CT容积灌注成像评价抗血管生成治疗联合化疗早期疗效的动物实验研究
发布时间：2018-08-11 13:26
【摘要】：目的建立兔VX2软组织肿瘤抗血管生成治疗模型,旨在通过CT灌注参数、肿瘤形态学和病理检查反映肿瘤抗血管生成治疗和联合化疗后的早期改变,进而探讨CT容积灌注成像动态监测及评估抗血管生成治疗反应的可行性。材料与方法建立40只新西兰大白兔VX2软组织肿瘤模型,随机分为4组,即恩度组10只、联合组10只、化疗组10只、对照组10只。恩度组给予重组人血管内皮抑素(恩度)抗血管生成治疗,联合组同时给予恩度和顺铂联合治疗,化疗组给予顺铂进行单纯化疗,对照组给予生理盐水进行安慰治疗。于治疗前和治疗第2、4、7天行CT容积灌注扫描,测量肿瘤体积,计算肿瘤的治疗期间的体积增长值和肿瘤坏死增长率,获取肿瘤灌注图像并测算灌注参数血流量(BF)、血容量(BV)、平均通过时间(MTT)、表面通透性(PMB)。采用免疫组化法检测肿瘤微血管密度(MVD)和血管内皮生长因子(VEGF)的表达。数据统计采用SPSS17.0统计软件,对结果采用Kolmogorov-Smirnov方法进行正态性检验。因MVD平均值和VEGF表达百分比数据太少,无法进行统计学分析。对其余各组数据进行重复测量资料方差分析,数值以x±s表示。按α=0.05标准,双侧P0.05,差异有统计学意义。结果对四组数据进行组间比较：治疗第4、7天,恩度组肿瘤体积增长值[(0.89±0.59)cm3,(1.31±0.32)cm3]和联合组肿瘤体积增长值[(0.80±0.31)cm3,(1.51±0.69)cm3]均明显低于对照组[(1.80±0.45)cm3,(3.41±0.87)cm3](均P0.05)。四组肿瘤坏死增长率差异无明显统计学意义。治疗第2、4天,恩度组BF值[(78.63±29.71)ml/100ml/min,(82.45±13.17)ml/100ml/min]和联合组[(76.83+22.89) ml/100ml/min,(85.58±17.89)ml/100ml/min]明显高于化疗组[(41.91±11.87)ml/100ml/min,(57.09±15.95)ml/100ml/min]和对照组[(52.61±8.2l)ml/100ml/min,(59.89±6.16)ml/100ml/min](均P0.05)；治疗第7天,恩度组BF值[(71.19±12.2l)ml/100ml/min]明显高于化疗组[(48.16±15.63)ml/100ml/min]和对照组[(42.04±4.55)ml/100ml/min](均P0.05)。治疗第2天恩度组PMB值[(70.36±23.46)ml/100ml/min]明显高于化疗组[(29.53±12.98)ml/100ml/min]和对照组[(27.69±9.45)ml/100ml/min];治疗4、7天,恩度组PMB值[(80.33±13.05)ml/100ml/min,(84.76±3.55)ml/100ml/min](?)口联合组PMB值[(78.12±12.95)ml/100ml/min,(69.83±8.00)ml/100ml/min]均明显高于化疗组[(47.78±20.09)ml/100ml/min,(39.10±17.50)ml/100ml/min]和对照组[(26.87±6.26)ml/1OOml/min,(29.58±11.33)ml/100ml/min](均P0.05)。四组BV、MTT值组间比较差异无统计学意义。各灌注参数值组内不同时间点之间比较：联合组BF、PMB值于治疗第4天明显高于治疗前；恩度组PMB值治疗后2、4、7天均明显高于治疗前。其他两组灌注参数值于治疗前后无明显差异。但从BF、PMB值的趋势图中得出：联合组BF、PMB值升高幅度和下降幅度均大于恩度组；化疗组BF、PMB值在治疗第4天出现一过性轻度升高。病理检查结果显示：化疗组和空白对照MVD随治疗时间延长逐渐增多,而恩度组和联合组MVD呈先轻度升高再下降的趋势。四组VEGF表达均呈强阳性,无明显差异。结论CT灌注参数BF、PMB值能够反映肿瘤血流量和血管功能变化,对抗血管生成治疗的早期疗效有很好的敏感性和准确性；BV和MTT值四组之间差异无统计学意义,对抗血管生成治疗及联合治疗的早期疗效无评价价值。恩度及联合治疗后肿瘤生长减缓但未退缩,且体积增长值的变化出现较BF、PMB值晚,肿瘤形态学的改变难以对早期疗效作出及时评价。VEGF表达在四组肿瘤间及组内不同时间点间差异不大,说明用单一血管生成因子来评价抗血管生成疗效不可取。CT灌注不能准确反映肿瘤MVD,但在反映肿瘤整体的血流灌注和血管功能变化有一定优势。
[Abstract]:Objective To establish a rabbit model of anti-angiogenesis therapy for VX2 soft tissue tumors. The purpose of this study is to reflect the early changes of anti-angiogenesis therapy and combined chemotherapy by CT perfusion parameters, tumor morphology and pathological examination, and to explore the feasibility of dynamic monitoring and evaluating anti-angiogenesis therapy response by CT volume perfusion imaging. Forty New Zealand white rabbits with VX2 soft tissue tumor were randomly divided into four groups: Endor group (10 rabbits), combined group (10 rabbits), chemotherapy group (10 rabbits) and control group (10 rabbits). CT volume perfusion was performed before treatment and on the 2nd, 4th and 7th day after treatment. The tumor volume was measured. The volume growth and necrosis rate were calculated. The perfusion images were obtained and the perfusion parameters, such as blood flow (BF), blood volume (BV), mean transit time (MTT) and surface permeability (PMB), were calculated. The expression of tumor microvessel density (MVD) and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry. The data were analyzed by SPSS 17.0 statistical software. The results were tested by Kolmogorov-Smirnov method