脑胶质瘤磁共振功能成像的实验与临床应用研究
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摘要
前言
脑胶质瘤的恶性程度不同，其治疗方法及预后亦不同，术前正确判断肿瘤的病理学级别及其预后有重要的临床意义。常规磁共振检查方法虽然在显示颅内肿瘤的形态学信息方面有着无可争议的价值，然而却难以获得肿瘤的病理学分级、肿瘤微血管生成以及生化学等功能性信息。磁共振弥散加权成像(DWI)是用于观察活体组织中水分子的微观弥散运动的成像方法；动态对比剂增强磁共振灌注成像(PWI)是随着磁共振快速成像技术的发展而出现的一种反映组织微循环血流灌注情况的磁共振检查方法；~1H磁共振波谱(~1HMRS)是一种新兴的无创性观测脑组织及肿瘤组织生化特性及代谢改变的方法，能够在体观察肿瘤的发生、发展及对治疗的反应。三者作为常规磁共振检查方法的补充，在脑胶质瘤的诊断及分级等评价方面会获取更多的功能性信息，为肿瘤的早期诊断及预后判定提供客观的依据。
本研究的创新之处在于将最前沿的肿瘤发生机制的研究理念和方法引入现有的影像研究领域，改良现有影像学研究方法，突破传统的影像学研究理念，从研究活体脑内微循环、脑代谢等着手，首次联合应用MRI功能检查技术活体对脑胶质瘤的生物学特性进行研究，并与组织病理学建立起相关性，实现形态与功能并重，从根本上提高肿瘤的早期诊断率。
目的
对大鼠脑胶质瘤动物模型的生物学特性进行MR DWI、PWI及~1HMRS研究，探讨三者在肿瘤病理学分级、肿瘤微循环及脑代谢异常等方面的诊断价值，结合组织学及微血管计数，建立DWI、PWI与组织学改变的内在联系。同时，对脑胶质瘤患者的~1HMRS与病理对照研究，总结~1HMRS在脑胶质瘤的诊断与鉴别诊断、病理学分级及预后判定等方面的价值。
材料与方法
41只Wistar大鼠作为研究对象，其中随机选择36只颅内注入5μl C6
胶质瘤细胞混悬液;5只大鼠在相同部位注射5闪Ham’sF一12培养液作正
常对照。C6肿瘤细胞移植1一4周后，每次随机选取8一10只大鼠分别于
种植后1周、2周、3周及4周后进行磁共振常规T，加权图像(TIWI)、飞加
权图像(几WI)、Tl增强扫描及D那、PWI检查;每次随机选择8只分别于种
植后2周及4周后进行‘HMRS检查;同时选择5只正常鼠作对照。磁共振
检查采用GE公司生产的signaM形iTM 1 .ST HisPeedPlu。超导型磁共振扫
描仪。使用直径为3英寸的双调谐正交表面线圈，置于鼠脑上。扫描方向
为平行于前后方向。分别在几WI及增强扫描图像上观察肿瘤特点，测量
肿瘤的径线值。生成伪彩色图像即表观弥散系数(ADC)图及局部脑血容
量(尤BV)图，分别计算肿瘤实质区及肿瘤周围区的ADC值及最大尤BV
值。在‘HMRS上测定肿瘤实质区及肿瘤周围区的N一乙酞基天门冬氨酸
(NAA)、胆碱类化合物(CHO)、肌酸和磷酸肌酸(CR)、脂质(Up)及乳酸
(LAC)、谷氨酸及谷氨酞胺(Glu一n)等代谢物波峰面积并与CR波面积进行
比较。MR检查后即刻处死动物并断头取脑，以肿瘤为中心横断面切片行
HE染色及单抗CD34免疫组织化学染色。光镜下计算高倍视野下肿瘤组
织的细胞构成比;应用CD34免疫组化染色血管内皮细胞和小血管壁并进
行微血管密度(MVD)计数。采用单向方差分析法检测肿瘤实质部分ADC
值与肿瘤细胞构成比， MVD与沈BV最大值间的相关性。
本组临床研究收集脑肿瘤患者22例(男14例，女8例)，年龄32一62
岁，平均46.7岁。所有患者均经手术及病理证实，其中恶性脑胶质瘤14例
(间变型星形细胞瘤8例，胶质母细胞瘤6例)，单发脑转移瘤8例(其中肺
癌脑转移3例，乳腺癌脑转移2例，肾癌脑转移2例，结肠癌脑转移1例)。
术前均行MRI平扫、Gd.DTpA增强扫描及，HMRs检查。对其中16例患者
分别于术后6个月一1年内进行MRI平扫及增强扫描复查。
实验结果
一、大鼠脑胶质瘤动物模型的常规MIU、D节江及PWI.表现及与组织学
的相关性
在C6种植后1一4周内，MR显示随种植周数的增加肿瘤径线值呈渐
进性增长趋势。种植后l一2周，几wi及增强扫描上肿瘤径线值的增长均
无统计学差异(P>0.05);种植后3一4周，几WI上肿瘤径线值的增长有统
计学差异，增强扫描上无统计学差异;而种植后1一2周与3一4周间比较，
毛Wl及增强扫描上肿瘤径线值的增长均具有显著的统计学差异(P<
0.01)。晚期阶段的肿瘤径线值在几wi上均较T;wl增强扫描范围大。
Dwi上，所有36例C6胶质瘤，肿瘤实质区信号强度均高于对侧相应
