff RG,et al.Locally ablative therapies of hepatocellular carcinoma.Onkologie,2001,24(Suppl 5):35-45.
[4]田建明,贾雨辰,张韵,等.肝动脉闭塞后的侧支循环通路的分析.中华放射学杂志,1992,26(5):344-346.
[5]Kinji I.Effect of repeated transcatheter arterial emolization on the survival time in patients with hepatocellular carcinoma.Cancer,1991,68(10):2150-2154.
[6]Furui S,Otomo K,Itai Y,et al.Hepatocellular carcinoma treated by transcatheter arterial embolization:progress evaluated by computed tomography.Radiology,1984,150(3):773-778.
[7]Konno T.Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium.Cancer,1990,66(9):1897-1903.
[8]Hatanaka Y,Yamashits Y,Takahashi M,et al.Unresectable hepatocellular carcinoma:analysis of prognostic factors in tran-scatheter management.Radiology,1995,195(3):747-752.
[9]王瑛,王武.肝癌栓塞治疗前后彩色多普勒超声与血管造影对照观察疗效的研究.中国超声医学杂志,2000,16(1):15-18.
[10]Yoshioka H,Nakagawa K,Shindou H,et al.MR imaging of the liver before and after transcatheter hepatic chemoembolization for hepatocellular carcinoma.Acta Radiologica,1990,31(1):63-67.
[11]Honda H,Tajima T,Kajiyama K,et al.Vascular changes in hepatocellular carcinoma:correlation of radiologic and pathologic findings.AJR,1999,173(5):1213-1217.
[12]Barinaga M.Designing therapies that target tumor blood vessels.Science.1997, 275(5299): 482-484.
[13]Folkman J, Tumor rangiogenesis: therapeutic implication.N Engl J Med, 1971, 285(21):1182-1186.
[14]Luiten RM, Fleuren GJ, Warnaar SO, et al.Target-specific activation of mastcells by immunoglobulin E reactive with a renal cell carcinoma-associated antigen.Lab Invest, 1996,74(2):467-475.
[15]Potgens AJ, Westphal HR,de waal RM, et al.The role of vascular permeability factor and basic fibroblast growth factor in tumor angiogenesis.Biol Chem Hoppe Seyler,1995,376(2):57-70.
[16]Takahashi Y,Tucker SL,Kitadai Y,et al.Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer.Arch Surg, 1997,132(5): 541-546.
[17]Appleton MA, Attanoos RL, Jasani B.Thrombomodulin as amarker of vascular and lymphatic tumours.Histopathology, 1996,29(2): 153-157.
[18]Kimura H, Nakajima T, Kagawa K,et al.Angiogenesis in hepatocellular carcinoma as evaluated by CD34 immunohistochemistry.Liver, 1998,18(1):14-19.
[19]Jain PK.Determinants of tumor blood flow: a review.Cancer Res, 1988,48(10): 2641-2658.
[20]Lu JP, Wang J, W ang T, et al.Microvessel density of malignant and benign hepatic lesions and MRI evaluation.World J Gastroenterol.2004,10(12): 1730-1734.
[21]Piao YF, He M, Shi Y, et al.Relationship between microvessel density and telomerase activity in hepatocellular carcinoma.World J Gastroenterol.2004,10(14):2147-2149.
[22]Poon RT, Ng IO, Lau C et al.Tumor microvessel density as a padictor of recurrnce after resection of hepatocellular carcinoma a prospective study.J Clin Oncol 2002,20(7) 1775-1785.
[23]Tanigawa N, Lu C, MitsuiT, et al.Quantitation of sinusoid like vessels in hepatocellular carcinoma its clinical and prognostic significance.Hepatology.1997, 26(5):1212-1216.
[24]Brasch R,Pham C,Shames D,et al.Assessing tumor angiogenesis using macromolecular MR imaging contrast media.J Magn Reson Imaging,1997,7(1):68-74.
[25]陈雁,周纯武,刘玉清.肿瘤微血管生成和肺癌及其影像学的联系.中国医学影像技术,2000,16(10):913-915.
[26]向昕,刘志伟,顾万清等.TAE后肝癌微血管密度及VEGF表达与再手术治疗研究.肝胆外科杂志,2004,12(1):24-27.
[27]林小军,张昌卿,张亚奇等.单纯切除与介入治疗后原发性肝癌肿瘤微血管密度变化研究.癌症,2000,19(10):919-922.
[28]李洪林,罗斗强,石木兰.MRI对评价肝癌Lp-TACE治疗的价值.临床放射学杂志,2000,19(10):629-632.
[29]Goldberg SN,Ahmed M.Minimally invasive image-guided therapies for hepatocellular carcinoma.J Clin Gastroenterol,2002,35[5 suppl2]:115-129.
[30]Katoh T,Mitani M,Noma K,et al.Delayed enhancement of hepatocellular carcinoma on dynamic CT:Sign of extrahepatic collaterals after transcatheter arterial chemoembolization or transcatheter arterial chemoinfusion.Abdominal Imaging,2002,27(1):34-39.
[31]Sumi S,Yamashita Y,Mitsuzaki K,et al.Power Doppler sonography assessment of tumor recurrence after chemoembolization therapy for hepatocellular carcinoma.AJR,1999,172(1):67-71.
[32]Ito K,Honjo K,Fujita T,et al.Therapeutic efficacy of transcatheter arterial chemoembolization for hepatocellular carcinoma:MRI and pathology.J Comput Assist Tomogr,1995,19(2):198-203.
[33]Hsu HC,Wei TC,Tasang YM,et al.Histologic assessment of resected hepatocellular carcinoma after transcatheter hepatic carterial embolization.Cancer,1986,57(6):1184-1191.
[34]Yong-Song Guan,Long Sun,Xiang-Ping Zhou,et al.Hepatocellular carcinoma treated with interventional procedures:CT and MRI follow-up.World J Gastroenterol,2004,10(24):3543-3548.
[35]Yah FH,Zhou KR,Cheng JM,et al.Role and limitation of FMPSP dynamic contrast scanning in the follow-up of patients with hepatocellcar carcinoma treated by TACE.World J Gastroenterol,2002,8(4):658-662.
[36]Murakami T,Nakamura H,Hori S,et al.Detection of viable tumor cells in hepatocellular carcinoma following transcatheter arterial chemoembolization with Iodized Oil:Pathologic correlation with dynamic turbo-FLASH MR imaging with Gd-DTPA.Acta Radiologica,1993,34(4):399-403.
[37]Castrucci M,Sironi S,De Cobelli F,et al.Plain and gadolinium-DTPA-enhanced MR imaging of hepatocellular carcinoma treated with transarterial chemoembolization.Abdominal Imaging,1996,21(6):488-494.
[38]Kubota K,Hisa N,Nishikawa T,et al.Evaluation of hepatocellular carcinoma after treatment with transcatheter arterial chemoembolization:comparison of Lipiodol-CT,power Doppler sonography,and dynamic MRI.Abdom Imaging,2001,26(2):184-190.
[39]Murakami T,Nakamura H,Tsuda K,et al.Treatment ofhepatocellular carcinoma by chemoembolization:Evaluation with 3DFT MR imaging.AJR,1993,160(2):295-299.
