磁共振灌注成像在脑胶质瘤的临床应用及动物实验研究
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摘要
胶质瘤是脑内最常见的原发占位性病变，其病理特点是存在异质性，因此活检有时会低估胶质瘤的级别。尽管近年来手术、放疗和化疗等水平不断提高，胶质瘤患者，尤其是高级别胶质瘤患者的预后仍非常差。为了制定最佳治疗方案和评估预后，准确的病理分级是必须的。血管增生程度是胶质瘤病理分级的一个重要指标，准确评估肿瘤血供对确定胶质瘤级别是有价值的。近年来迅速发展的MR灌注加权成像技术(perfusion weighted imaging，MR PWI)能反映组织的微血管分布及血流灌注情况，提供血流动力学方面的信息。因此，MR PWI可以通过各种血流动力学指标对肿瘤血管化及血容量、血流量进行定性和定量分析，并用于协助胶质瘤术前分级及定位活检。本研究旨在探讨MR PWI对胶质瘤术前分级的作用和价值以及大鼠C6脑胶质瘤模型进行MR PWI研究的可行性。
目的：
1 探讨MR PWI在术前评估脑胶质瘤组织病理学分级中的价值。
第四军医大学博士学位论文
2检测细胞核因子KB(NF一B)在脑胶质瘤中的表达，并探讨
其与脑胶质瘤血管生成的关系。
3探讨脑胶质瘤相对脑血容量(rCBV)与血管内皮细胞生长因子
(VEGF)蛋白表达及肿瘤微血管密度(MVD)间的相关性。
4探讨大鼠C6脑胶质瘤模型应用常规MR动态观察的价值及对
其进行MR PWI研究的可行性。
方法:
1对30例术前疑为幕上胶质瘤的患者行MR检查，术后经病理组
织学证实。MR扫描顺序为常规MR平扫、PWI及常规MR增
强扫描。PWI序列为梯度回波一平面回波(GE一EPI)序列，原始
灌注图像数据经工作站软件计算出脑CBV图和CBF图，在CBV
图和CBF图上获取胶质瘤最大rCBV值(rCBV)和最大rCBF
〔rCBF)值，并与病理组织学分级做对照。对rCBV与rCBF
两组数据进行非参数相关分析，观察两组间的相关性。
2应用免疫组织化学方法检测NF一Bp65及vEGF在30例胶质
瘤及10例正常脑组织中的表达情况，同时观察肿瘤内MVD，
将NF一Bp65蛋白表达与vEGF蛋白表达及MvD计数进行统
计学分析。
3按VEGF表达阳性与阴性将胶质瘤分为两组，即VEGF阳性组
与VEGF阴性组，做统计学分析，观察两组间最大rCBV值是
否有统计学差异。采用直线相关分析观察最大rCBV值与MVD
间的关系。
4采用立体定向的方法将1、106/lo，1浓度c6胶质瘤细胞种植于
大鼠右侧尾状核部位，建立大鼠C6脑胶质瘤模型，观察大鼠
术后的一般情况和常规MR表现，在大鼠濒死前行MR PWI检
查，PWI检查后处死大鼠或大鼠自然死亡后立即获取肿瘤标本，
做病理学检查。
第四军医大学博士学位论文
结果:
1低级别(I一11级)胶质瘤rCBV、:CBF范围分别为0.72一4.26
和0.82一2.89，均值分别为2.10士0.88和1.52士0.65。高级别(111
一IV级)胶质瘤rCBV、rCBF范围分别为0.89一10.02和
1.50一6.40，均值分别为5.23士1.89和4.81士1.60。高、低级别胶
质瘤间的rCBV和rCBF比较有统计学意义(p< 0.01)。非参数
相关性分析表明rCBV与rCBF间有显著的正相关性(r=0.772，
P<0 .001)。
2 30例胶质瘤中17例NF一KBp65蛋白表达阳性，阳性表达率
为56.7%，阳性产物定位于肿瘤细胞核。10例正常脑组织中NF-
KBp65无l例阳性表达。NF一KBp65表达与VEGF表达、MVD
计数显著相关(p<0.01)。
3 30例胶质瘤组织中vEGF阳性表达率为53.3%(16/30)，正常
脑组织中未见VEGF染色。VEGF阳性组:CBV的范围为1 .11
一10.02，中位数5.36;VEGF阴性组rCBV的范围为0.72一6.32，
中位数2.89。统计结果表明，VEGF阳性组与VEGF阴性组
rCBVt匕较有统计学意义(p<0.01)。30例胶质瘤中MVD的范
围为12.47一69.39，平均40.18士15.19。rCBV的范围为0.72一
10.02，平均3.98士1.52。经直线相关分析，两者间具有显著正
相关性(r=0.780，p<0.001)。
4采用立体定向的方法将C6胶质瘤细胞种植于大鼠右侧尾状核
部位，可以建立稳定的胶质瘤模型。常规MR能够动态观察大
鼠C6胶质瘤模型的生长及发展。大鼠C6胶质瘤为实性肿瘤，
MRI表现为长Tl长TZ信号，瘤组织有明显强化，有瘤周水
肿，晚期瘤组织中央有坏死，肿瘤体积达到一定程度后可出现
占位效应。在MR PWI的CBV图上胶质瘤呈高灌注表现。肿
瘤最大CBV值的均数和标准差为1 44.46士22.51，正常脑组织
CBV值的均数和标准差为75.79士13.21，t检验两者有显著差
异(p=0．000)。肿瘤最大rCBV值的均数和标准差为2．0 1±
0．1 7。
结论：
1 MR PWI可以提供常规MR图像所无法获得的肿瘤血供信息；
结合常规MR图像，MR PWI对胶质瘤术前分级和治疗方案的
制定有临床实用价值。
2 NF．K B p65是脑胶质瘤相关的一种癌蛋白，在胶质瘤的发生
中发挥重要调节作用。NF．K B对’VEGF可能有正向调节作用，
进而影响胶质瘤血管生成。
3 MR PWI的最大rCBV值与MVD和VEGF具有良好的相关性，
可以作为术前评价脑胶质瘤血管生成的可靠指标。
4大鼠C6胶质瘤细胞立体定向接种可建立一种稳定的脑胶质瘤
模型，常规MR能够在活体上对大鼠C6?
Gliomas are most common primary neoplasms of the brain. They have a heterogeneous histologic spectrum, and at biopsy their grade thus tends to be underestimated. In spite of improvements in the results of surgery, radiation therapy and chemotherapy, the prognosis of patients with gliomas, particularly those with high-grade tumors, remains poor. For planning the optimal treatment strategy and assessing prognosis, accurate histologic grading is essential, and for this, vascular proliferation is an important criteria; in determining the histologic grade of a glioma, the evaluation of tumor vascularity is therefore valuable. Recent developments in MR perfusion weighted imaging (MR PWI) techniques can assess distribution of microvessel and blood perfusion of tissue,and provide hemodynamics information. So MR PWI have permitted the creation of cerebral blood volume (CBV) maps, leading to the
