乙酰唑胺负荷CT灌注成像对脑胶质瘤肿瘤血管生成的评价
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摘要
第一部分乙酰唑胺负荷CT灌注成像与CO2负荷CT灌注成像在大鼠C6胶质瘤应用中的比较研究
目的：研究用计算机体层摄影术(Computed tomography, CT)的灌注成像评价C6胶质瘤在乙酰唑胺和10%CO2与90%空气混合气分别作为负荷刺激因素下的血供变化情况。分析乙酰唑胺负荷CT灌注成像的可行性以及CT灌注参数负荷前后灌注参数变化率与血管内皮生长因子(Vascular endothelial growth factor, VEGF)和FⅧ-微血管密度(Microvessel density, MVD)之间的相关性。
材料与方法：雄性SD大鼠32只,年龄3个月,体重250-300g,其中20只大鼠种植C6胶质瘤,12只大鼠作为正常对照组。10只原位种植C6胶质瘤大鼠和6只正常大鼠分别行静息CT灌注检查和静脉注射乙酰唑胺15分钟后CT灌注检查。另外10只原位种植C6胶质瘤大鼠和6只正常大鼠分别行静息CT灌注检查和吸入10%CO215分钟后行256层CT灌注检查。灌注成像实验组以胶质瘤区域(对照组以右侧尾状核层面)为中心扫描。原始图像采用Philips CT自带脑灌注软件处理后产生灌注曲线及伪彩图像,两次扫描前均测定大鼠的血液CO2分压、酸碱度(Potential of hydrogen, pH)等血气分析指标。检查结束后24小时内,处死大鼠并取脑固定,在尾状核中心层面全脑切片,观察肿瘤大体形态学表现后用石蜡包埋,在C6细胞种植部位(对照组在右侧尾状核层面)切片,染色,显微镜下进行组织病理学观察,并进行免疫组化检查VEGF和FⅧ-MVD。采用SPSS17.0统计学分析软件(SPSS Inc., Chicago, IL,美国)。应用ANOVA检验比较不同实验组之间的脑血容量(Cerebral blood volume,CBV)、脑血流量(Cerebral blood flow, CBF)、通透性和平均通过时间(Mean transit time, MTT)的变化差异有无统计学意义。在多重比较过程中,Bonferroni矫正后,P<0.01有统计学意义。比较乙酰唑胺负荷和CO2负荷前后灌注参数变化率用独立样本t检验。灌注参数CBV, CBF和通透性等与VEGF及FⅧ-MVD之间的相关性用Pearson相关分析,计算相关系数。P<0.05有统计学意义。
结果：C6大鼠均病理证实为胶质瘤。肿瘤边缘CBF, CBV和通透性较肿瘤实质部分高(p<0.01)。胶质瘤肿瘤实质部分较正常对照组CBF,CBV和通透性高(P<0.01)。12只正常大鼠(6只大鼠乙酰唑胺负荷,6只大鼠CO：负荷)负荷后CBF及CBV均上升(P<0.01)。在对照组中,CBF变化百分率乙酰唑胺负荷为117.42%,而10%CO2负荷为65.86%,二者差异有统计学意义(P<0.01)。CBV变化百分率乙酰唑胺负荷为107.51%,而10%CO2负荷为92.95%,二者差异无统计学意义(P=0.02)。大鼠C6胶质瘤实质部分,CBF变化百分率两种负荷之间的差异有统计学意义,乙酰唑胺负荷为72.73%,而10%CO2负荷为28.47%(P<0.01)。CBV变化百分率乙酰唑胺负荷为37.85%,而10%CO2负荷为24.69%。C6胶质瘤大鼠对侧正常脑组织与正常大鼠脑组织的CBF, CBV和通透性参数的变化百分率差异无统计学意义。瘤周水肿组织和对照组灌注参数变化百分率差异无统计学意义。肿瘤实质部分和肿瘤边缘之间灌注参数变化百分率差异无统计学意义。VEGF和FⅧ-MVD与CBV变化百分率间存在明显相关性(P<0.01)。CBF变化百分率与VEGF相关性较强。
结论：乙酰唑胺负荷CT灌注成像可以和CO2负荷CT灌注成像一样较好地评价C6胶质瘤负荷刺激因素下的血供变化情况。CBV变化百分率可以一定程度上反映VEGF和FⅧ-MVD, CBF变化百分率可以一定程度上反映VEGF。
第二部分乙酰唑胺负荷CT灌注成像对大鼠C6胶质瘤血管生成的评价
目的：研究不同种植天数C6胶质瘤乙酰唑胺(Acetazolamide,ACZ)负荷CT灌注参数变化率差异以及灌注参数变化率与CD105-MVD, VEGF,血管成熟指数(Vascular maturity index, VMI)和Ki67的相关性,探讨CT灌注参数及其变化率在评价C6胶质瘤血管生成中的病理基础和价值。
材料与方法：雄性SD (Sprgue Dawley)大鼠32只，年龄3个月,体重250-300g。将大鼠采用数字表法随机分为4组,8只为正常对照组,8只为种植C6胶质瘤10天组,8只为种植C6胶质瘤14天组,8只为种植C6胶质瘤18天组。肿瘤组大鼠通过立体定向仪于鼠脑右侧尾状核区种植C6胶质瘤细胞复制大鼠脑胶质瘤模型。对照组同部分注射等量生理盐水。大鼠C6胶质瘤10天组,14天组,18天组分别于肿瘤种植10天,14天,18天行ACZ负荷CT灌注检查。大鼠平放于CT检查床,四肢固定,阴茎背静脉留置静脉留置针,高压注射器注射对比剂。原位种植C6胶质瘤大鼠和正常大鼠分别行静息CT灌注检查,间隔1小时后行ACZ负荷CT灌注检查(静脉注射ACZ,15分钟后)。灌注成像以尾状核层面为中心。采用Philips CT自带脑灌注软件处理后产生灌注曲线及伪彩图像,两次扫描前均测定大鼠的动脉血二氧化碳分压(Carbon dioxide partial pressure,PaCO2)、 pH值指标。