[40]Numata K,Tanaka K,Kiba T,et al.Using contrast-enhanced sonography to assess the effectiveness of transcatheter arterial embolization for hepatocellular carcinoma.AJR,2001,176(5):1199-1205.
[41]Murakami T,KimT,NakamuraH.Hepatitis,cirrhosis,and hepatoma.J Magn Resort Imaging,1998,8(2):346-368.
[42]潘平,刘爱连,宋清伟等.动态增强磁共振在评价肝细胞癌微血管密度中的意义.中国医学计算机成像杂志,2001,7(5):326-330.
[43]Hanahan D,Folkman J.Patterns and emerging mechanisms of the an-giogenic switch during tumorigenesis.Cell,1996,86(3):353-364.
[44]Suzuki K,Hayashi N,Miyamoto Y,et al.Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma.Cancer Res,1996,56(13):3004-3009.
[45]Park YN,Kim YB,Yang KM,et al.Increased expression of vascular endothelial growth factor and angiogenesis in early stage of multistep hepatocarcinogenesis.Arch Pathol Lab Med,2000,124(7):1061-1065.
[46]Semela D,Dufour JF.Angiogenesis and hepatocellular carcinoma.J Hepato,2004,41(5):864-880.
[47]Miles KA.Functional computed tomography in oncology.Eurn J Cancer,2002,38(16):2079-2084.
[48]史丽静,田建明,王培军等.多层螺旋计算机X线体层扫描肝脏灌注成像的临床应用初步研究.中华肝脏病杂志,2003,11(9):522-525.
[49]葛英辉,谢晓东,宋彬等.肝脏螺旋CT血管造影一动脉系统三维成像初探.胃肠病学和肝病学杂志,1999,8(1):40-43.
[50]Tsushima Y,Unno Y,Koizumi J,et al.Hepatic perfusion change after transcatheter arterial emlolization(TAE) of hepatocellular carcinoma measurement by dynamic computed tomography.Dig Dis Sci,1998,43(2):317-322.
[51].Ichikawa T,Haradome H,Hachiya J,et al.Characterization of hepatic lesions by perfusion-weightedMR imagingwith echoplanar sequence.Am J Roentgenol,1998,170(4):1029-1034.
[52]Villringer A,Rosen BR,Belliveau JW,et al.Dynamic imaging with lanthanide chelates in normal brain:contrast due to magnetic susceptibility effects.Magn Reson Med,1988,6(2):164-174.
[53]Chan JH,Tsui EY,Luk SH,et al.Detection of hepatic tumor perfusion following transcatheter arterial chemoembolization with dynamic susceptibility contrast-enhanced echoplanar imaging.Clin Imaging, 1999,23(3):190-194.
[54]Guan S, Zhao WD, Zhou KR, et al.Assessment of hemodynamics in precancerous lesion of hepatocellular carcinoma: evaluation with MR perfusion.World J Gastroenterol, 2007, 13(8): 1182-1186.
[55]Materne R, Smith AM, Peeters F, et al.Assessment of hepatic perfusion parameters with dynamic MRI.Magn Reson Med, 2002,47(1): 135-142.
[56]Scharf J, Zapletal C, Hess T, et al.Assessment of hepatic perfusion in pigs by pharmacokinetic analysis of dynamic MR images.J Magn Reson Imaging, 1999,9(4): 568-572.
[57]Zhao JG, Feng GS, Kong et al.Changes of tumor microcirculation after transcatheter arterial chemoembolization: first pass perfusion MR imaging and Chinese ink casting in a rabbit model.World J Gastroenterol, 2004,10(10): 1415-1420.
[58]Kamel IR, Bluemke DA, Eng J, et al.The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma.J Vasc Interv Radiol, 2006,17(3):505-512.
[59]Li W, Brophy DP, Chen Q, et al.Semiquantitative assessment of uterine perfusion using first pass dynamic contrast-enhanced MR imaging for patients treated with uterine fibroid embolization.J Magn Reson Imaging, 2000,12(6): 1004-1008.
[60]Pandharipande PV, Krinsky GA, Rusinek H, et al.Perfusion imaging of the liver current challenges and future goals.Radiology, 2005,234(3):66l-673.
[61]Ostergaard L.Principles of cerebral perfusion imaging by bolus tracking.J Magn Reson Imaging, 2005, 22(6): 710-717.
[62]Mateme R, Smith AM, Peeters F, et al.Assessment of hepatic perfusion parameters with dynamic MRI.Magn Reson Med,2002,47(1): 135-142.
[63]el-Khalily H,Hoeffken H,yon Wichert P,et al.Hepatic perfusion scintigraphy.Relationship of liver perfasion and ascites in patients with liver cirrhosis.Clin Nuel Med,1996,21(2):132-135.
[64]Ichikawa T, Araki T.Fast magnetic resonance imaging of liver.Eur J Radiol, 1999, 29(3): 186-210.
[65]Shimizu A, Ito K, Koike S, et al.Cirrhosis or chronic hepatitis evaluation of small( [66]Yoshioka H, Takahashi N, Yamaguchi M,et al.Double arterial phase dynamic MRI with sensitivity encoding(SENSE)for hyper-vascular hepatocellular carcinomas.J Magn Reson Imaging,2002,16(2):259-266.
[67]Bipat S, van Leeuwen MS, Ijzermans JN,et al.Imaging and treatment of patients with colorectal liver metastases in the Netherlands: a survey.Neth J Med,2006,64(5): 147-151.
[68]Totman JJ, O'Gorman RL, Kane PA, et al.Comparison of the hpatic perfusion index measured with gadolinium-enhanced volumeric MRI in controls and in patients withcolorectal cancer.BrRadiol,2005,78(926):105-109.
[69]Tsui EY, Chan JH, Cheung YK, et al.Evaluation of therapeutic effectiveness of transarterial chemoembolization for hepatocellular carcinoma:correlation of dynamic susceptibility contrast-enhanced echoplanar imaging and hepatic angiography.Journal of Clinical Imaging, 2000, 24(4):210-216.
[70]Murtz P, Flacke S, Traber F, et al.Abdomen: diffusion-weighted MR imaging with pulse triggered single-shot sequences.Radiology, 2002; 224(1): 258-264.
[71]Chow LC, Bammer R, Moseley ME, et al.Single breathhold diffusion-weighted imaging of the abdomen.J Magn Reson Imaging, 2003, 18(3): 377-382.
[72]Chenevert TL, Meyer CR, Moffat BA, et al.Diffusion MRI: a new strategy for assessment of cancer therapeutic efficacy.Molecular Imaging, 2002,l(4):336-343.
[73]Kamel IR, Bluemke DA, Ramsey D, et al.Role of diffusion-weighted imaging inestimating tumor necrosis after chemoembolization of hepatocellular carcinoma.Am J Roentgenol, 2003, 181(3): 708-710.
[74]Geschwind JF, Artemov D, Abraham S, et al.Chemoembolization of liver tumor in a rabbit model: assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis.Journal of Vascular and Interventional Radiology.2000,11(10):1245-255.