部位的正常脑白质。种植后1一3周，肿瘤实质区与肿瘤周围区ADC值差
异不显著(P>0.05)，仅种植后4周肿瘤实质区与肿瘤周围区ADC值有统
计学差异(P<0.05)。肿瘤种植后1一4周，随种植周数的增加，肿瘤实质
区ADC值呈逐渐递减趋势;种植后3一4周，肿瘤实质区及肿瘤周围区ADC
值与种植后1一2周及对侧脑白质相比，均具有显著性统计学差异(P<
0.01)。胶质瘤实质区的ADC值随镜下肿瘤组织细胞构成比增加而降低，
相关回归分析呈明显的负相关(r二一0.682，P<0.01)。
种植后1周及5例种植后2周的肿瘤沈BV图分布较均匀，接近于对侧
脑白质;种植后3一4周的肿瘤此BV图分布明显不均匀，肿瘤实质区尤BV
多有不同程度的增高。肿瘤种植后1一4
Preface
Presurgical determination of malignancy and prognosis of cerebral gliomas plays an important role in clinical work due to different methods of treatment. Routine MR imaging is difficult to provide functional information such as pathological grading, angiogenesis, and biochemical information though it may be useful for morphological diagnosis of gliomas. Diffusion weighted imaging (DWI) allows us to observe the microcosmic movement of the water molecules in the living tissues; dynamic contrast-enhanced perfusion imaging ( PWI) can evaluate the cerebral hemodynamic status noninvasively, which is developing with the presence of fast MR imaging technique. And proton MR spectroscopy (1 HMRS) can determine the biochemical and metabolic levels of both brain tissues and cerebral tumors noninvasively, may be helpful for observation of occurrence, development, as well as therapeutic reaction of brain tumors. All of these three methods, as complementary methods for routine MR examination, may give us more functional in
formation in the diagnosis of gliomas, and provide the objective criterion for the early diagnosis and prognostic assessment.
Our studies introduce leading theory of tumorigenesis into territory of imaging study, improve present methods of imaging study, break through traditional imaging study theory and engage in the study of microcirculation and cerebral metabolites noninvasively. For the first time, we combine MR functional techniques to study the biological characteristics of cerebral gliomas, correlated with histopathology in order to improve the early diagnostic rate of gliomas.