检查结束后24小时内,处死大鼠并取脑固定,在肿瘤中心层面切片,进行脑组织苏木素伊红(Hematoxylin and eosin,HE)染色及免疫组化检查CD105-MVD、FⅧ-MVD、α-平滑肌肌动蛋白(Alpha-smooth muscle actin, α-SMA)-MVD, VEGF和Ki67。VMI=(a-SMA-MVD/FⅧ-MVD)应用SPSS17.0进行统计分析。采用配对样本t检验,比较对照组和胶质瘤组大鼠ACZ负荷前后的CT灌注参数差异是否有统计学意义。应用ANOVA检验比较不同实验组之间的灌注参数变化百分率差异有无统计学意义。在多重比较过程中,Bonferroni矫正后,P<0.01有统计学意义。灌注参数与CD105-MVD, VEGF, VMI(?)(?)Ki67之间的相关性用Pearson相关分析。P<0.05为有统计学意义。
结果：四组大鼠在ACZ负荷后15分钟动脉血PaCO2升高,血浆pH值降低(P<0.01)。CBF和CBV在负荷前后的差异均有统计学意义。CBF变化百分率对照组与胶质瘤14天,18天差异有统计学意义。CBV变化百分率对照组与胶质瘤10天、14天、18天差异有统计学意义。CD105-MVD胶质瘤为10.64±6.13,正常组织为0.84±0.28,二者有统计学意义。Pearson相关分析显示,CBV变化百分率,CBF变化百分率,通透性,CBV, CBF与免疫组化的CD105-MVD, VEGF, VMI(?)(?)Ki67之间存在明显相关性。即CD105-MVD, VEGF, VMI和Ki67可以通过CBF变化百分率,CBV变化百分率,通透性以及CBF, CBV反映出来。
结论：不同种植天数C6胶质瘤ACZ负荷实验CT灌注成像灌注参数变化率不完全-致。CT灌注成像结合ACZ负荷实验得到的血流量变化率、血容量变化率、CBF、CBV以及通透性等参数可以一定程度上反映胶质瘤肿瘤血管生成情况。
第三部分CT灌注成像对人脑胶质瘤患者肿瘤血管生成的评价
目的：拟对256层CT灌注成像评价人脑胶质瘤肿瘤血管生成进行研究,探讨人脑胶质瘤患者256层CT灌注成像的可行性及灌注参数对评价肿瘤血管生成的价值,以期为临床评价胶质瘤患者血管生成及预后提供一种新的安全、有效的评价手段。
材料和方法：2010年1月一2012年2月对55例病例行脑256层CT灌注扫描,其中正常对照组15例,胶质瘤病例组40例。应用256层CT对受检者进行CT灌注成像检查。利用Mi STAR后处理软件,在病灶最大层面选取感兴趣区(Region of interest, ROI),获得感兴趣区的CBF, CBV, MTT和表面通透性等参数。采用SPSS17.0软件,应用ANOVA检验比较对照组、低级别胶质瘤组和高级别胶质瘤组灌注参数的差异有无统计学意义。在多重比较过程中,Bonferroni矫正后,P<0.01有统计学意义。应用配对样本t检验比较胶质瘤肿瘤实质和肿瘤边缘灌注参数之间的差异有无统计学意义。灌注参数CBF, CBV, MTT和表面通透性与病理指标CDl05-MVD,缺氧诱导因子-1α(Hypoxia-inducible factor-1alpha, HIF-la), VMI, CD34-MVD, a-SMA-MVD之间的相关性用Pearson相关分析,P<0.05有统计学意义。
结果：40例胶质瘤患者均经病理证实为脑胶质瘤,其中低级别胶质瘤15例,高级别胶质瘤25例。高级别胶质瘤组的CBF, CBV和表面通透性高于低级别胶质瘤组,低级别胶质瘤组的CBF, CBV和表面通透性高于对照组(P<0.01)。表面通透性为2.88ml/min/100g时,敏感度为96%,特异度为93%；CBV为3.91ml/100g时,敏感度为92%,特异度为93%；CBF为38.90ml/100g/min时,敏感度为92%,特异度为86%。高级别胶质瘤肿瘤边缘CBV, CBF和表面通透性参数高于肿瘤实质部分(P<0.01),高级别胶质瘤肿瘤边缘和实质MTT差异无统计学意义(P=0.14)。CBF, CBV和表面通透性与免疫组化指标CD105-MVD, HIF-1α, VMI, CD34-MVD以及a-SMA-MVD有明显相关性(p<0.05)
结论：人脑256-CT灌注成像灌注参数CBV, CBF和表面通透性可以一定程度上反映胶质瘤的肿瘤血管生成情况。
Part Ⅰ. Comparison between Acetazolamide Challenge and10%Carbon Dioxide using Perfusion CT in Rat C6Glioma
PURPOSE:Perfusion computed tomography (PCT) was used to investigate cerebral and C6glioma perfusion changes induced by acetazolamide (ACZ) and a mixture of10%carbon dioxide and90%air challenges. Correlations were investigated between PCT with ACZ and the results of Vascular endothelial growth factor (VEGF) and FⅧ-microvessel density (MVD).