[75]Herneth AM,GuccioneS,Bednarski M.Apparent diffusion coefficient:a quantitative parameter for in vivo tumor characterization.Eur J Radiol,2003,45(3):208-213.
[76]尚全良,肖恩华,贺忠等.肝癌经导管动脉灌注化疗栓塞术疗效的MR扩散加权成像动态研究.中华放射学杂志,2006,40(3):235-240.
[2]Yoshioka H,Nakagawa K,Shindou H,et al.MR imaging of the liver before and after transcatheter hepatic chemo-embolization for hepatocellular carcinoma.Acta Radiologica, 1990, 31(1):63-67.
[3]Hsu HC, Wei TC, Tasang YM, et al.Histologic assessment of resected hepatocellular carcinoma after transcatheter hepatic carterial embolization.Cancer, 1986,57(6): 1184-1191.
[4]Yan FH, Zhou KR, Cheng JM, et al.Role andl imitation of FMPSP dynamic contrast scanning in the follow-up of patients with hepatocellcar carcinoma treated by TACE.World J Gastroenterol, 2002,8(4):658-662.
[5]Murakami T, Nakamura H, Tsuda K, et al.Treatment of hepatocellular carcinoma by chemoembolization: Evaluation with 3DFT MR imaging.AJR,1993,160(2):295-299.
[6]Numata K, Tanaka K, Kiba T, et al.Using contrast-enhanced sonography to assess the effectiveness of transcatheter arterial embolization for hepatocellular carcinoma.AJR, 2001,176(5): 1199-1205.
[7]Ippolito D, Sironi S, Pozzi M et al.Perfusion computed tomographic assessment of early hepatocellular carcinoma in cirrhotic liver disease: initial observations.J Comput Assist Tomogr, 2008;32(6):855-858.
[8]Kobayashi T, Hayashi T, Funabasama S et al.Three-dimensional perfusion imaging of hepatocellular carcinoma using 256-slice multidetector-row computed tomography.Radiat Med, 2008;26(9):557-561.
[9]Chen G, Ma DQ, He W, et al.Computed tomography perfusion in evaluating the therapeutic effect of transarterial chemoembolization for hepatocellular carcinoma.World J Gastroenterol, 2008;14(37):5738-5743
[10]Tsushima Y, Unno Y, Koizumi J, et al.Hepatic perfusion change after transcatheter arterial emlolization (TAE) of hepatocellular carcinoma measurement by dynamic computed tomography.Dig Dis Sci,1998, 43(2):317-322.
[11]Ito K, Honjo K, Fujita T, et al.Therapeutic efficacy of transcatheter arterial hemoembolization for hepatocellular carcinoma: MRI and pathology.Comput AssistTomogr, 1995, 19(2): 198-203.
[12]Svagzdys S, Lesauskaite V, Pavalkis D,et al.Microvessel density as a new prognostic marker after radiotherapy in rectal cancer.BMC Cancer, 2009,9(1):95-120
[13]White MJ, O'Gorman RL, Charles-Edwards EM,et al.Parametric mapping of the hepatic perfusion index with gadolinium-enhanced volumetric MRI.British Journal of Radiology, 2007,80(950): 113-120
[14]Ichikawa T, Haradome H, Hachiya J, et al.Characterization of hepatic lesions by perfusion-weighted MR imaging with echoplanar sequence.AmJ Roentgenol, 1998,170(4):1029-1034.
[15]Chan JH, Tsui EY, Luk SH,et al.Detection of hepatic tumor perfusion following transcatheter arterial chemoembolization with dynamic susceptibility contrast-enhanced echoplanar imaging.Clin Imaging, 1999, 23(3):190-194.
[16]Tsui EY, Chan JH, Cheung YK,et al.Evaluation of therapeutic effectiveness of transarterial chemoembolization for hepatocellular carcinoma: correlation of dynamic susceptibility contrast-enhanced echoplanar imaging and hepatic angiography.Journal of Clinical Imaging, 2000, 24(4):210-216.
[17]Herneth AM, GuccioneS, Bednarski M.Apparent diffusion coefficient: a quantitative parameter for in vivo tumor characterization.Eur J Radiol,2003,45(3):208-213.
[18]Kamel IR, Bluemke DA, Ramsey D, et al.Role of diffusion-weighted imaging in estimating tumor necrosis after chemoembolization of hepatocellular carcinoma.Am J Roentgenol, 2003, 181(3): 708-710.
[19]Kamel IR, Liapi E, Reyes DK, et al.Unresectable hepatocellular carcinoma: serial early vascular and cellular changes after transarterial chemoembolization as detected with MR imaging.Radiology, 2009,250(2):324-326.
[20]Okada M, Kudo S, Miyazaki 0,et al.Antitumoral efficacy and pharmacokinetic properties of pirarubicn upon hepatic intra-arterial injection in the rabbit VX2 tumor model.Br J Cancer, 1995, 71 (3):518-524.
[21]Ramirez LH, Julieron M, Bonnay M, et al.Stimulation of tumor growth in vitro and in vivo by suramin on the VX2 model.Invest New Drugs,1995,13(1):51-53.
[22]Geschwind JF,Artemov D,Abraham S,et al.Chemoembolization of liver tumor in a rabbit model:assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis.J Vasc Interv Radiol,2000,11(10):1245-1255.
[23]Lee KH,Liapi E,Buijs M et al.Considerations for implantation site of VX2carcinoma into rabbit liver.J Vasc Interv Radiol,2009;20(1):113-117.
[24]Prat F,Centarti M,Sibille A,et al.Extracorporea high-intensity focused ultrasound for VX2 liver tumors in the rabbit.Hepatology,1995,21(3):832-836.
[25]王晓东,任军,杨仁杰等.VX2活细胞数与兔肝癌模型成功率及成瘤时间的关系.现代肿瘤医学,2005,13(5):589-591.
[26]吴文娟,崔慧先,李海涛等.兔VX2肝癌模型的建立及超声观察.中华超声影像学杂志,2005,14(2):147-150
[27]曹玮,王执民,张洪新等.兔VX2肝癌模型的移植方式及生长特性的研究.实用放射学杂志,2003,19(2),97-99
[1]Colagrande S,Politi LS,Messerini L,et al.Solitary necrotic nodule of the liver:imaging and correlation with pathologic features.Abdom Imaging,2003,28(1):41-44.
[2]Murtz P,Flacke S,Traber F,et al.Abdomen:diffusion-weighted MR imaging with pulse triggered single-shot sequences.Radiology,2002,224(1):258-264.
[3]Chow LC,Bammer R,Moseley ME,et al.Single breathhold diffusion-weighted imaging of the abdomen.J Magn Reson Imaging,2003,18(3):377-382.
[4]Willatt JM,Hussain HK,Adusumilli S et al.MR Imaging of hepatocellular carcinoma in the cirrhotic liver:challenges and controversies.Radiology,2008,247(2):311-330.
[5]Lim JH,Kim CK,Lee WJ,et al.Detection of hepatocellular carcinomas and dysplastic nodules in cirrhotic livers:accuracy of helical CT in transplant patients.AJR Am J Roentgenol,2000,175(3):693-698.
[6]Semelka RC, Cance WQ Marcos HB, et al.Liver metastases: comparison of current MR techniques and spiral CT during arterial portography for detection in 20 surgically staged cases.Radiology, 1999,213(1 ):86—91.