Purpose
DWI, PWI, and 1HMRS study of biological characteristics of animal model
of gliomas in rat brain was performed to evaluate these three methods in the determination of pathological grading, microcirculation, and metabolites of the tumor, and to establish internal connection between DWI/PWI and histology/ microvessel counting. Meanwhile, correlation between l HMRS manifestations of patients suffered from gliomas and pathological results were performed to evaluate l HMRS in the diagnosis, differential diagnosis, pathological grading, as well as prognostic assessment of cerebral gliomas.
Materials and Methods
41 female Wistar rats were used for this study. 36 rats Glial tumors were implanted into the left hemisphere by intracerebral injection of 1 x 10s C6 glioma cells in 5ul Ham' s F12 medium. As a control, five rats also received stereotac-tic injection of 5ul Ham' s F12 medium without tumor cells in the same location. Between 1 and 4 weeks after the C6 glioma cells were injected intracere-brally, eight to ten different rats were imaged at each weekly time point. The brain of each rat was imaged with precontrast T, weighted spin-echo imaging (T1WI), 12 weighted spin-echo imaging (T2WI), diffusion weighted imaging (DWI), perfusion weighted imaging (PWI), and postcontrast T,WI. Meanwhile, 'HMRS were performed in eight different rats at 2 weeks and 4 weeks after implantation respectively. Five rats were also done for comparison. MR examination was performed using GE Signa MR/iTM 1. 5T Hispeed Plus superconductive MR system. A cylindrical surface coil with 3 inch in diameter was positioned over the rat head. Images were acquired parallel to the anterior-posterior direction ( " horizontally" ). Transverse diameter values of tumors were measured on both T2WI and postcontrast TjWI. Apparent diffusion coefficient (ADC) maps and regional cerebral blood volume (rCBV) maps were formatted, and ADC values and maximal rCBV values in both tumoral regions and peritu-moral regions were calculated. Relative metabolite levels including N-acetylas-partate (NAA), choline ( CHO) , creatine compounds ( CR) , lipid ( Lip), lactate ( LAC) , glutamate and glutamine ( Glu-n) were measured, related to the peak area, and expressed with reference to CR. Immediately after MRI,
each rat was killed and the brain was removed and post-fixed overnight. After the brains were fixed, they were paraffin-embedded, sectioned, and examined
脑胶质瘤的恶性程度不同，其治疗方法及预后亦不同，术前正确判断肿瘤的病理学级别及其预后有重要的临床意义。常规磁共振检查方法虽然在显示颅内肿瘤的形态学信息方面有着无可争议的价值，然而却难以获得肿瘤的病理学分级、肿瘤微血管生成以及生化学等功能性信息。磁共振弥散加权成像(DWI)是用于观察活体组织中水分子的微观弥散运动的成像方法；动态对比剂增强磁共振灌注成像(PWI)是随着磁共振快速成像技术的发展而出现的一种反映组织微循环血流灌注情况的磁共振检查方法；~1H磁共振波谱(~1HMRS)是一种新兴的无创性观测脑组织及肿瘤组织生化特性及代谢改变的方法，能够在体观察肿瘤的发生、发展及对治疗的反应。三者作为常规磁共振检查方法的补充，在脑胶质瘤的诊断及分级等评价方面会获取更多的功能性信息，为肿瘤的早期诊断及预后判定提供客观的依据。
本研究的创新之处在于将最前沿的肿瘤发生机制的研究理念和方法引入现有的影像研究领域，改良现有影像学研究方法，突破传统的影像学研究理念，从研究活体脑内微循环、脑代谢等着手，首次联合应用MRI功能检查技术活体对脑胶质瘤的生物学特性进行研究，并与组织病理学建立起相关性，实现形态与功能并重，从根本上提高肿瘤的早期诊断率。