MATERIALS AND METHODS:Dynamic PCT was performed on32male Sprague-Dawley rats (age3month, weight250-300g. selected randomly) including20rats with rat C6glioma and12rats served as controls. Ten rats with orthotopically implanted C6gliomas and6normal rats underwent PCT at rest and15minutes after1mg/kg intravenous ACZ. Another ten rats with C6gliomas and six normal rats underwent PCT at rest and15minutes after inhalation of a mixture of10%carbon dioxide and90%air which lasted for15minutes. The interval between PCT with challenge and at rest was at least1hour. All examinations were performed with a256-slice scanner. PCT was performed at glioma area and the right caudate nucleus in controls. The raw data were processed using Philips CT brain perfusion software which could provide time-density curve (TDC) curves and colour maps. Carbon dioxide partial pressure (PaCO2) and potential of hydrogen (pH) were recorded. At the end of the experiment, each animal was sacrificed in24hours. Their brains were resected and fixed, which were cut at the level of the right caudate nucleus. A coronal5μm thick slice of brain tissue from each rat was cut and stained according to the standard hematoxylin and eosin (HE) staining protocol. The samples were examined using immunohistochemical staining for VEGF and FⅧ-MVD. The statistical analysis was performed using the SPSS17.0package (SPSS Inc., Chicago, IL. USA). ANOVA test was used to compare the difference among different groups, after confirmation of normal distribution of the data. In the multiple comparison procedure. P<0.01was considered significant after Bonferroni correction. Independent-samples t tests were used to compare the difference between perfusion parameters changes with ACZ challenge and perfusion parameters changes with10%carbon dioxide. Pearson correlation coefficients were used to investigate relationships between cerebral blood flow (CBF) percentage changes, cerebral blood volume (CBV) percentage changes, permeability and the results of VEGF and FⅧ-MVD. P less than0.05was considered significant.
RESULTS:In the end of this experiment, those C6rats were dissected and proven to be gliomas. The tumor periphery had higher CBF, CBV, and permeability values than tumor central parenchyma (P<0.01). Tumor central parenchyma had higher CBF, CBV, and permeability values than controls (P<0.01). Twelve normal rats (6rats with ACZ stimuli,6rats with10%carbon dioxide stimuli) had increased CBF and CBV values after challenge (P<0.01). In controls, CBF percentage change apparently differed using ACZ stimuli (117.42%) compared to10%carbon dioxide (65.86%)(P<0.01). As for CBV percentage change, there was no significant difference between ACZ stimuli (107.51%) and10%carbon dioxide (92.95%)(P=0.02). In parenchyma of rat C6glioma, CBF percentage change was different using ACZ stimuli (72.73%) compared to10%carbon dioxide (28.47%)(P<0.01). CBV percentage change was37.85%with ACZ and24.69%with10%carbon dioxide. There was no significant difference in CBF, CBV and permeability percentage change between contralateral normal tissue and controls, beween peritumoral edema tissue and controls, and between tumor central parenchyma and the periphery. Significant correlations were observed between VEGF and FⅧ-MVD and blood volume percentage change (P<0.01). Blood flow percentage change correlated well with VEGF.
CONCLUSION:PCT with ACZ is suitable for evaluation of blood vessels in C6gliomas instead of inhalation of10%carbon dioxide without the side effects induced by10%carbon dioxide. CBV percentage is correlated change with the FⅧ-MVD and VEGF in gliomas. CBF percentage change is correlated with the VEGF in gliomas.
Part II. Cerebral Perfusion CT with Acetazolamide Challenge in C6Gliomas
PURPOSE:PCT with ACZ challenge was used to investigate perfusion changes of C6gliomas at10days,14days and18days. Correlations were investigated between PCT with ACZ and the results of CD105-MVD, VEGF, vascular maturity index (VMI) and Ki67.