[7]Krinsky GA, Lee VS, Theise ND, et al.Hepatocellular carcinoma and dysplastic nodules in patients with cirrhosis: prospective diagnosis with MR imaging and explanation correlation.Radiology, 2001, 219(2):445-454.
[1]Weidner N.Intratumor microvessel density as a prognostic factor in cancer.Am J Pathol,1995,147(1):9-19.
[2]Cha C,DeMatteo RP,Blumgart LH,et al.Surgery and ablative therapy for hepatocellular carcinoma.J Clin Gastroenterol,2002,35(5 Suppl 2):130-137.
[3]Tang ZY.Hepatocellular carcinoma-cause,treatment and metastasis.World J Gastroenterol,2001,7(4):445-454.
[4]Sturm JW,Keese MA,Bonninghoff RG,et al.Locally ablative therapies of hepatocellular carcinoma.Onkologie,2001,24(Suppl 5):35-45.
[5]Kinji I.Effect of repeated transcatheter arterial emolization on the survival time in patients with hepatocellular carcinoma.Cancer,1991,68(10):2150-2154.
[6]田建明,贾雨辰,张韵,等.肝动脉闭塞后的侧支循环通路的分析.中华放射学杂志,1992,26(5):344-346.
[7]Furui S,Otomo K,ltai Y,et al.Hepatocellular carcinoma treated by transcatheter arterial embolization:progress evaluated by computed tomography.Radiology,1984,150(3):773-778.
[8]Konno T.Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium.Cancer,1990,66(9):1897-1903.
[9]Hatanaka Y,Yamashits Y,Takahashi M,et al.Unresectable hepatocellular carcinoma:analysis of prognostic factors in tran-scatheter management.Radiology,1995,195(3):747-752.
[10]王瑛,王武.肝癌栓塞治疗前后彩色多普勒超声与血管造影对照观察疗效的研究.中国超声医学杂志,2000,16(1):15-18.
[11]Yoshioka H,Nakagawa K,Shindou H,et al.MR imaging of the liver before and after transcatheter hepatic chemoembolization for hepatocellular carcinoma.Acta Radiologica,1990,31(1):63-67.
[12]Honda H,Tajima T,Kajiyama K,et al.Vascular changes in hepatocellular carcinoma:correlation of radiologic and pathologic findings.AJR,1999,173(5):1213-1217.
[13]Barinaga M.Designing therapies that target tumor blood vessels.Science.1997,275(5299):482-484..
[14]Folkman J, Tumor rangiogenesis: therapeutic implication.N Engl J Med, 1971, 285(21):1182-1186.
[15]Luiten RM, Fleuren GJ, Warnaar SO, et al.Target-specific activation of mastcells by immunoglobulin E reactive with a renal cell carcinoma-Associated antigen.Lab Invest, 1996,74(2):467-475.
[16]Potgens AJ, Westphal HR,de waal RM, et al.The role of vascular Permeability factor and basic fibroblast growth factor in tumorangiogenesis.Biol Chem Hoppe Seyler,1995,376(2):57-70.
[17]Tseng PL, Tai MH, Huang CC, et al.Over expression of VEGF is associated with positive p53 immunostaining in hepatocellular carcinoma (HCC) and adverse outcome of HCC patients.Surg Oncol, 2008, 98(5):349-357J
[18]Li YJ, Wen G, Wang Q.Expression of vascular endothelial growth factor and its receptor Flk-1/KDR in benign and malignant breast neoplasms.Nan Fang Yi Ke Da Xue Xue Bao,2009,29(1):70-71
[19]Takahashi Y,Tucker SL,Kitadai Y,et al.Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer.Arch Surg, 1997,132(5): 541-546.
[20]Appleton MA, Attanoos RL, Jasani B.Thrombomodulin as a marker of vascular and lymphatic tumours.Histopathology, 1996,29(2): 153-157.
[21]Kimura H, Nakajima T, Kagawa K, et al.Angiogenesis in hepatocellular carcinoma as evaluated by CD34 immunohistochemistry.Liver, 1998,18(1): 14-19.
[22]Oxboel J, Binderup T, Knigge U, et al.Quantitative gene-expression of the tumor angiogenesis markers vascular endothelial growth factor, integrin alphaV and integrin beta3 in human neuroendocrine tumors.Oncol Rep.2009,21(3):769-775.
[23]Jain PK.Determinants of tumor blood flow: a review.Cancer Res,1988,48(10): 2641-2658.
[24]Lu JP, Wang J, Wang T, et al.Microvessel density of malignant and benign hepatic lesions and MRI evaluation.World J Gastroenterol,2004,10(12):1730-1734.
[25]Piao YF,He M,Shi Y,et al.Relationship between microvessel density and telomerase activity in hepatocellular carcinoma.World J Gastroenterol,2004,10(14):2147-2149.
[26]Pooh RT,Ng IO,Lau C,et al.Tumor microvessel density as a padictor of recurrnce after resection of hepatocellular carcinoma a prospective study.J Clin Oncol,2002,20(7) 1775-1785.
[27]Svagzdys S,Lesauskaite V,Pavalkis D,et a.Microvessel density as a new prognostic marker after radiotherapy in rectal cancer.BMC Cancer,2009,9(1):95-120.
[28]Tanigawa N,Lu C,MitsuiT,et al.Quantitation of sinusoid like vessels in hepatocellular carcinoma its clinical and prognostic significance.Hepatology,1997,26(5):1212-1216.
[29]陈永杰,付艳忠,赵志华等.原发性肝癌组织中血管内皮生长因子、微血管密度检测.郑州大学学报(医学版),2007,42(5):925-927.
[30]Brasch R,Pham C,Shames D,et al.Assessing tumor angiogenesis using macromolecular MR imaging contrast media.J Magn Resort Imaging,1997,7(1):68-74.
[31]陈雁,周纯武,刘玉清.肿瘤微血管生成和肺癌及其影像学的联系.中国医学影像技术,2000,16(10):913-915.
[32]向昕,刘志伟,顾万清等.TAE后肝癌微血管密度及VEGF表达与再手术治疗研究.肝胆外科杂志,2004,12(1):24-27.
[33]孙卫东,何维新,任普海.经导管肝动脉化疗栓塞后肝癌微血管密度、血管内皮生长因子表达的变化,现代实用医学,2007;19(7):547-548.
[34]林小军,张昌卿,张亚奇等.单纯切除与介入治疗后原发性肝癌肿瘤微血管密度变化研究.癌症,2000,19(10):919-922.
[35]Goldberg SN,Ahmed M.Minimally invasive image-guided therapies for hepatocellular carcinoma.J Clin Gastroenterol,2002;35[5 suppl2]:115-129.
[36]Ito K,Honjo K,Fujita T,et al.Therapeutic efficacy of transcatheter arterial chemoembolization for hepatocellular carcinoma:MRI and pathology.J Comput Assist Tomogr,1995,19(2):198-203.
[37]Hsu HC,Wei TC,Tasang YM,et al.Histologic assessment of resected hepatocellular carcinoma after transcatheter hepatic carteriai embolization.Cancer,1986,57(6):1184-1191.