目的
对大鼠脑胶质瘤动物模型的生物学特性进行MR DWI、PWI及~1HMRS研究，探讨三者在肿瘤病理学分级、肿瘤微循环及脑代谢异常等方面的诊断价值，结合组织学及微血管计数，建立DWI、PWI与组织学改变的内在联系。同时，对脑胶质瘤患者的~1HMRS与病理对照研究，总结~1HMRS在脑胶质瘤的诊断与鉴别诊断、病理学分级及预后判定等方面的价值。
材料与方法
41只Wistar大鼠作为研究对象，其中随机选择36只颅内注入5μl C6
胶质瘤细胞混悬液;5只大鼠在相同部位注射5闪Ham’sF一12培养液作正
常对照。C6肿瘤细胞移植1一4周后，每次随机选取8一10只大鼠分别于
种植后1周、2周、3周及4周后进行磁共振常规T，加权图像(TIWI)、飞加
权图像(几WI)、Tl增强扫描及D那、PWI检查;每次随机选择8只分别于种
植后2周及4周后进行‘HMRS检查;同时选择5只正常鼠作对照。磁共振
检查采用GE公司生产的signaM形iTM 1 .ST HisPeedPlu。超导型磁共振扫
描仪。使用直径为3英寸的双调谐正交表面线圈，置于鼠脑上。扫描方向
为平行于前后方向。分别在几WI及增强扫描图像上观察肿瘤特点，测量
肿瘤的径线值。生成伪彩色图像即表观弥散系数(ADC)图及局部脑血容
量(尤BV)图，分别计算肿瘤实质区及肿瘤周围区的ADC值及最大尤BV
值。在‘HMRS上测定肿瘤实质区及肿瘤周围区的N一乙酞基天门冬氨酸
(NAA)、胆碱类化合物(CHO)、肌酸和磷酸肌酸(CR)、脂质(Up)及乳酸
(LAC)、谷氨酸及谷氨酞胺(Glu一n)等代谢物波峰面积并与CR波面积进行
比较。MR检查后即刻处死动物并断头取脑，以肿瘤为中心横断面切片行
HE染色及单抗CD34免疫组织化学染色。光镜下计算高倍视野下肿瘤组
织的细胞构成比;应用CD34免疫组化染色血管内皮细胞和小血管壁并进
行微血管密度(MVD)计数。采用单向方差分析法检测肿瘤实质部分ADC
值与肿瘤细胞构成比， MVD与沈BV最大值间的相关性。
本组临床研究收集脑肿瘤患者22例(男14例，女8例)，年龄32一62
岁，平均46.7岁。所有患者均经手术及病理证实，其中恶性脑胶质瘤14例
(间变型星形细胞瘤8例，胶质母细胞瘤6例)，单发脑转移瘤8例(其中肺
癌脑转移3例，乳腺癌脑转移2例，肾癌脑转移2例，结肠癌脑转移1例)。
术前均行MRI平扫、Gd.DTpA增强扫描及，HMRs检查。对其中16例患者
分别于术后6个月一1年内进行MRI平扫及增强扫描复查。
实验结果
一、大鼠脑胶质瘤动物模型的常规MIU、D节江及PWI.表现及与组织学
的相关性
在C6种植后1一4周内，MR显示随种植周数的增加肿瘤径线值呈渐
进性增长趋势。种植后l一2周，几wi及增强扫描上肿瘤径线值的增长均
无统计学差异(P>0.05);种植后3一4周，几WI上肿瘤径线值的增长有统
计学差异，增强扫描上无统计学差异;而种植后1一2周与3一4周间比较，
毛Wl及增强扫描上肿瘤径线值的增长均具有显著的统计学差异(P<
0.01)。晚期阶段的肿瘤径线值在几wi上均较T;wl增强扫描范围大。
Dwi上，所有36例C6胶质瘤，肿瘤实质区信号强度均高于对侧相应
部位的正常脑白质。种植后1一3周，肿瘤实质区与肿瘤周围区ADC值差
异不显著(P>0.05)，仅种植后4周肿瘤实质区与肿瘤周围区ADC值有统
计学差异(P<0.05)。肿瘤种植后1一4周，随种植周数的增加，肿瘤实质
区ADC值呈逐渐递减趋势;种植后3一4周，肿瘤实质区及肿瘤周围区ADC
值与种植后1一2周及对侧脑白质相比，均具有显著性统计学差异(P<
0.01)。胶质瘤实质区的ADC值随镜下肿瘤组织细胞构成比增加而降低，
相关回归分析呈明显的负相关(r二一0.682，P<0.01)。
种植后1周及5例种植后2周的肿瘤沈BV图分布较均匀，接近于对侧
脑白质;种植后3一4周的肿瘤此BV图分布明显不均匀，肿瘤实质区尤BV
多有不同程度的增高。肿瘤种植后1一4
Preface
Presurgical determination of malignancy and prognosis of cerebral gliomas plays an important role in clinical work due to different methods of treatment. Routine MR imaging is difficult to provide functional information such as pathological grading, angiogenesis, and biochemical information though it may be useful for morphological diagnosis of gliomas. Diffusion weighted imaging (DWI) allows us to observe the microcosmic movement of the water molecules in the living tissues; dynamic contrast-enhanced perfusion imaging ( PWI) can evaluate the cerebral hemodynamic status noninvasively, which is developing with the presence of fast MR imaging technique. And proton MR spectroscopy (1 HMRS) can determine the biochemical and metabolic levels of both brain tissues and cerebral tumors noninvasively, may be helpful for observation of occurrence, development, as well as therapeutic reaction of brain tumors. All of these three methods, as complementary methods for routine MR examination, may give us more functional in
formation in the diagnosis of gliomas, and provide the objective criterion for the early diagnosis and prognostic assessment.