qualitative and quantitative assessment of tumor vascularity. These maps have helped in the assessment of tumor grade and in targeting the site of biopsy. The purpose of this study was to evaluate the role of MR PWI in pre-operation grading of gliomas and investigate the feasibility of rat C6 brain glioma model in MR PWI research.
Objective:
1 To evaluate the value of MR PWI in preoperative grading of cerebral gliomas.
2 To investigate the expression of NF- k B protein and the relationship between the expression of NF- k B and angiogenesis in cerebral gliomas.
3 To investigate the correlation of rCBV with vascular endothelial
growth factor ( VEGF ) protein expression and microvessel density (MVD) in cerebral gliomas.
4 To study the value of conventional MR in long-term follow-up and
the feasibility in MR PWI research of rat C6 brain glioma model.
Methods:
1 MR examinations were performed preoperatively in 30 patients with suspected supratentorial gliomas. All the 30 cases were proved by operation and pathology. The procedures of MR examinations included plain MR scan, PWI and routine contrast-enhanced MR scan. The pulse sequence of PWI was GE-EPI. The CBV and CBF maps were calculated from the original data of perfusion images and the maximum rCBV and maximum rCBF of gliomas were acquired from CBV and CBF maps through measurement on the region of interest (ROI). The
results of maximum rCBV and rCBF were correlated with those of histopathologic gradings. The correlation between rCBV and rCBF was evaluated using spearman's rank correlation analysis.
2 The expression of NF- k B p65 protein, VEGF protein and MVD in 30 cases of cerebral gliomas and 10 cases of normal brain tissue were detected inimunohistochemically.The correlation of NF- k B, VEGF and MVD was studied.
3 According to the situation of VEGF protein expression, all the 30 cases were divided into two groups including positive VEGF protein expression group [VEGF( + )] and negative VEGF protein expression group [VEGF(-)]. Wilcoxon test was used for comparing the difference between the two groups. Linear correlation analysis was used for observing the correlation between rCBV and MVD in gliomas.
4 By using the sterotatic method to implant C6 cells into the right caudate nucleus of rat, to set up the rat C6 brain gliomas model.
The cell density of inoculation is 1x106 /10ul. On the following days, common condition and MR features of the rats were observed. MR PWI were performed in the dying rats. The specimens of tumors for pathological study were collected in the dying time or after the death of rats immediately.
