神经系统肿瘤及瘤周血管的磁共振成像研究
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摘要
胶质瘤是最常见的成人原发性脑肿瘤。肿瘤新生血管的生成不仅与胶质瘤的增殖密切相关,同时也被视为抗肿瘤治疗的途径之一,越来越多的抑制肿瘤血管生成的药物被研发出来,并陆续进入临床前期试验。现代磁共振成像技术(MRI)能无创地检测活体内的血管生成情况,在胶质瘤的诊治与新研发的抗肿瘤药物的疗效评价中受到了广泛关注。本论文的研究内容分两个部分：
第一部分:目的：探讨磁共振灌注成像(perfusion MRI)测定局部相对脑血容量(rCBF)在少突胶质细胞瘤(oligodendroglioma, OG)(含少突胶质细胞-星形细胞混合胶质瘤(mixed oligoastrocytoma,OA))患者生存评价中的价值。方法：回顾性分析1998年-2004年之间,经病理证实的54例(女23例、男31例；年龄：21-73岁)OG(含OA)患者的临床资料。所有患者在临床干预前均进行MRI常规检查及perfusionMRI检查。对于perfusion MRI影像数据,运用专业影像工作站进行图像后处理,测量并计算肿瘤瘤体脑血容量指数与对侧正常脑白质脑血容量指数的比值,得到每位患者脑肿瘤的rCBV。随后经神经外科活检或手术切除获取肿瘤标本进行病理学检查,并依照St. Anne医院分类法将肿瘤分类为A组与B组。所有患者确诊后根据具体情况给予相应治疗,定期随访并进行磁共振复查,直至死亡或至少期满5年。另按照WHO标准将患者分成Ⅱ级组和Ⅲ级组用以检测该分类方法的预后效能。采用ROC方法界定预测中位生存时间的rCBV阈值。记录如下指标并对其进行单因素及多因素生存分析：患者年龄、性别、是否接受肿瘤切除、是否接受放疗、是否接受化疗、肿瘤分类、首次MRI检查肿瘤有否增强、rCBV值。结果：本组患者中位生存时间为3年。当阈值取2.2时,rCBV能对本组患者3年的生存状态进行最佳判断。在单因素分析中,肿瘤的分类、是否增强、rCBV,以及患者的年龄、性别均作为生存预测因子被检出。其中,除肿瘤是否增强外,其余的指标均被选择进入多因素Cox回归模型。WHO分类方法(Ⅱ级/Ⅲ-Ⅳ级)也被检测为独立的生存预测因子。结论：临床干预前运用磁共振灌注成像测定的rCBV值,能够预测OG或OA患者的预后。与肿瘤是否有强化相比,rCBV测定对此类肿瘤恶性程度的分类(ⅡA级/ⅡB级)及生存预后更具价值。
第二部分:目的：探讨原发性脑肿瘤患者肿瘤侧主动运动区(SM1)BOLD信号减弱的病理生理学机制。方法：SM1皮层未见肿瘤侵犯的25名额叶或顶叶原发性脑肿瘤患者(低级别胶质瘤(LGG)(n=8),高级别胶质瘤(HGG)(n=7),脑膜瘤(n=10))术前行简单运动任务的BOLD fMRI检查。随后给予Carbogen气体(二氧化碳/氧混合气体)吸入检测患者全脑的BOLD反应信号。采用动态磁敏感造影剂首过磁共振灌注成像技术,检测脑血容量(CBV)、脑血流量(CBF)及平均通过时间(MTT)等血流灌注参数。在SM1具有最高T值的运动任务激活区内绘制1cm3的感兴趣区(ROI),提取血流灌注及BOLD反应参数,采用两侧参数的比值考察其不对称性。结果：HGG及脑膜瘤患者肿瘤侧SM1运动任务激活程度显著下降,且与SM1到肿瘤的距离相关。肿瘤侧SM1的CBV在HGG患者较对侧下降,在脑膜瘤患者则保持正常。局部基础血流灌注的改变不能解释SM1区的激活程度下降。Carbogen吸入激发的BOLD反应是SM1运动任务激活程度不对称性的最有价值的预测因子(R=0.51)。94.9+4.9%的运动任务相关的激活体积被纳入Carbogen吸入激发的BOLD反应区域内。结论：Carbogen吸入激发的BOLD反应参数图能更好地解释脑肿瘤患者功能区运动任务激活程度的改变。
这两项研究结果均显示,MRI技术在检测与评价脑肿瘤的血管生成具有良好的应用前景。
Glioma is the most frequent primary brain tumor in adults. Tumoral vascularization by means of the mechanism of angiogenesis not only correlates closely to tumoral growth, but also has been proven as a new approach to cancer treatment using recent developed anti-angiogenic agents. Modern magnetic resonance imaging (MRI) is able to noninvasively investigate the tumoral vascularization in vivo. It plays a more important role in diagnostic and treatment of glioma as well as in the estimation of new drugs created for tumoral medications, including anti-angiogenic therapy. This thesis consists two parts:
PartⅠ:OBJECTIVE:To evaluate retrospectively whether cerebral blood volume measurement based on pretreatment perfusion MRI is a prognostic biomarker for survival in patients with oligodendroglioma or mixed oligoastrocytoma. MATERIALS AND METHODS:Between 1998 and 2004,54 patients (23 females and 31 males), aged 21-73 years, with oligodendroglioma (or mixed tumour) were examined prior to beginning treatment with dynamic susceptibility-weighted contrast (DSC) perfusion MRI with gadolinium first-pass technique. The relative cerebral blood volume (rCBV) was calculated by dividing the measurement within the tumour by the measurement of the normal-appearing contralateral region. Patients were classified in two groups, grade A and grade B, according to the St. Anne Hospital classification and followed-up clinically by means of MRI until their death or for a minimum of 5 years. Patients were also classified in gradeⅡand gradeⅢ-Ⅳ, according to the World Health Organisation (WHO) classification, and were analyzed with the same methods. Age, sex, treatment, tumor grade, contrast agent uptake, and rCBV were tested using survival curves with Kaplan-Meier method, and their differences were analysed using the log-rank test. RESULTS:In this population, median survival was 3 years. A rCBV threshold value of 2.2 was validated as a prognostic factor, for survival in these patients with oligodendrogliomas. Age, sex, contrast uptake, and maximum rCBV were found to be prognostic factors in univariate analysis. Multivariate analysis revealed that tumour grade (grade A/grade B), rCBV, age, and sex were prognostic factors independent of the other factors. The tumour grade according to the WHO classification (ⅡversusⅢ-Ⅳ) was also detected as an independent prognostic factor. CONCLUSION:Pretreatment rCBV measured by DSC perfusion MRI was found to be a prognostic factor for survival in patients with oligodendroglioma or mixed tumour, by using the St. Anne Hospital classification, which separate the IIB from the IIA.