[38]李洪林,罗斗强,石木兰.MRI对评价肝癌Lp-TACE治疗的价值.临床放射学杂志,2000,19(10):629-631.
[39]Yah FH,Zhou KR,Cheng JM,et al.Role and limitation of FMPSP dynamic contrast scanning in the follow-up of patients with hepatocellcar carcinoma treated by TACE.World J Gastroenterol,2002,8(4):658-662.
[40]Murakami T,Nakamura H,Hori S,et al.Detection of viable tumor cells in hepatocellula rcarcinoma following transcatheter arterial chemoembolization with Iodized Oil:Pathologic correlation with dynamic turbo-FLASH MR imaging with Gd-DT-PA.Acta Radiologica,1993,34(4):399-403.
[41]Castrucci M,Sironi S,De Cobelli F,et al.Plain and gadolinium-DTPA-enhanced MR imaging of hepatocellular carcinoma treated with transarterial chemoembolization.Abdominal Imaging,1996,21(6):488-494.
[42]Kubota K,Hisa N,Nishikawa T,et al.Evaluation of hepatoceilular carcinoma after treatment with transcatheter arterial chemoembolization:comparison of Lipiodol-CT,power Doppler sonography,and dynamic MRI.Abdom Imaging,2001;26(2):184-190.
[43]Murakami T,Nakamura H,Tsuda K,et al.Treatment of hepatocellular carcinoma by chemoembolization:Evaluation with 3DFT MR imaging.AJR,1993,160(2):295-299.
[44]Numata K,Tanaka K,Kiba T,et al.Using contrast-enhanced sonography to assess the effectiveness of transcatheter arterial embolization for hepatocellular carcinoma.AJR,2001,176(5):1199-1205.
[45]Murakami T,KimT,Nakamura H.Hepatitis,cirrhosis,and hepatoma.J Magn Reson Imaging,1998,8(2):346-358.
[46]潘平,刘爱连,宋清伟等.动态增强磁共振在评价肝细胞癌微血管密度中的意义.中国医学计算机成像杂志,2001,7(5)326-330.
[47]Chenevert TL,Meyer CR,Moffat BA,et al.Diffusion MRI:a new strategy for assessment of cancer therapeutic efficacy.Molecular Imaging,2002,1(4):336-343.
[48]Hanahan D,Folkman J.Patterns and emergingmechanisms of the an- giogenic switch during tumorigenesis.Cell,1996,86(3):353-364.
[49]Park YN,Kim YB,Yang KM,et al.Increased expression of vascular endothelial growth factor and angiogenesis in early stage of multistep hepatocarcinogenesis.Arch Pathol Lab Med,2000,124(7):1061-1065.
[50]Vossen JA,Kamel IR,Buijs M et al.Role of functional magnetic resonance imaging in assessing metastatic leiomyosarcoma response to chemoembolization.J Comput Assist Tomogr,2008,32(3):347-352.
[51]Kamel IR,Bluemke DA,Ramsey D,et al.Role of diffusion-weighted imaging inestimating tumor necrosis after chemoembolization of hepatocellular carcinoma.Am J Roentgenol,2003,181(3):708-710.
[52]Geschwind JF,Artemov D,Abraham S,et al.Chemoembolization of liver tumor in a rabbit model:assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis.Journal of Vascular and Interventional Radiology,2000,11(10):1245-255.
[53]Herneth AM,Guccione S,Bednarski M.Apparent diffusion coefficient:a quantitative parameter for in vivo tumor characterization.Eur J Radiol,2003,45(3):208-213.
[54]尚全良,肖恩华,贺忠等.肝癌经导管动脉灌注化疗栓塞术疗效的MR扩散加权成像动态研究.中华放射学志,2006,40(3):235-240.
[55]Kamel IR,Liapi E,Reyes DK,et al.Unresectable hepatocellular carcinoma:serial early vascular and cellular changes after transarterial chemoembolization as detected with MR imaging.Radiology,2009,250(2):324-326.
[56]Suzuki K,Hayashi N,Miyamoto Y,et al.Expression of vascular permeability factor/vascular endothelial growth factor in humanhepatocellular carcinoma.Cancer Res,1996,56(13):3004-3009.
[57]Semela D,Dufour JF.Angiogenesis and hepatocellular carcinoma.J Hepatol,2004,41(5):864-880.
[58]Miles KA.Functional computed tomography in oncology.EurnJ Cancer,2002,38(16):2079-2084.
[59]Ippolito D,Sironi S,Pozzi Met al.Perfusion computed tomographic assessment of early hepatocellular carcinoma in cirrhotic liver disease:initial observations.J Comput Assist tomogr,2008,32(6):855-858.
[60]Kobayashi T,Hayashi T,Funabasama S et al.Three-dimensional perfusion imaging of hepatocellular carcinoma using 256-slice multidetector-row computed tomography.Radiat Med,2008,26(9):557-561.
[61]Chert G,Ma DQ,He W,et al.Computed tomography perfusion in evaluating the therapeutic effect of transarterial chemoembolization for hepatocellular carcinoma.World J Gastroenterol,2008,14(37):5738-5743.
[62]史丽静,田建明,王培军等.多层螺旋计算机X线体层扫描肝脏灌注成像的临床应用初步研究.中华肝脏病杂志,2003,11(9):522-525.
[63]葛英辉,谢晓东,宋彬等.肝脏螺旋CT血管造影一动脉系统三维成像初探.胃肠病学和肝病学杂志,1999,8(1):40-43.
[64]Tsushima Y,Unno Y,Koizumi J,et al.Hepatic perfusion change after transcatheter arterial emlolization(TAE) of hepatocellular carcinoma measurement by dynamic computed tomography.Dig Dis Sci,1998,43(2):317-322.
[65]Ichikawa T,Haradome H,Hachiya J,et al.Characterization of hepatic lesions by perfusion-weighted MR imaging with echoplanar sequence.Am J Roentgenol,1998, 170(4): 1029-1034
[66]Villringer A, Rosen BR, Beiliveau JW, et al.Dynamic imaging with lanthanide chelates in normal brainxontrast due to magnetic susceptibility effects.Magn Reson Med, 1988,6(2): 164-174.
[67]Chan JH, Tsui EY, Luk SH,et al.Detection of hepatic tumor perfusion following transcatheter arterial chemoembolization with dynamic susceptibility contrast-enhanced echoplanar imaging.Clin Imaging, 1999, 23(3): 190-194.
[68]Guan S, Zhao WD, Zhou KR, et al.Assessment of hemodynamics in precancerous lesion of hepatocellular carcinoma: evaluation with MR perfusion.World J Gastroenterol, 2007,13(8): 1182-1186.
[69]Materne R, Smith AM, Peeters F, et al.Assessment of hepatic perfusion parameters with dynamic MRI.Magn Reson Med, 2002,47(1): 135-142.
[70]Scharf J, Zapletal C, Hess T, et al.Assessment of hepatic perfusion in pigs by pharmacokinetic analysis of dynamic MR images.J Magn Reson Imaging, 1999,9(4):568-572.