Our studies introduce leading theory of tumorigenesis into territory of imaging study, improve present methods of imaging study, break through traditional imaging study theory and engage in the study of microcirculation and cerebral metabolites noninvasively. For the first time, we combine MR functional techniques to study the biological characteristics of cerebral gliomas, correlated with histopathology in order to improve the early diagnostic rate of gliomas.
Purpose
DWI, PWI, and 1HMRS study of biological characteristics of animal model
of gliomas in rat brain was performed to evaluate these three methods in the determination of pathological grading, microcirculation, and metabolites of the tumor, and to establish internal connection between DWI/PWI and histology/ microvessel counting. Meanwhile, correlation between l HMRS manifestations of patients suffered from gliomas and pathological results were performed to evaluate l HMRS in the diagnosis, differential diagnosis, pathological grading, as well as prognostic assessment of cerebral gliomas.
Materials and Methods
41 female Wistar rats were used for this study. 36 rats Glial tumors were implanted into the left hemisphere by intracerebral injection of 1 x 10s C6 glioma cells in 5ul Ham' s F12 medium. As a control, five rats also received stereotac-tic injection of 5ul Ham' s F12 medium without tumor cells in the same location. Between 1 and 4 weeks after the C6 glioma cells were injected intracere-brally, eight to ten different rats were imaged at each weekly time point. The brain of each rat was imaged with precontrast T, weighted spin-echo imaging (T1WI), 12 weighted spin-echo imaging (T2WI), diffusion weighted imaging (DWI), perfusion weighted imaging (PWI), and postcontrast T,WI. Meanwhile, 'HMRS were performed in eight different rats at 2 weeks and 4 weeks after implantation respectively. Five rats were also done for comparison. MR examination was performed using GE Signa MR/iTM 1. 5T Hispeed Plus superconductive MR system. A cylindrical surface coil with 3 inch in diameter was positioned over the rat head. Images were acquired parallel to the anterior-posterior direction ( " horizontally" ). Transverse diameter values of tumors were measured on both T2WI and postcontrast TjWI. Apparent diffusion coefficient (ADC) maps and regional cerebral blood volume (rCBV) maps were formatted, and ADC values and maximal rCBV values in both tumoral regions and peritu-moral regions were calculated. Relative metabolite levels including N-acetylas-partate (NAA), choline ( CHO) , creatine compounds ( CR) , lipid ( Lip), lactate ( LAC) , glutamate and glutamine ( Glu-n) were measured, related to the peak area, and expressed with reference to CR. Immediately after MRI,
each rat was killed and the brain was removed and post-fixed overnight. After the brains were fixed, they were paraffin-embedded, sectioned, and examined
引文
1. Johnson PC, Hunt SJ, Drayer BP. Human cerebral gliomas: correlation of postmortem MR imaging and neuropathologic findings. Radiology. 1989; 170:211-217.