MATERIALS AND METHODS:Dynamic PCT was performed on32male Sprague-Dawley rats (age3month, weight250-300g, selected randomly) including8rats with rat C6glioma10days,8rats with rat C6glioma14days,8rats with rat C6glioma18days and8rats served as controls. Intravenous catheter for contrast medium administration pre-and post-challenge was put in the vena dorsalis penis of rats.24rats with orthotopically implanted C6gliomas and6normal rats underwent PCT at rest and15minutes after1mg/kg intravenous ACZ. The interval between PCT with challenge and at rest was at least1hour. All examinations were performed with a256-sIice scanner. PCT was performed at glioma area and the right caudate nucleus in controls. The raw data were processed using Philips CT brain perfusion software which could provide TDC curves and colour maps. PaCO2and pH were recorded. At the end of the experiment, each animal was sacrificed in24hours. Their brains were resected and fixed, which were cut at the level of the right caudate nucleus. A coronal5um thick slice of brain tissue from each rat was cut and stained according to the standard HE staining protocol. The samples were examined using immunohistochemical staining for CD105-MVD, FⅧ-MVD, VEGF, alpha-smooth muscle actin (a-SMA)-MVD and Ki67. VMI was calculated as follows:VMI (%)=α-SMA-MVD/FⅧ-MVD X100%. The statistical analysis was performed using the SPSS17.0package. Paired-samples t tests were used to compare the difference between perfusion parameters pre-and post-ACZ challenge. ANOVA test was used to compare the difference among different groups, after confirmation of normal distribution of the data. In the multiple comparison procedure, P<0.01was considered significant after Bonferroni correction. Pearson correlation coefficients were used to investigate relationships between CBF percentage changes, CBV percentage changes, permeability, CBF, CBV and the results of CD105-MVD, VEGF, VMI and Ki67. P less than0.05was considered significant.
RESULTS:Gliomas of4groups were all proved to have elevated PaCO2and decreased pH after ACZ challenge (P<0.01). Significant CBF. CBV difference was observed before and after ACZ challenge. Rat glioma in14days and18days group had higher CBF than controls (P<0.01). Rat glioma inl0days,14days and18days group had higher CBV than controls (P<0.01). CD105-MVD of Rat C6glioma is10.64±6.13. CD105-MVD of controls was0.84±0.28. Significant correlations were observed between CD105-MVD. VEGF, VMI, Ki67and CBV percentage change, CBF percentage change, permeability. CBV and CBF (P<0.01).
CONCLUSION:There was difference between10days,14days.18days gliomas and controls. PCT with ACZ challenge could provide useful parameters, such as CBF percentage change, CBV percentage change, permeability, CBF. and CBV, which could correlate with glioma angiogenesis.
Part Ⅲ. Evaluation of human glioma angiogenesis using Perfusion CT
PURPOSE:To evaluate the feasibility of human glioma perfusion CT and analyse the relationship between perfusion parameters and human glioma angiogenesis.
MATERIALS AND METHODS:From January2010to February2012,55subjects underwent perfusion256-CT imaging. Among them, the histopathological results of40patients were gliomas. Perfusion CT imaging was performed in15healthy volunteers served as controls. The raw data were processed using CT perfusion software. Perfusion parameters including CBF, CBV, MTT and permeability surface-area product. The statistical analysis was performed using the SPSS17.0package. ANOVA test was used to compare the difference among controls, low grade glioma group and high grade glioma. In the multiple comparison procedure. P<0.01was considered significant after Bonferroni correction. Paired-samples t tests were used to compare the difference between perfusion parameters of peripheral and solid tissue. Pearson correlation coefficients were used to investigate relationships between CBF. CBV. permeability surface-area product and the results of CD105-MVD, Hypoxia-inducible factor-1alpha (HIF-1α), VMI. CD34-MVD and a-SMA-MVD. P less than0.05was considered significant.
RESULTS:Twenty-five patients were proved to be high grade gliomas, and fifteen patients were proved to be low grade gliomas. Significant CBF, CBV difference was observed between high grade gliomas and low grade gliomas (P<0.01). Cutoff value of permeability surface-area product was2.88ml/min/100g, the sensitivity and specificity of which were96%and93%. Cutoff value of CBV was3.91ml/100g. the sensitivity and specificity of which were92%and93%. Cutoff value of CBF was38.90ml/100g/min. the sensitivity and specificity of which were92%and86%. Significant CBF, CBV difference was observed between low grade gliomas and controls (P<0.01). The periphery had higher CBF, CBV and permeability surface-area product than the solid tissue in high grade gliomas (P<0.01). There was no significant difference in MTT (P=0.14). Significant correlations were observed between CD105-MVD, HIF-la, VMI, CD34-MVD. a-SMA-MVD and CBV, CBF, permeability surface-area product (P<0.01).