Results:
1 The rCBV and rCBF in grade I-II gliomas were 0.72-4.26 and 0.82-2.89 respectively, with a mean of 2.10+0.88 and 1.52+0.65. The rCBV and rCBF in grade III-IV gliomas varied from 0.89-10.02 and 1.50-6.04 with a mean 5.23+1.89 and 4.81+1.60. The difference in rCBV and rCBF was statistically significant
between grade I-II and III-IV gliomas (student t test, p<0.01). There was a strong correlation between rCBV a
目的：
1 探讨MR PWI在术前评估脑胶质瘤组织病理学分级中的价值。
第四军医大学博士学位论文
2检测细胞核因子KB(NF一B)在脑胶质瘤中的表达，并探讨
其与脑胶质瘤血管生成的关系。
3探讨脑胶质瘤相对脑血容量(rCBV)与血管内皮细胞生长因子
(VEGF)蛋白表达及肿瘤微血管密度(MVD)间的相关性。
4探讨大鼠C6脑胶质瘤模型应用常规MR动态观察的价值及对
其进行MR PWI研究的可行性。
方法:
1对30例术前疑为幕上胶质瘤的患者行MR检查，术后经病理组
织学证实。MR扫描顺序为常规MR平扫、PWI及常规MR增
强扫描。PWI序列为梯度回波一平面回波(GE一EPI)序列，原始
灌注图像数据经工作站软件计算出脑CBV图和CBF图，在CBV
图和CBF图上获取胶质瘤最大rCBV值(rCBV)和最大rCBF
〔rCBF)值，并与病理组织学分级做对照。对rCBV与rCBF
两组数据进行非参数相关分析，观察两组间的相关性。
2应用免疫组织化学方法检测NF一Bp65及vEGF在30例胶质
瘤及10例正常脑组织中的表达情况，同时观察肿瘤内MVD，
将NF一Bp65蛋白表达与vEGF蛋白表达及MvD计数进行统
计学分析。
3按VEGF表达阳性与阴性将胶质瘤分为两组，即VEGF阳性组
与VEGF阴性组，做统计学分析，观察两组间最大rCBV值是
否有统计学差异。采用直线相关分析观察最大rCBV值与MVD
间的关系。
4采用立体定向的方法将1、106/lo，1浓度c6胶质瘤细胞种植于
大鼠右侧尾状核部位，建立大鼠C6脑胶质瘤模型，观察大鼠
术后的一般情况和常规MR表现，在大鼠濒死前行MR PWI检
查，PWI检查后处死大鼠或大鼠自然死亡后立即获取肿瘤标本，
做病理学检查。
第四军医大学博士学位论文
结果:
1低级别(I一11级)胶质瘤rCBV、:CBF范围分别为0.72一4.26
和0.82一2.89，均值分别为2.10士0.88和1.52士0.65。高级别(111
一IV级)胶质瘤rCBV、rCBF范围分别为0.89一10.02和
1.50一6.40，均值分别为5.23士1.89和4.81士1.60。高、低级别胶
质瘤间的rCBV和rCBF比较有统计学意义(p< 0.01)。非参数
相关性分析表明rCBV与rCBF间有显著的正相关性(r=0.772，
P<0 .001)。
2 30例胶质瘤中17例NF一KBp65蛋白表达阳性，阳性表达率
为56.7%，阳性产物定位于肿瘤细胞核。10例正常脑组织中NF-
KBp65无l例阳性表达。NF一KBp65表达与VEGF表达、MVD
计数显著相关(p<0.01)。
3 30例胶质瘤组织中vEGF阳性表达率为53.3%(16/30)，正常
脑组织中未见VEGF染色。VEGF阳性组:CBV的范围为1 .11
一10.02，中位数5.36;VEGF阴性组rCBV的范围为0.72一6.32，
中位数2.89。统计结果表明，VEGF阳性组与VEGF阴性组
rCBVt匕较有统计学意义(p<0.01)。30例胶质瘤中MVD的范
围为12.47一69.39，平均40.18士15.19。rCBV的范围为0.72一
10.02，平均3.98士1.52。经直线相关分析，两者间具有显著正
相关性(r=0.780，p<0.001)。
4采用立体定向的方法将C6胶质瘤细胞种植于大鼠右侧尾状核
部位，可以建立稳定的胶质瘤模型。常规MR能够动态观察大
鼠C6胶质瘤模型的生长及发展。大鼠C6胶质瘤为实性肿瘤，
MRI表现为长Tl长TZ信号，瘤组织有明显强化，有瘤周水
肿，晚期瘤组织中央有坏死，肿瘤体积达到一定程度后可出现
占位效应。在MR PWI的CBV图上胶质瘤呈高灌注表现。肿
瘤最大CBV值的均数和标准差为1 44.46士22.51，正常脑组织
CBV值的均数和标准差为75.79士13.21，t检验两者有显著差
异(p=0．000)。肿瘤最大rCBV值的均数和标准差为2．0 1±
0．1 7。
结论：
1 MR PWI可以提供常规MR图像所无法获得的肿瘤血供信息；
结合常规MR图像，MR PWI对胶质瘤术前分级和治疗方案的
制定有临床实用价值。
2 NF．K B p65是脑胶质瘤相关的一种癌蛋白，在胶质瘤的发生
中发挥重要调节作用。NF．K B对’VEGF可能有正向调节作用，
进而影响胶质瘤血管生成。
3 MR PWI的最大rCBV值与MVD和VEGF具有良好的相关性，
可以作为术前评价脑胶质瘤血管生成的可靠指标。
4大鼠C6胶质瘤细胞立体定向接种可建立一种稳定的脑胶质瘤
模型，常规MR能够在活体上对大鼠C6?