2. Aronen HJ, Gazit IE, Louis DN, et al. Cerebral blood volume maps of gliomas: comparison with tumor grade and histologic findings. Radiology. 1994; 191: 41-51.
3. Roberts H. C., Roberts T. P., Brasch R. C., et al. Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade. AJNR 2000; 21: 891-899.
4. Siegal T, Rubinstein R, Tzuk-Shina T, et al. Utility of relative cerebral blood volume mapping derived from perfusion magnetic resonance imaging in the routine follow up of brain tumors. J Neurosurg. 1997;86:22-27.
5. Weidner N, Barbarishi M, Gasparini G, et al. Microvascular densty qualification in breast carcinoma. Applied Immunhistochemistry, 1995;3 (2):75-79.
6. Barth RF. Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol 1998; 36:91-102.
7. Vittorio M, Morreale MD, Barbaba H, et al. A brain tumor model utilizing stereotactic implantation of a permanent cannula. J Neurosurg 1993;78:959-964.
8. Thorsen F, Ersland L, Nordli H, et al. Imaging of experimental rat gliomas using a clinical MR scanner. J Neurooncol. 2003;63 (3):225-31.
9. Maeda M., Maley J. E. Crosby D. L. Application of contrast agents in the evaluation of stroke: conventional MR and echo-planar MR imaging. J Magn Reson Med 1997;7:. 723-728.
10. Tien RD, Felsberg GJ, Friedman H, et al. MR imaging of high-grade cerebral gliomas: Value of dlffusion-weighted echoplanar pulse sequences. AJR
Am J Roentgenol 1994; 162:671-677.
11. Brunberg JA, Chenevert TL, McKeever PE, et al. In vivo MR determination of water diffusion coefficients and diffusion anisotropy: Correlation with structural alternation in gliomas of the cerebral hemispheres. AJNR Am J Neuroradiol 1995; 16: 361-371.
12. Zagzag D, Friedlander DR, Margolis B, et al. Molecular events implicated in brain tumor angiogenesis and invasion. Pediatr Neurosurg 2000; 33: 49-55.
13. Sugahara T, Korogi Y, Kochi M, et al. Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas. J Magn Reson Imaging 1999; 9: 53-60.
14. Chang YW, Yoon HK, Shin HJ, et al. MR imaging of glioblastoma in children: usefulness of diffusion/perfusion-weighted MRI and MR spectroscopy. Pediatr Radiol 2003;33:836-842.
15. Pathak AP, Schmainda KM, Ward BD, et al. MR-derived cerebral blood volume maps: issues regarding histological validation and assessment of tumor angiogenesis. Magn Reson Med 2001; 46:735-747.
16. Le Duc G, Peoc'h M, Remy C, et al. Use of T_2-weighted susceptibility contrast MRI for mapping the blood volume in the glioma-bearing rat brain. Magn Reson Med 1999; 42:754-761.
17. Knopp EA, Cha S, Johnson G, et al. Glial neoplasms: dynamic contrast-enhanced T_2 weighted MR imaging. Neroradiology 1999 ;211:791-798.
18. Cha S, Johnson G, Wadghiri YZ, et al. Dynamic, contrast-enhanced perfusion MRI in mouse gliomas: correlation with histopathology. Magn Reson Med 2003;49:848 - 855.