CONCLUSION:PCT could provide useful parameters, such as CBF, CBV and permeability surface-area product, which could correlate with glioma angiogenesis.
目的：研究用计算机体层摄影术(Computed tomography, CT)的灌注成像评价C6胶质瘤在乙酰唑胺和10%CO2与90%空气混合气分别作为负荷刺激因素下的血供变化情况。分析乙酰唑胺负荷CT灌注成像的可行性以及CT灌注参数负荷前后灌注参数变化率与血管内皮生长因子(Vascular endothelial growth factor, VEGF)和FⅧ-微血管密度(Microvessel density, MVD)之间的相关性。
材料与方法：雄性SD大鼠32只,年龄3个月,体重250-300g,其中20只大鼠种植C6胶质瘤,12只大鼠作为正常对照组。10只原位种植C6胶质瘤大鼠和6只正常大鼠分别行静息CT灌注检查和静脉注射乙酰唑胺15分钟后CT灌注检查。另外10只原位种植C6胶质瘤大鼠和6只正常大鼠分别行静息CT灌注检查和吸入10%CO215分钟后行256层CT灌注检查。灌注成像实验组以胶质瘤区域(对照组以右侧尾状核层面)为中心扫描。原始图像采用Philips CT自带脑灌注软件处理后产生灌注曲线及伪彩图像,两次扫描前均测定大鼠的血液CO2分压、酸碱度(Potential of hydrogen, pH)等血气分析指标。检查结束后24小时内,处死大鼠并取脑固定,在尾状核中心层面全脑切片,观察肿瘤大体形态学表现后用石蜡包埋,在C6细胞种植部位(对照组在右侧尾状核层面)切片,染色,显微镜下进行组织病理学观察,并进行免疫组化检查VEGF和FⅧ-MVD。采用SPSS17.0统计学分析软件(SPSS Inc., Chicago, IL,美国)。应用ANOVA检验比较不同实验组之间的脑血容量(Cerebral blood volume,CBV)、脑血流量(Cerebral blood flow, CBF)、通透性和平均通过时间(Mean transit time, MTT)的变化差异有无统计学意义。在多重比较过程中,Bonferroni矫正后,P<0.01有统计学意义。比较乙酰唑胺负荷和CO2负荷前后灌注参数变化率用独立样本t检验。灌注参数CBV, CBF和通透性等与VEGF及FⅧ-MVD之间的相关性用Pearson相关分析,计算相关系数。P<0.05有统计学意义。
结果：C6大鼠均病理证实为胶质瘤。肿瘤边缘CBF, CBV和通透性较肿瘤实质部分高(p<0.01)。胶质瘤肿瘤实质部分较正常对照组CBF,CBV和通透性高(P<0.01)。12只正常大鼠(6只大鼠乙酰唑胺负荷,6只大鼠CO：负荷)负荷后CBF及CBV均上升(P<0.01)。在对照组中,CBF变化百分率乙酰唑胺负荷为117.42%,而10%CO2负荷为65.86%,二者差异有统计学意义(P<0.01)。CBV变化百分率乙酰唑胺负荷为107.51%,而10%CO2负荷为92.95%,二者差异无统计学意义(P=0.02)。大鼠C6胶质瘤实质部分,CBF变化百分率两种负荷之间的差异有统计学意义,乙酰唑胺负荷为72.73%,而10%CO2负荷为28.47%(P<0.01)。CBV变化百分率乙酰唑胺负荷为37.85%,而10%CO2负荷为24.69%。C6胶质瘤大鼠对侧正常脑组织与正常大鼠脑组织的CBF, CBV和通透性参数的变化百分率差异无统计学意义。瘤周水肿组织和对照组灌注参数变化百分率差异无统计学意义。肿瘤实质部分和肿瘤边缘之间灌注参数变化百分率差异无统计学意义。VEGF和FⅧ-MVD与CBV变化百分率间存在明显相关性(P<0.01)。CBF变化百分率与VEGF相关性较强。
结论：乙酰唑胺负荷CT灌注成像可以和CO2负荷CT灌注成像一样较好地评价C6胶质瘤负荷刺激因素下的血供变化情况。CBV变化百分率可以一定程度上反映VEGF和FⅧ-MVD, CBF变化百分率可以一定程度上反映VEGF。
第二部分乙酰唑胺负荷CT灌注成像对大鼠C6胶质瘤血管生成的评价
目的：研究不同种植天数C6胶质瘤乙酰唑胺(Acetazolamide,ACZ)负荷CT灌注参数变化率差异以及灌注参数变化率与CD105-MVD, VEGF,血管成熟指数(Vascular maturity index, VMI)和Ki67的相关性,探讨CT灌注参数及其变化率在评价C6胶质瘤血管生成中的病理基础和价值。
材料与方法：雄性SD (Sprgue Dawley)大鼠32只，年龄3个月,体重250-300g。将大鼠采用数字表法随机分为4组,8只为正常对照组,8只为种植C6胶质瘤10天组,8只为种植C6胶质瘤14天组,8只为种植C6胶质瘤18天组。肿瘤组大鼠通过立体定向仪于鼠脑右侧尾状核区种植C6胶质瘤细胞复制大鼠脑胶质瘤模型。对照组同部分注射等量生理盐水。大鼠C6胶质瘤10天组,14天组,18天组分别于肿瘤种植10天,14天,18天行ACZ负荷CT灌注检查。大鼠平放于CT检查床,四肢固定,阴茎背静脉留置静脉留置针,高压注射器注射对比剂。原位种植C6胶质瘤大鼠和正常大鼠分别行静息CT灌注检查,间隔1小时后行ACZ负荷CT灌注检查(静脉注射ACZ,15分钟后)。灌注成像以尾状核层面为中心。采用Philips CT自带脑灌注软件处理后产生灌注曲线及伪彩图像,两次扫描前均测定大鼠的动脉血二氧化碳分压(Carbon dioxide partial pressure,PaCO2)、 pH值指标。