for normality. The data of MVD and VEGF expression percentage were too small to be analyzed statistically. According to the criterion of alpha = 0.05, there was a significant difference between the four groups. Results On the 4th and 7th day of treatment, the tumor volume growth value in Endor group [(0.89.59) cm 3, (1.31.32) cm 3] and the tumor volume growth value in combination group [(0.80.31) cm 3, (1.51.69) cm 3] were all compared. There was no significant difference in tumor necrosis rate among the four groups. On the 2nd and 4th day of treatment, BF value in Endor group [(78.63 [(29.71) ml / 100ml / min, (82.45 [13.17) ml / 100ml / min] and combination group [(76.83 + 22.89) ml / 100ml / min, (85.58 [(17.89) ml / 100ml / min] were significantly higher than those in chemotherapy group [(4. 1.91 [(11.91 [(11.87) ml / 100ml / 100 ml / min, (57.09 [(57.09 [(15.95) ml / 100 ml / 100 ml / min] and control group [(52.61 [(8.2) ml / 100 ml / 100 ml / min, [(59.89 [(6.16.16) ml / 100 ml / 100 ml / min] (all P 0.05); on the 7day after treatment, BF value [(71.19 [(71.19 [(71.19 [(12.12.2) ml / 100 ml / 100 ml / min] in entgroup] was significantly higher than that in chemotherapy group [(48.16 [(18.16 [(15.63) ml / 100 ml / 100 ml / Day 2 of treatment PMB value [(70.36 +23.46) ml / 100ml / 100 ml / min] in Endurant group was significantly higher than that in chemotherapy group [[(29.53 +12.98) ml / 100 ml / 100 ml / min] and control group [(27.69 [(27.69 [(9.45) ml / 100 ml / 100 ml / 100 ml / min]; PMB value [(80.33 [(13.33 [13.05) ml / 100 ml / 100 ml / min, (84.76 [3.76 [3.55] ml / 100 ml / 100 ml / 100 ml / 100 ml / min] [(78.12 [(12.12.12.95) ml / 12.95 ml / 100 ml, (69.69 [(9.69 [9./min] Compared with chemotherapy group [(47.78 [20.09] ml / 100ml / min, (39.10 [17.50] ml / 100ml / min] and control group [(26.87 [6.26) ml / 1Oml / min, (29.58 [11.33] ml / 100ml / min] (all P 0.05)]. There was no significant difference in BV and MTT values among the four groups. Comparison of different time points in each perfusion parameter group: BF, PMB values in the combined group were significantly higher than those in the fourth day of treatment. Before treatment, the value of PMB in Endor group was significantly higher than that before treatment 2, 4 and 7 days after treatment. There was no significant difference between the other two groups before and after treatment. The results of physical examination showed that MVD of chemotherapy group and blank control group increased gradually with the prolongation of treatment time, while MVD of Endor group and combined group increased slightly at first and then decreased. The expression of VEGF in the four groups was strongly positive, and there was no significant difference. There was no significant difference between BV and MTT, and there was no value in evaluating the early effect of anti-angiogenesis therapy and combination therapy. It is difficult to evaluate the early curative effect in time. The expression of VEGF has little difference among the four groups of tumors and at different time points within the group, which indicates that it is not advisable to evaluate the anti-angiogenesis effect with a single angiogenic factor.