19. Zhu X. P., Li, K. L. Kamaly-Asl I. D. et al. Quantification of endothelial permeability, leakage space, and blood volume in brain tumors using combined T_1 and T_2 contrast-enhanced dynamic MR imaging. J Magn Reson Imaging 2000; 11: 575-585.
2. Aronen HJ, Gazit IE, Louis DN, et al. Cerebral blood volume maps of gliomas: comparison with tumor grade and histologic findings. Radiology. 1994; 191: 41-51.
3. Roberts H. C., Roberts T. P., Brasch R. C., et al. Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade. AJNR 2000; 21: 891-899.
4. Siegal T, Rubinstein R, Tzuk-Shina T, et al. Utility of relative cerebral blood volume mapping derived from perfusion magnetic resonance imaging in the routine follow up of brain tumors. J Neurosurg. 1997;86:22-27.
5. Weidner N, Barbarishi M, Gasparini G, et al. Microvascular densty qualification in breast carcinoma. Applied Immunhistochemistry, 1995;3 (2):75-79.
6. Barth RF. Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol 1998; 36:91-102.
7. Vittorio M, Morreale MD, Barbaba H, et al. A brain tumor model utilizing stereotactic implantation of a permanent cannula. J Neurosurg 1993;78:959-964.
8. Thorsen F, Ersland L, Nordli H, et al. Imaging of experimental rat gliomas using a clinical MR scanner. J Neurooncol. 2003;63 (3):225-31.
9. Maeda M., Maley J. E. Crosby D. L. Application of contrast agents in the evaluation of stroke: conventional MR and echo-planar MR imaging. J Magn Reson Med 1997;7:. 723-728.
10. Tien RD, Felsberg GJ, Friedman H, et al. MR imaging of high-grade cerebral gliomas: Value of dlffusion-weighted echoplanar pulse sequences. AJR
Am J Roentgenol 1994; 162:671-677.
11. Brunberg JA, Chenevert TL, McKeever PE, et al. In vivo MR determination of water diffusion coefficients and diffusion anisotropy: Correlation with structural alternation in gliomas of the cerebral hemispheres. AJNR Am J Neuroradiol 1995; 16: 361-371.
12. Zagzag D, Friedlander DR, Margolis B, et al. Molecular events implicated in brain tumor angiogenesis and invasion. Pediatr Neurosurg 2000; 33: 49-55.
13. Sugahara T, Korogi Y, Kochi M, et al. Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas. J Magn Reson Imaging 1999; 9: 53-60.
14. Chang YW, Yoon HK, Shin HJ, et al. MR imaging of glioblastoma in children: usefulness of diffusion/perfusion-weighted MRI and MR spectroscopy. Pediatr Radiol 2003;33:836-842.
15. Pathak AP, Schmainda KM, Ward BD, et al. MR-derived cerebral blood volume maps: issues regarding histological validation and assessment of tumor angiogenesis. Magn Reson Med 2001; 46:735-747.
16. Le Duc G, Peoc'h M, Remy C, et al. Use of T_2-weighted susceptibility contrast MRI for mapping the blood volume in the glioma-bearing rat brain. Magn Reson Med 1999; 42:754-761.
17. Knopp EA, Cha S, Johnson G, et al. Glial neoplasms: dynamic contrast-enhanced T_2 weighted MR imaging. Neroradiology 1999 ;211:791-798.
18. Cha S, Johnson G, Wadghiri YZ, et al. Dynamic, contrast-enhanced perfusion MRI in mouse gliomas: correlation with histopathology. Magn Reson Med 2003;49:848 - 855.
19. Zhu X. P., Li, K. L. Kamaly-Asl I. D. et al. Quantification of endothelial permeability, leakage space, and blood volume in brain tumors using combined T_1 and T_2 contrast-enhanced dynamic MR imaging. J Magn Reson Imaging 2000; 11: 575-585.