检查结束后24小时内,处死大鼠并取脑固定,在肿瘤中心层面切片,进行脑组织苏木素伊红(Hematoxylin and eosin,HE)染色及免疫组化检查CD105-MVD、FⅧ-MVD、α-平滑肌肌动蛋白(Alpha-smooth muscle actin, α-SMA)-MVD, VEGF和Ki67。VMI=(a-SMA-MVD/FⅧ-MVD)应用SPSS17.0进行统计分析。采用配对样本t检验,比较对照组和胶质瘤组大鼠ACZ负荷前后的CT灌注参数差异是否有统计学意义。应用ANOVA检验比较不同实验组之间的灌注参数变化百分率差异有无统计学意义。在多重比较过程中,Bonferroni矫正后,P<0.01有统计学意义。灌注参数与CD105-MVD, VEGF, VMI(?)(?)Ki67之间的相关性用Pearson相关分析。P<0.05为有统计学意义。
结果：四组大鼠在ACZ负荷后15分钟动脉血PaCO2升高,血浆pH值降低(P<0.01)。CBF和CBV在负荷前后的差异均有统计学意义。CBF变化百分率对照组与胶质瘤14天,18天差异有统计学意义。CBV变化百分率对照组与胶质瘤10天、14天、18天差异有统计学意义。CD105-MVD胶质瘤为10.64±6.13,正常组织为0.84±0.28,二者有统计学意义。Pearson相关分析显示,CBV变化百分率,CBF变化百分率,通透性,CBV, CBF与免疫组化的CD105-MVD, VEGF, VMI(?)(?)Ki67之间存在明显相关性。即CD105-MVD, VEGF, VMI和Ki67可以通过CBF变化百分率,CBV变化百分率,通透性以及CBF, CBV反映出来。
结论：不同种植天数C6胶质瘤ACZ负荷实验CT灌注成像灌注参数变化率不完全-致。CT灌注成像结合ACZ负荷实验得到的血流量变化率、血容量变化率、CBF、CBV以及通透性等参数可以一定程度上反映胶质瘤肿瘤血管生成情况。
第三部分CT灌注成像对人脑胶质瘤患者肿瘤血管生成的评价
目的：拟对256层CT灌注成像评价人脑胶质瘤肿瘤血管生成进行研究,探讨人脑胶质瘤患者256层CT灌注成像的可行性及灌注参数对评价肿瘤血管生成的价值,以期为临床评价胶质瘤患者血管生成及预后提供一种新的安全、有效的评价手段。
材料和方法：2010年1月一2012年2月对55例病例行脑256层CT灌注扫描,其中正常对照组15例,胶质瘤病例组40例。应用256层CT对受检者进行CT灌注成像检查。利用Mi STAR后处理软件,在病灶最大层面选取感兴趣区(Region of interest, ROI),获得感兴趣区的CBF, CBV, MTT和表面通透性等参数。采用SPSS17.0软件,应用ANOVA检验比较对照组、低级别胶质瘤组和高级别胶质瘤组灌注参数的差异有无统计学意义。在多重比较过程中,Bonferroni矫正后,P<0.01有统计学意义。应用配对样本t检验比较胶质瘤肿瘤实质和肿瘤边缘灌注参数之间的差异有无统计学意义。灌注参数CBF, CBV, MTT和表面通透性与病理指标CDl05-MVD,缺氧诱导因子-1α(Hypoxia-inducible factor-1alpha, HIF-la), VMI, CD34-MVD, a-SMA-MVD之间的相关性用Pearson相关分析,P<0.05有统计学意义。
结果：40例胶质瘤患者均经病理证实为脑胶质瘤,其中低级别胶质瘤15例,高级别胶质瘤25例。高级别胶质瘤组的CBF, CBV和表面通透性高于低级别胶质瘤组,低级别胶质瘤组的CBF, CBV和表面通透性高于对照组(P<0.01)。表面通透性为2.88ml/min/100g时,敏感度为96%,特异度为93%；CBV为3.91ml/100g时,敏感度为92%,特异度为93%；CBF为38.90ml/100g/min时,敏感度为92%,特异度为86%。高级别胶质瘤肿瘤边缘CBV, CBF和表面通透性参数高于肿瘤实质部分(P<0.01),高级别胶质瘤肿瘤边缘和实质MTT差异无统计学意义(P=0.14)。CBF, CBV和表面通透性与免疫组化指标CD105-MVD, HIF-1α, VMI, CD34-MVD以及a-SMA-MVD有明显相关性(p<0.05)
结论：人脑256-CT灌注成像灌注参数CBV, CBF和表面通透性可以一定程度上反映胶质瘤的肿瘤血管生成情况。
Part Ⅰ. Comparison between Acetazolamide Challenge and10%Carbon Dioxide using Perfusion CT in Rat C6Glioma
PURPOSE:Perfusion computed tomography (PCT) was used to investigate cerebral and C6glioma perfusion changes induced by acetazolamide (ACZ) and a mixture of10%carbon dioxide and90%air challenges. Correlations were investigated between PCT with ACZ and the results of Vascular endothelial growth factor (VEGF) and FⅧ-microvessel density (MVD).
