CT容積灌注成像評價抗血管生成治療聯(lián)合化療早期療效的動物實驗研究
發(fā)布時間：2018-08-11 13:26
【摘要】：目的建立兔VX2軟組織腫瘤抗血管生成治療模型,旨在通過CT灌注參數(shù)、腫瘤形態(tài)學和病理檢查反映腫瘤抗血管生成治療和聯(lián)合化療后的早期改變,進而探討CT容積灌注成像動態(tài)監(jiān)測及評估抗血管生成治療反應(yīng)的可行性。材料與方法建立40只新西蘭大白兔VX2軟組織腫瘤模型,隨機分為4組,即恩度組10只、聯(lián)合組10只、化療組10只、對照組10只。恩度組給予重組人血管內(nèi)皮抑素(恩度)抗血管生成治療,聯(lián)合組同時給予恩度和順鉑聯(lián)合治療,化療組給予順鉑進行單純化療,對照組給予生理鹽水進行安慰治療。于治療前和治療第2、4、7天行CT容積灌注掃描,測量腫瘤體積,計算腫瘤的治療期間的體積增長值和腫瘤壞死增長率,獲取腫瘤灌注圖像并測算灌注參數(shù)血流量(BF)、血容量(BV)、平均通過時間(MTT)、表面通透性(PMB)。采用免疫組化法檢測腫瘤微血管密度(MVD)和血管內(nèi)皮生長因子(VEGF)的表達。數(shù)據(jù)統(tǒng)計采用SPSS17.0統(tǒng)計軟件,對結(jié)果采用Kolmogorov-Smirnov方法進行正態(tài)性檢驗。因MVD平均值和VEGF表達百分比數(shù)據(jù)太少,無法進行統(tǒng)計學分析。對其余各組數(shù)據(jù)進行重復(fù)測量資料方差分析,數(shù)值以x±s表示。按α=0.05標準,雙側(cè)P0.05,差異有統(tǒng)計學意義。結(jié)果對四組數(shù)據(jù)進行組間比較：治療第4、7天,恩度組腫瘤體積增長值[(0.89±0.59)cm3,(1.31±0.32)cm3]和聯(lián)合組腫瘤體積增長值[(0.80±0.31)cm3,(1.51±0.69)cm3]均明顯低于對照組[(1.80±0.45)cm3,(3.41±0.87)cm3](均P0.05)。四組腫瘤壞死增長率差異無明顯統(tǒng)計學意義。治療第2、4天,恩度組BF值[(78.63±29.71)ml/100ml/min,(82.45±13.17)ml/100ml/min]和聯(lián)合組[(76.83+22.89) ml/100ml/min,(85.58±17.89)ml/100ml/min]明顯高于化療組[(41.91±11.87)ml/100ml/min,(57.09±15.95)ml/100ml/min]和對照組[(52.61±8.2l)ml/100ml/min,(59.89±6.16)ml/100ml/min](均P0.05)；治療第7天,恩度組BF值[(71.19±12.2l)ml/100ml/min]明顯高于化療組[(48.16±15.63)ml/100ml/min]和對照組[(42.04±4.55)ml/100ml/min](均P0.05)。治療第2天恩度組PMB值[(70.36±23.46)ml/100ml/min]明顯高于化療組[(29.53±12.98)ml/100ml/min]和對照組[(27.69±9.45)ml/100ml/min];治療4、7天,恩度組PMB值[(80.33±13.05)ml/100ml/min,(84.76±3.55)ml/100ml/min](?)口聯(lián)合組PMB值[(78.12±12.95)ml/100ml/min,(69.83±8.00)ml/100ml/min]均明顯高于化療組[(47.78±20.09)ml/100ml/min,(39.10±17.50)ml/100ml/min]和對照組[(26.87±6.26)ml/1OOml/min,(29.58±11.33)ml/100ml/min](均P0.05)。四組BV、MTT值組間比較差異無統(tǒng)計學意義。各灌注參數(shù)值組內(nèi)不同時間點之間比較：聯(lián)合組BF、PMB值于治療第4天明顯高于治療前；恩度組PMB值治療后2、4、7天均明顯高于治療前。其他兩組灌注參數(shù)值于治療前后無明顯差異。但從BF、PMB值的趨勢圖中得出：聯(lián)合組BF、PMB值升高幅度和下降幅度均大于恩度組；化療組BF、PMB值在治療第4天出現(xiàn)一過性輕度升高。病理檢查結(jié)果顯示：化療組和空白對照MVD隨治療時間延長逐漸增多,而恩度組和聯(lián)合組MVD呈先輕度升高再下降的趨勢。四組VEGF表達均呈強陽性,無明顯差異。結(jié)論CT灌注參數(shù)BF、PMB值能夠反映腫瘤血流量和血管功能變化,對抗血管生成治療的早期療效有很好的敏感性和準確性；BV和MTT值四組之間差異無統(tǒng)計學意義,對抗血管生成治療及聯(lián)合治療的早期療效無評價價值。恩度及聯(lián)合治療后腫瘤生長減緩但未退縮,且體積增長值的變化出現(xiàn)較BF、PMB值晚,腫瘤形態(tài)學的改變難以對早期療效作出及時評價。VEGF表達在四組腫瘤間及組內(nèi)不同時間點間差異不大,說明用單一血管生成因子來評價抗血管生成療效不可取。CT灌注不能準確反映腫瘤MVD,但在反映腫瘤整體的血流灌注和血管功能變化有一定優(yōu)勢。
[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.
【學位授予單位】：天津醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R730.55
本文編號：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.
【學位授予單位】：天津醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R730.55
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