【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R730.55
本文编号：2177123
[Abstract]:Objective To establish a rabbit model of anti-angiogenesis therapy for VX2 soft tissue tumors. The purpose of this study is to reflect the early changes of anti-angiogenesis therapy and combined chemotherapy by CT perfusion parameters, tumor morphology and pathological examination, and to explore the feasibility of dynamic monitoring and evaluating anti-angiogenesis therapy response by CT volume perfusion imaging. Forty New Zealand white rabbits with VX2 soft tissue tumor were randomly divided into four groups: Endor group (10 rabbits), combined group (10 rabbits), chemotherapy group (10 rabbits) and control group (10 rabbits). CT volume perfusion was performed before treatment and on the 2nd, 4th and 7th day after treatment. The tumor volume was measured. The volume growth and necrosis rate were calculated. The perfusion images were obtained and the perfusion parameters, such as blood flow (BF), blood volume (BV), mean transit time (MTT) and surface permeability (PMB), were calculated. The expression of tumor microvessel density (MVD) and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry. The data were analyzed by SPSS 17.0 statistical software. The results were tested by Kolmogorov-Smirnov method for normality. The data of MVD and VEGF expression percentage were too small to be analyzed statistically. According to the criterion of alpha = 0.05, there was a significant difference between the four groups. Results On the 4th and 7th day of treatment, the tumor volume growth value in Endor group [(0.89.59) cm 3, (1.31.32) cm 3] and the tumor volume growth value in combination group [(0.80.31) cm 3, (1.51.69) cm 3] were all compared. There was no significant difference in tumor necrosis rate among the four groups. On the 2nd and 4th day of treatment, BF value in Endor group [(78.63 [(29.71) ml / 100ml / min, (82.45 [13.17) ml / 100ml / min] and combination group [(76.83 + 22.89) ml / 100ml / min, (85.58 [(17.89) ml / 100ml / min] were significantly higher than those in chemotherapy group [(4. 1.91 [(11.91 [(11.87) ml / 100ml / 100 ml / min, (57.09 [(57.09 [(15.95) ml / 100 ml / 100 ml / min] and control group [(52.61 [(8.2) ml / 100 ml / 100 ml / min, [(59.89 [(6.16.16) ml / 100 ml / 100 ml / min] (all P 0.05); on the 7day after treatment, BF value [(71.19 [(71.19 [(71.19 [(12.12.2) ml / 100 ml / 100 ml / min] in entgroup] was significantly higher than that in chemotherapy group [(48.16 [(18.16 [(15.63) ml / 100 ml / 100 ml / Day 2 of treatment PMB value [(70.36 +23.46) ml / 100ml / 100 ml / min] in Endurant group was significantly higher than that in chemotherapy group [[(29.53 +12.98) ml / 100 ml / 100 ml / min] and control group [(27.69 [(27.69 [(9.45) ml / 100 ml / 100 ml / 100 ml / min]; PMB value [(80.33 [(13.33 [13.05) ml / 100 ml / 100 ml / min, (84.76 [3.76 [3.55] ml / 100 ml / 100 ml / 100 ml / 100 ml / min] [(78.12 [(12.12.12.95) ml / 12.95 ml / 100 ml, (69.69 [(9.69 [9./min] Compared with chemotherapy group [(47.78 [20.09] ml / 100ml / min, (39.10 [17.50] ml / 100ml / min] and control group [(26.87 [6.26) ml / 1Oml / min, (29.58 [11.33] ml / 100ml / min] (all P 0.05)]. There was no significant difference in BV and MTT values among the four groups. Comparison of different time points in each perfusion parameter group: BF, PMB values in the combined group were significantly higher than those in the fourth day of treatment. Before treatment, the value of PMB in Endor group was significantly higher than that before treatment 2, 4 and 7 days after treatment. There was no significant difference between the other two groups before and after treatment. The results of physical examination showed that MVD of chemotherapy group and blank control group increased gradually with the prolongation of treatment time, while MVD of Endor group and combined group increased slightly at first and then decreased. The expression of VEGF in the four groups was strongly positive, and there was no significant difference. There was no significant difference between BV and MTT, and there was no value in evaluating the early effect of anti-angiogenesis therapy and combination therapy. It is difficult to evaluate the early curative effect in time. The expression of VEGF has little difference among the four groups of tumors and at different time points within the group, which indicates that it is not advisable to evaluate the anti-angiogenesis effect with a single angiogenic factor.
【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R730.55
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