MATERIALS AND METHODS:Dynamic PCT was performed on32male Sprague-Dawley rats (age3month, weight250-300g. selected randomly) including20rats with rat C6glioma and12rats served as controls. Ten rats with orthotopically implanted C6gliomas and6normal rats underwent PCT at rest and15minutes after1mg/kg intravenous ACZ. Another ten rats with C6gliomas and six normal rats underwent PCT at rest and15minutes after inhalation of a mixture of10%carbon dioxide and90%air which lasted for15minutes. The interval between PCT with challenge and at rest was at least1hour. All examinations were performed with a256-slice scanner. PCT was performed at glioma area and the right caudate nucleus in controls. The raw data were processed using Philips CT brain perfusion software which could provide time-density curve (TDC) curves and colour maps. Carbon dioxide partial pressure (PaCO2) and potential of hydrogen (pH) were recorded. At the end of the experiment, each animal was sacrificed in24hours. Their brains were resected and fixed, which were cut at the level of the right caudate nucleus. A coronal5μm thick slice of brain tissue from each rat was cut and stained according to the standard hematoxylin and eosin (HE) staining protocol. The samples were examined using immunohistochemical staining for VEGF and FⅧ-MVD. The statistical analysis was performed using the SPSS17.0package (SPSS Inc., Chicago, IL. USA). ANOVA test was used to compare the difference among different groups, after confirmation of normal distribution of the data. In the multiple comparison procedure. P<0.01was considered significant after Bonferroni correction. Independent-samples t tests were used to compare the difference between perfusion parameters changes with ACZ challenge and perfusion parameters changes with10%carbon dioxide. Pearson correlation coefficients were used to investigate relationships between cerebral blood flow (CBF) percentage changes, cerebral blood volume (CBV) percentage changes, permeability and the results of VEGF and FⅧ-MVD. P less than0.05was considered significant.
RESULTS:In the end of this experiment, those C6rats were dissected and proven to be gliomas. The tumor periphery had higher CBF, CBV, and permeability values than tumor central parenchyma (P<0.01). Tumor central parenchyma had higher CBF, CBV, and permeability values than controls (P<0.01). Twelve normal rats (6rats with ACZ stimuli,6rats with10%carbon dioxide stimuli) had increased CBF and CBV values after challenge (P<0.01). In controls, CBF percentage change apparently differed using ACZ stimuli (117.42%) compared to10%carbon dioxide (65.86%)(P<0.01). As for CBV percentage change, there was no significant difference between ACZ stimuli (107.51%) and10%carbon dioxide (92.95%)(P=0.02). In parenchyma of rat C6glioma, CBF percentage change was different using ACZ stimuli (72.73%) compared to10%carbon dioxide (28.47%)(P<0.01). CBV percentage change was37.85%with ACZ and24.69%with10%carbon dioxide. There was no significant difference in CBF, CBV and permeability percentage change between contralateral normal tissue and controls, beween peritumoral edema tissue and controls, and between tumor central parenchyma and the periphery. Significant correlations were observed between VEGF and FⅧ-MVD and blood volume percentage change (P<0.01). Blood flow percentage change correlated well with VEGF.
CONCLUSION:PCT with ACZ is suitable for evaluation of blood vessels in C6gliomas instead of inhalation of10%carbon dioxide without the side effects induced by10%carbon dioxide. CBV percentage is correlated change with the FⅧ-MVD and VEGF in gliomas. CBF percentage change is correlated with the VEGF in gliomas.
Part II. Cerebral Perfusion CT with Acetazolamide Challenge in C6Gliomas
PURPOSE:PCT with ACZ challenge was used to investigate perfusion changes of C6gliomas at10days,14days and18days. Correlations were investigated between PCT with ACZ and the results of CD105-MVD, VEGF, vascular maturity index (VMI) and Ki67.