[71]Zhao JG, Feng GS, Kong XQ, et al.Changes of tumor microcirculation after transcatheter arterial chemoembolization: first pass perfusion MR imaging andChinese ink casting in a rabbit model.World J Gastroenterol, 2004,10(10): 1415-1420.
[72]Kamel IR, Bluemke DA, Eng J, et al.The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma.J Vasc Interv Radiol, 2006,17(3):505—512.
[73]Li W, Brophy DP, Chen Q, et al.Semiquantitative assessment of uterine perfusion using first pass dynamic contrast-enhanced MR imaging for patients treated withuterine fibroid embolization.J Magn Reson Imaging, 2000,12(6): 1004-1008.
[74]Pandharipande PV, Krinsky GA, Rusinek H,et al.Perfusion imaging of the liver current challenges and future goals.Radiology,2005,234(3):661-673.
[75]Ostergaard L.Principles of cerebral perfusion imaging by bolus tracking.J Magn Reson Imaging,2005,22(6):710-717.
[76]el-Khalily H,Hoeffken H,yon Wichert P,et al.Hepatic perfusion scintigraphy.Relationship of liver perfusion and ascites in patients with liver cirrhosis.Clin Nuel Med,1996,21(2):132-135.
[77]Yoshioka H,Takahashi N,Yamaguchi M,et al.Double arterial phase dynamic MRI with sensitivity encoding(SENSE) for hyper-vascular hepatocellular carcinomas.J Magn Reson Imaging,2002,16(2):259-266.
[78]Bipat S,van Leeuwen MS,Ijzermans JN,et al.Imaging and treatment of patients with colorectal liver metastases in the Netherlands:a survey.Neth J Med,2006,64(5):147-151.
[79]Totman JJ,O'Gorman RL,Kane PA,et al.Comparison of the hepatic perfusion index measured with gadolinium-enhanced volumeric MRI in controls and in patients with colorectal cancer.BrRadiol,2005,78(926):105-109.
[80]Wang J,Zhang Y,Wolf RL,et al.Amplitude-modulated continuous arterial spin-labeling 3.0-T perfusion MR imaging with a single coil:feasibility study.Radiology,2005,235(1):218-228.
[81]Taouli B,Losada M,Holland A,et al.Magnetic resonance imaging of hepatocellular carcinoma.Gastroenterology,2004,127(5 Suppl 1):S144-152.
[82]连海英.磁共振灌注成像在肝硬化的临床应用.国外医学临床放射学分册.2006,29(1):36-39.
[83]White MJ,O'Gorman RL,Charles-Edwards EM,et al.Parametric mapping of the hepatic perfusion index with gadolinium-enhanced volumetric MRI.British Journal of Radiology,2007,80(950):113-120
[84]Breedis C,Young G.The blood supply of neoplasms in the liver.Am J Pathol.1954;30(5):969-977.
[85]Blomley M J,Coulden R,Dawson P,et al.Liver perfusion studied with Ultrafast CT.J Comput Assisted Tomogr,1995,19(3):424-433.
[86]Leggett DA, Kelley BB, Bunce IH, et al.Colorectal cancer: diagnostic potential of CT measurements of hepatic perfusion and implications for contrast enhancement protocols.Radiology, 1997,205(3):716-720.
[87]Harvey CJ, Blomley MJ, Eckersley RJ, et al.Developments in ultrasound media.Eur Radiol, 2001,11 (4):675-689
[88]Miles KA, Hayball MP, Dixon AK.Functional images of hepatic perfusion obtained with dynamic CT.Radiology, 1993,188(2):405-41 1.
[89]Tsushima Y, Blomley MJ, Kusano S, et al.Measuring portal venous perfusion with contrast- enhanced CT: comparison of direct and indirect methods.Acad Radiol.2002; 9(3):276-282.
[90]Cha S, Knopp EA, Johnson G, et al.Intracranial mass lesion: Dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging.Radiology, 2002, 223(1): 11-29.
[91]Sugahara T, Korogi Y, Kochi M, et al.Perfusion-sensitive MR imaging of gliomas: comparison between gradient-echo and spin-echo echo-planar imaging techniques.ANJR Am J Neumradiol, 2001, 22(7): 1306-1315.
[92]Tian JL,Zhang JS.Hepatic perfusion disorders: etiopathogenesis and related diseases.World J Gastroenterol,2006,12(20):3265-3270.
[93]Bhartia B,Ward J,Guthrie JA,et al.Hepatocellular carcinoma in cirrhotic livers double-contrast thin-section MR imaging with pathologic correlation of explanted tissue.AJR,2003,180(3):577-584.
[94]Peeters F, Annet L, Hermoye L, et al.Inflow correction of hepatic pefusion measurements using Tl-weighted, fast gradient-echo, contrast-enhanced MRI.Magn Reson Med, 2004, 51(4): 710-717.
[95]Yang ZH, Ye XH, Tan Y, et al.Evaluation of cirrhotic liver with perfusion-weighted magnetic resonance imaging: a preliminary experimental study in animal models with half-liver cirrhosis.Chin Med Sci J, 2006,21(4):252-257.
[96]张皓,顾爱华,缪竞陶等.晚期肝硬化肝脏MR灌注成像的灌注量化分析.放射学实践,2006,21(12)1236-1239.
[97]Shimizu A,ItoK,Koike S,et al.Cirrhosis or chronic hepatitis evaluation of small (＜or=2cm) early-enhancing hepatic lesions with serial contrast-enhanced dynamic MR imaging.Radiology,2003,226(2):550-555.
[98]Bipat S,van Leeuwen MS,Ijzermans JN,et al.lmaging and treatment of patients with colorectal liver metastases in the Netherlands a survey.Neth J Med,2006,64(5):147-151.
[99]Totman JJ,O'gorman RL,Kane PA,et al.Comparison of the hepatic perfusion index measured with gadolinium-enhanced volumetric MRI incontrols and in patients with colorectal cancer.British Journal of Radiology,2005,78(926):105-109.
[100]Kutara K,Asano K,Kito A,et al.Contrast harmonic imaging of canine hepatic tumors.J Vet Med Sci,2006,68(5):433-438.
[101]张铁宁,张皓,缪竟陶等.MR灌注成像在肝脏常见占位性病变诊断及鉴别诊断中的价值初探.中国医学影像技术,2006,22(12):1849-1852.
[102]Tsui EY,Chan JH,Cheung YK,et al.Evaluation of therapeutic effectiveness of transarterial chemoembolization for hepatocellular carcinoma:correlation of dynamic susceptibility contrast-enhanced echoplanar imaging and hepatic angiography.Journal of Clinical Imaging,2000,24(4):210-216.
[103]Ichikawa T,Araki T.Fast magnetic resonance imaging of liver.Eur J Radiol,1999,29(3):186-210.
[1]Cha C,DeMatteo RP,Blumgart LH,et al.Surgery and ablative therapy for hepatocellular carcinoma.J Clin Gastroenteroi,2002,35(5 Suppl 2):130-137.
[2]Tang ZY.Hepatocellular carcinoma-cause,treatment and metastasis.World J Gastroenterol,2001,7(4):445-454.
[3]Sturm JW,KeeseMA,Bonninghoff RG,et al.Locally ablative therapies of hepatocellular carcinoma.Onkologie,2001,24(Suppl 5):35-45.