Gliomas are most common primary neoplasms of the brain. They have a heterogeneous histologic spectrum, and at biopsy their grade thus tends to be underestimated. In spite of improvements in the results of surgery, radiation therapy and chemotherapy, the prognosis of patients with gliomas, particularly those with high-grade tumors, remains poor. For planning the optimal treatment strategy and assessing prognosis, accurate histologic grading is essential, and for this, vascular proliferation is an important criteria; in determining the histologic grade of a glioma, the evaluation of tumor vascularity is therefore valuable. Recent developments in MR perfusion weighted imaging (MR PWI) techniques can assess distribution of microvessel and blood perfusion of tissue,and provide hemodynamics information. So MR PWI have permitted the creation of cerebral blood volume (CBV) maps, leading to the
qualitative and quantitative assessment of tumor vascularity. These maps have helped in the assessment of tumor grade and in targeting the site of biopsy. The purpose of this study was to evaluate the role of MR PWI in pre-operation grading of gliomas and investigate the feasibility of rat C6 brain glioma model in MR PWI research.
Objective:
1 To evaluate the value of MR PWI in preoperative grading of cerebral gliomas.
2 To investigate the expression of NF- k B protein and the relationship between the expression of NF- k B and angiogenesis in cerebral gliomas.
3 To investigate the correlation of rCBV with vascular endothelial
growth factor ( VEGF ) protein expression and microvessel density (MVD) in cerebral gliomas.
4 To study the value of conventional MR in long-term follow-up and
the feasibility in MR PWI research of rat C6 brain glioma model.
Methods:
1 MR examinations were performed preoperatively in 30 patients with suspected supratentorial gliomas. All the 30 cases were proved by operation and pathology. The procedures of MR examinations included plain MR scan, PWI and routine contrast-enhanced MR scan. The pulse sequence of PWI was GE-EPI. The CBV and CBF maps were calculated from the original data of perfusion images and the maximum rCBV and maximum rCBF of gliomas were acquired from CBV and CBF maps through measurement on the region of interest (ROI). The
results of maximum rCBV and rCBF were correlated with those of histopathologic gradings. The correlation between rCBV and rCBF was evaluated using spearman's rank correlation analysis.
2 The expression of NF- k B p65 protein, VEGF protein and MVD in 30 cases of cerebral gliomas and 10 cases of normal brain tissue were detected inimunohistochemically.The correlation of NF- k B, VEGF and MVD was studied.
3 According to the situation of VEGF protein expression, all the 30 cases were divided into two groups including positive VEGF protein expression group [VEGF( + )] and negative VEGF protein expression group [VEGF(-)]. Wilcoxon test was used for comparing the difference between the two groups. Linear correlation analysis was used for observing the correlation between rCBV and MVD in gliomas.
4 By using the sterotatic method to implant C6 cells into the right caudate nucleus of rat, to set up the rat C6 brain gliomas model.
The cell density of inoculation is 1x106 /10ul. On the following days, common condition and MR features of the rats were observed. MR PWI were performed in the dying rats. The specimens of tumors for pathological study were collected in the dying time or after the death of rats immediately.
Results:
1 The rCBV and rCBF in grade I-II gliomas were 0.72-4.26 and 0.82-2.89 respectively, with a mean of 2.10+0.88 and 1.52+0.65. The rCBV and rCBF in grade III-IV gliomas varied from 0.89-10.02 and 1.50-6.04 with a mean 5.23+1.89 and 4.81+1.60. The difference in rCBV and rCBF was statistically significant
between grade I-II and III-IV gliomas (student t test, p<0.01). There was a strong correlation between rCBV a
引文
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