MATERIALS AND METHODS:Dynamic PCT was performed on32male Sprague-Dawley rats (age3month, weight250-300g, selected randomly) including8rats with rat C6glioma10days,8rats with rat C6glioma14days,8rats with rat C6glioma18days and8rats served as controls. Intravenous catheter for contrast medium administration pre-and post-challenge was put in the vena dorsalis penis of rats.24rats with orthotopically implanted C6gliomas and6normal rats underwent PCT at rest and15minutes after1mg/kg intravenous ACZ. The interval between PCT with challenge and at rest was at least1hour. All examinations were performed with a256-sIice scanner. PCT was performed at glioma area and the right caudate nucleus in controls. The raw data were processed using Philips CT brain perfusion software which could provide TDC curves and colour maps. PaCO2and pH were recorded. At the end of the experiment, each animal was sacrificed in24hours. Their brains were resected and fixed, which were cut at the level of the right caudate nucleus. A coronal5um thick slice of brain tissue from each rat was cut and stained according to the standard HE staining protocol. The samples were examined using immunohistochemical staining for CD105-MVD, FⅧ-MVD, VEGF, alpha-smooth muscle actin (a-SMA)-MVD and Ki67. VMI was calculated as follows:VMI (%)=α-SMA-MVD/FⅧ-MVD X100%. The statistical analysis was performed using the SPSS17.0package. Paired-samples t tests were used to compare the difference between perfusion parameters pre-and post-ACZ challenge. ANOVA test was used to compare the difference among different groups, after confirmation of normal distribution of the data. In the multiple comparison procedure, P<0.01was considered significant after Bonferroni correction. Pearson correlation coefficients were used to investigate relationships between CBF percentage changes, CBV percentage changes, permeability, CBF, CBV and the results of CD105-MVD, VEGF, VMI and Ki67. P less than0.05was considered significant.
RESULTS:Gliomas of4groups were all proved to have elevated PaCO2and decreased pH after ACZ challenge (P<0.01). Significant CBF. CBV difference was observed before and after ACZ challenge. Rat glioma in14days and18days group had higher CBF than controls (P<0.01). Rat glioma inl0days,14days and18days group had higher CBV than controls (P<0.01). CD105-MVD of Rat C6glioma is10.64±6.13. CD105-MVD of controls was0.84±0.28. Significant correlations were observed between CD105-MVD. VEGF, VMI, Ki67and CBV percentage change, CBF percentage change, permeability. CBV and CBF (P<0.01).
CONCLUSION:There was difference between10days,14days.18days gliomas and controls. PCT with ACZ challenge could provide useful parameters, such as CBF percentage change, CBV percentage change, permeability, CBF. and CBV, which could correlate with glioma angiogenesis.
Part Ⅲ. Evaluation of human glioma angiogenesis using Perfusion CT
PURPOSE:To evaluate the feasibility of human glioma perfusion CT and analyse the relationship between perfusion parameters and human glioma angiogenesis.
MATERIALS AND METHODS:From January2010to February2012,55subjects underwent perfusion256-CT imaging. Among them, the histopathological results of40patients were gliomas. Perfusion CT imaging was performed in15healthy volunteers served as controls. The raw data were processed using CT perfusion software. Perfusion parameters including CBF, CBV, MTT and permeability surface-area product. The statistical analysis was performed using the SPSS17.0package. ANOVA test was used to compare the difference among controls, low grade glioma group and high grade glioma. In the multiple comparison procedure. P<0.01was considered significant after Bonferroni correction. Paired-samples t tests were used to compare the difference between perfusion parameters of peripheral and solid tissue. Pearson correlation coefficients were used to investigate relationships between CBF. CBV. permeability surface-area product and the results of CD105-MVD, Hypoxia-inducible factor-1alpha (HIF-1α), VMI. CD34-MVD and a-SMA-MVD. P less than0.05was considered significant.
RESULTS:Twenty-five patients were proved to be high grade gliomas, and fifteen patients were proved to be low grade gliomas. Significant CBF, CBV difference was observed between high grade gliomas and low grade gliomas (P<0.01). Cutoff value of permeability surface-area product was2.88ml/min/100g, the sensitivity and specificity of which were96%and93%. Cutoff value of CBV was3.91ml/100g. the sensitivity and specificity of which were92%and93%. Cutoff value of CBF was38.90ml/100g/min. the sensitivity and specificity of which were92%and86%. Significant CBF, CBV difference was observed between low grade gliomas and controls (P<0.01). The periphery had higher CBF, CBV and permeability surface-area product than the solid tissue in high grade gliomas (P<0.01). There was no significant difference in MTT (P=0.14). Significant correlations were observed between CD105-MVD, HIF-la, VMI, CD34-MVD. a-SMA-MVD and CBV, CBF, permeability surface-area product (P<0.01).
CONCLUSION:PCT could provide useful parameters, such as CBF, CBV and permeability surface-area product, which could correlate with glioma angiogenesis.
引文
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