[4]田建明,贾雨辰,张韵,等.肝动脉闭塞后的侧支循环通路的分析.中华放射学杂志,1992,26(5):344-346.
[5]Kinji I.Effect of repeated transcatheter arterial emolization on the survival time in patients with hepatocellular carcinoma.Cancer,1991,68(10):2150-2154.
[6]Furui S,Otomo K,Itai Y,et al.Hepatocellular carcinoma treated by transcatheter arterial embolization:progress evaluated by computed tomography.Radiology,1984,150(3):773-778.
[7]Konno T.Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium.Cancer,1990,66(9):1897-1903.
[8]Hatanaka Y,Yamashits Y,Takahashi M,et al.Unresectable hepatocellular carcinoma:analysis of prognostic factors in tran-scatheter management.Radiology,1995,195(3):747-752.
[9]王瑛,王武.肝癌栓塞治疗前后彩色多普勒超声与血管造影对照观察疗效的研究.中国超声医学杂志,2000,16(1):15-18.
[10]Yoshioka H,Nakagawa K,Shindou H,et al.MR imaging of the liver before and after transcatheter hepatic chemoembolization for hepatocellular carcinoma.Acta Radiologica,1990,31(1):63-67.
[11]Honda H,Tajima T,Kajiyama K,et al.Vascular changes in hepatocellular carcinoma:correlation of radiologic and pathologic findings.AJR,1999,173(5):1213-1217.
[12]Barinaga M.Designing therapies that target tumor blood vessels.Science.1997, 275(5299): 482-484.
[13]Folkman J, Tumor rangiogenesis: therapeutic implication.N Engl J Med, 1971, 285(21):1182-1186.
[14]Luiten RM, Fleuren GJ, Warnaar SO, et al.Target-specific activation of mastcells by immunoglobulin E reactive with a renal cell carcinoma-associated antigen.Lab Invest, 1996,74(2):467-475.
[15]Potgens AJ, Westphal HR,de waal RM, et al.The role of vascular permeability factor and basic fibroblast growth factor in tumor angiogenesis.Biol Chem Hoppe Seyler,1995,376(2):57-70.
[16]Takahashi Y,Tucker SL,Kitadai Y,et al.Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer.Arch Surg, 1997,132(5): 541-546.
[17]Appleton MA, Attanoos RL, Jasani B.Thrombomodulin as amarker of vascular and lymphatic tumours.Histopathology, 1996,29(2): 153-157.
[18]Kimura H, Nakajima T, Kagawa K,et al.Angiogenesis in hepatocellular carcinoma as evaluated by CD34 immunohistochemistry.Liver, 1998,18(1):14-19.
[19]Jain PK.Determinants of tumor blood flow: a review.Cancer Res, 1988,48(10): 2641-2658.
[20]Lu JP, Wang J, W ang T, et al.Microvessel density of malignant and benign hepatic lesions and MRI evaluation.World J Gastroenterol.2004,10(12): 1730-1734.
[21]Piao YF, He M, Shi Y, et al.Relationship between microvessel density and telomerase activity in hepatocellular carcinoma.World J Gastroenterol.2004,10(14):2147-2149.
[22]Poon RT, Ng IO, Lau C et al.Tumor microvessel density as a padictor of recurrnce after resection of hepatocellular carcinoma a prospective study.J Clin Oncol 2002,20(7) 1775-1785.
[23]Tanigawa N, Lu C, MitsuiT, et al.Quantitation of sinusoid like vessels in hepatocellular carcinoma its clinical and prognostic significance.Hepatology.1997, 26(5):1212-1216.
[24]Brasch R,Pham C,Shames D,et al.Assessing tumor angiogenesis using macromolecular MR imaging contrast media.J Magn Reson Imaging,1997,7(1):68-74.
[25]陈雁,周纯武,刘玉清.肿瘤微血管生成和肺癌及其影像学的联系.中国医学影像技术,2000,16(10):913-915.
[26]向昕,刘志伟,顾万清等.TAE后肝癌微血管密度及VEGF表达与再手术治疗研究.肝胆外科杂志,2004,12(1):24-27.
[27]林小军,张昌卿,张亚奇等.单纯切除与介入治疗后原发性肝癌肿瘤微血管密度变化研究.癌症,2000,19(10):919-922.
[28]李洪林,罗斗强,石木兰.MRI对评价肝癌Lp-TACE治疗的价值.临床放射学杂志,2000,19(10):629-632.
[29]Goldberg SN,Ahmed M.Minimally invasive image-guided therapies for hepatocellular carcinoma.J Clin Gastroenterol,2002,35[5 suppl2]:115-129.
[30]Katoh T,Mitani M,Noma K,et al.Delayed enhancement of hepatocellular carcinoma on dynamic CT:Sign of extrahepatic collaterals after transcatheter arterial chemoembolization or transcatheter arterial chemoinfusion.Abdominal Imaging,2002,27(1):34-39.
[31]Sumi S,Yamashita Y,Mitsuzaki K,et al.Power Doppler sonography assessment of tumor recurrence after chemoembolization therapy for hepatocellular carcinoma.AJR,1999,172(1):67-71.
[32]Ito K,Honjo K,Fujita T,et al.Therapeutic efficacy of transcatheter arterial chemoembolization for hepatocellular carcinoma:MRI and pathology.J Comput Assist Tomogr,1995,19(2):198-203.
[33]Hsu HC,Wei TC,Tasang YM,et al.Histologic assessment of resected hepatocellular carcinoma after transcatheter hepatic carterial embolization.Cancer,1986,57(6):1184-1191.
[34]Yong-Song Guan,Long Sun,Xiang-Ping Zhou,et al.Hepatocellular carcinoma treated with interventional procedures:CT and MRI follow-up.World J Gastroenterol,2004,10(24):3543-3548.
[35]Yah FH,Zhou KR,Cheng JM,et al.Role and limitation of FMPSP dynamic contrast scanning in the follow-up of patients with hepatocellcar carcinoma treated by TACE.World J Gastroenterol,2002,8(4):658-662.
[36]Murakami T,Nakamura H,Hori S,et al.Detection of viable tumor cells in hepatocellular carcinoma following transcatheter arterial chemoembolization with Iodized Oil:Pathologic correlation with dynamic turbo-FLASH MR imaging with Gd-DTPA.Acta Radiologica,1993,34(4):399-403.
[37]Castrucci M,Sironi S,De Cobelli F,et al.Plain and gadolinium-DTPA-enhanced MR imaging of hepatocellular carcinoma treated with transarterial chemoembolization.Abdominal Imaging,1996,21(6):488-494.
[38]Kubota K,Hisa N,Nishikawa T,et al.Evaluation of hepatocellular carcinoma after treatment with transcatheter arterial chemoembolization:comparison of Lipiodol-CT,power Doppler sonography,and dynamic MRI.Abdom Imaging,2001,26(2):184-190.
[39]Murakami T,Nakamura H,Tsuda K,et al.Treatment ofhepatocellular carcinoma by chemoembolization:Evaluation with 3DFT MR imaging.AJR,1993,160(2):295-299.
[40]Numata K,Tanaka K,Kiba T,et al.Using contrast-enhanced sonography to assess the effectiveness of transcatheter arterial embolization for hepatocellular carcinoma.AJR,2001,176(5):1199-1205.
[41]Murakami T,KimT,NakamuraH.Hepatitis,cirrhosis,and hepatoma.J Magn Resort Imaging,1998,8(2):346-368.
[42]潘平,刘爱连,宋清伟等.动态增强磁共振在评价肝细胞癌微血管密度中的意义.中国医学计算机成像杂志,2001,7(5):326-330.
[43]Hanahan D,Folkman J.Patterns and emerging mechanisms of the an-giogenic switch during tumorigenesis.Cell,1996,86(3):353-364.
[44]Suzuki K,Hayashi N,Miyamoto Y,et al.Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma.Cancer Res,1996,56(13):3004-3009.
[45]Park YN,Kim YB,Yang KM,et al.Increased expression of vascular endothelial growth factor and angiogenesis in early stage of multistep hepatocarcinogenesis.Arch Pathol Lab Med,2000,124(7):1061-1065.
[46]Semela D,Dufour JF.Angiogenesis and hepatocellular carcinoma.J Hepato,2004,41(5):864-880.
[47]Miles KA.Functional computed tomography in oncology.Eurn J Cancer,2002,38(16):2079-2084.
[48]史丽静,田建明,王培军等.多层螺旋计算机X线体层扫描肝脏灌注成像的临床应用初步研究.中华肝脏病杂志,2003,11(9):522-525.
[49]葛英辉,谢晓东,宋彬等.肝脏螺旋CT血管造影一动脉系统三维成像初探.胃肠病学和肝病学杂志,1999,8(1):40-43.
[50]Tsushima Y,Unno Y,Koizumi J,et al.Hepatic perfusion change after transcatheter arterial emlolization(TAE) of hepatocellular carcinoma measurement by dynamic computed tomography.Dig Dis Sci,1998,43(2):317-322.
[51].Ichikawa T,Haradome H,Hachiya J,et al.Characterization of hepatic lesions by perfusion-weightedMR imagingwith echoplanar sequence.Am J Roentgenol,1998,170(4):1029-1034.
[52]Villringer A,Rosen BR,Belliveau JW,et al.Dynamic imaging with lanthanide chelates in normal brain:contrast due to magnetic susceptibility effects.Magn Reson Med,1988,6(2):164-174.
[53]Chan JH,Tsui EY,Luk SH,et al.Detection of hepatic tumor perfusion following transcatheter arterial chemoembolization with dynamic susceptibility contrast-enhanced echoplanar imaging.Clin Imaging, 1999,23(3):190-194.
[54]Guan S, Zhao WD, Zhou KR, et al.Assessment of hemodynamics in precancerous lesion of hepatocellular carcinoma: evaluation with MR perfusion.World J Gastroenterol, 2007, 13(8): 1182-1186.
[55]Materne R, Smith AM, Peeters F, et al.Assessment of hepatic perfusion parameters with dynamic MRI.Magn Reson Med, 2002,47(1): 135-142.
[56]Scharf J, Zapletal C, Hess T, et al.Assessment of hepatic perfusion in pigs by pharmacokinetic analysis of dynamic MR images.J Magn Reson Imaging, 1999,9(4): 568-572.
[57]Zhao JG, Feng GS, Kong et al.Changes of tumor microcirculation after transcatheter arterial chemoembolization: first pass perfusion MR imaging and Chinese ink casting in a rabbit model.World J Gastroenterol, 2004,10(10): 1415-1420.
[58]Kamel IR, Bluemke DA, Eng J, et al.The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma.J Vasc Interv Radiol, 2006,17(3):505-512.
[59]Li W, Brophy DP, Chen Q, et al.Semiquantitative assessment of uterine perfusion using first pass dynamic contrast-enhanced MR imaging for patients treated with uterine fibroid embolization.J Magn Reson Imaging, 2000,12(6): 1004-1008.
[60]Pandharipande PV, Krinsky GA, Rusinek H, et al.Perfusion imaging of the liver current challenges and future goals.Radiology, 2005,234(3):66l-673.
[61]Ostergaard L.Principles of cerebral perfusion imaging by bolus tracking.J Magn Reson Imaging, 2005, 22(6): 710-717.
[62]Mateme R, Smith AM, Peeters F, et al.Assessment of hepatic perfusion parameters with dynamic MRI.Magn Reson Med,2002,47(1): 135-142.
[63]el-Khalily H,Hoeffken H,yon Wichert P,et al.Hepatic perfusion scintigraphy.Relationship of liver perfasion and ascites in patients with liver cirrhosis.Clin Nuel Med,1996,21(2):132-135.
[64]Ichikawa T, Araki T.Fast magnetic resonance imaging of liver.Eur J Radiol, 1999, 29(3): 186-210.
[65]Shimizu A, Ito K, Koike S, et al.Cirrhosis or chronic hepatitis evaluation of small(
[67]Bipat S, van Leeuwen MS, Ijzermans JN,et al.Imaging and treatment of patients with colorectal liver metastases in the Netherlands: a survey.Neth J Med,2006,64(5): 147-151.
[68]Totman JJ, O'Gorman RL, Kane PA, et al.Comparison of the hpatic perfusion index measured with gadolinium-enhanced volumeric MRI in controls and in patients withcolorectal cancer.BrRadiol,2005,78(926):105-109.
[69]Tsui EY, Chan JH, Cheung YK, et al.Evaluation of therapeutic effectiveness of transarterial chemoembolization for hepatocellular carcinoma:correlation of dynamic susceptibility contrast-enhanced echoplanar imaging and hepatic angiography.Journal of Clinical Imaging, 2000, 24(4):210-216.
[70]Murtz P, Flacke S, Traber F, et al.Abdomen: diffusion-weighted MR imaging with pulse triggered single-shot sequences.Radiology, 2002; 224(1): 258-264.
[71]Chow LC, Bammer R, Moseley ME, et al.Single breathhold diffusion-weighted imaging of the abdomen.J Magn Reson Imaging, 2003, 18(3): 377-382.
[72]Chenevert TL, Meyer CR, Moffat BA, et al.Diffusion MRI: a new strategy for assessment of cancer therapeutic efficacy.Molecular Imaging, 2002,l(4):336-343.
[73]Kamel IR, Bluemke DA, Ramsey D, et al.Role of diffusion-weighted imaging inestimating tumor necrosis after chemoembolization of hepatocellular carcinoma.Am J Roentgenol, 2003, 181(3): 708-710.
[74]Geschwind JF, Artemov D, Abraham S, et al.Chemoembolization of liver tumor in a rabbit model: assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis.Journal of Vascular and Interventional Radiology.2000,11(10):1245-255.
[75]Herneth AM,GuccioneS,Bednarski M.Apparent diffusion coefficient:a quantitative parameter for in vivo tumor characterization.Eur J Radiol,2003,45(3):208-213.
[76]尚全良,肖恩华,贺忠等.肝癌经导管动脉灌注化疗栓塞术疗效的MR扩散加权成像动态研究.中华放射学杂志,2006,40(3):235-240.