PartⅡ:OBJECTIVE:To identify pathophysiological mechanisms associated with impaired peritumoral BOLD signal. MATERIALS AND METHODS:25 patients referred for resection of primary frontal or parietal neoplasms (low grade glioma (LGG) (n=8); high grade glioma (HGG) (n=7); meningioma (n=10)) without macroscopic tumoral infiltration of the primary sensorimotor cortex (SM1) were examined preoperatively using BOLD fMRI during simple motor tasks. Overall cerebral BOLD signal was estimated using vasoreactivity to carbogen inhalation. Using bolus of gadolinium, cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP) were estimated. In a lcm3 region-of-interest centered on maximal T-value in SMI contralateral to movements, interhemispheric asymmetry was evaluated using interhemispheric ratios for BOLD and perfusion parameters. RESULTS:During motor tasks contralateral to the tumor, ipsitumoral sensorimotor activations were decreased in HGG and meningiomas, correlated to the distance between the tumor and SMI. Whereas CBV was decreased in ipsitumoral SMI for HGG, it remained normal in meningiomas. Changes in basal perfusion could not explain motor activation impairment in SMI. Decreased interhemispheric ratio of the BOLD response to carbogen was the best predictor to model the asymmetry of motor activation (R=0.51). Moreover,94.9±4.9% of all motor activations overlapped significant BOLD response to carbogen inhalation. CONCLUSION:The map of BOLD response to carbogen inhalation could be able to better interpret the alterations of SM1 activation in patients with brain tumor.
These two studies indicated that MRI techniques in testing and evaluation of tumoral vascularisation have a good application prospect.
第一部分:目的：探讨磁共振灌注成像(perfusion MRI)测定局部相对脑血容量(rCBF)在少突胶质细胞瘤(oligodendroglioma, OG)(含少突胶质细胞-星形细胞混合胶质瘤(mixed oligoastrocytoma,OA))患者生存评价中的价值。方法：回顾性分析1998年-2004年之间,经病理证实的54例(女23例、男31例；年龄：21-73岁)OG(含OA)患者的临床资料。所有患者在临床干预前均进行MRI常规检查及perfusionMRI检查。对于perfusion MRI影像数据,运用专业影像工作站进行图像后处理,测量并计算肿瘤瘤体脑血容量指数与对侧正常脑白质脑血容量指数的比值,得到每位患者脑肿瘤的rCBV。随后经神经外科活检或手术切除获取肿瘤标本进行病理学检查,并依照St. Anne医院分类法将肿瘤分类为A组与B组。所有患者确诊后根据具体情况给予相应治疗,定期随访并进行磁共振复查,直至死亡或至少期满5年。另按照WHO标准将患者分成Ⅱ级组和Ⅲ级组用以检测该分类方法的预后效能。采用ROC方法界定预测中位生存时间的rCBV阈值。记录如下指标并对其进行单因素及多因素生存分析：患者年龄、性别、是否接受肿瘤切除、是否接受放疗、是否接受化疗、肿瘤分类、首次MRI检查肿瘤有否增强、rCBV值。结果：本组患者中位生存时间为3年。当阈值取2.2时,rCBV能对本组患者3年的生存状态进行最佳判断。在单因素分析中,肿瘤的分类、是否增强、rCBV,以及患者的年龄、性别均作为生存预测因子被检出。其中,除肿瘤是否增强外,其余的指标均被选择进入多因素Cox回归模型。WHO分类方法(Ⅱ级/Ⅲ-Ⅳ级)也被检测为独立的生存预测因子。结论：临床干预前运用磁共振灌注成像测定的rCBV值,能够预测OG或OA患者的预后。与肿瘤是否有强化相比,rCBV测定对此类肿瘤恶性程度的分类(ⅡA级/ⅡB级)及生存预后更具价值。
第二部分:目的：探讨原发性脑肿瘤患者肿瘤侧主动运动区(SM1)BOLD信号减弱的病理生理学机制。方法：SM1皮层未见肿瘤侵犯的25名额叶或顶叶原发性脑肿瘤患者(低级别胶质瘤(LGG)(n=8),高级别胶质瘤(HGG)(n=7),脑膜瘤(n=10))术前行简单运动任务的BOLD fMRI检查。随后给予Carbogen气体(二氧化碳/氧混合气体)吸入检测患者全脑的BOLD反应信号。采用动态磁敏感造影剂首过磁共振灌注成像技术,检测脑血容量(CBV)、脑血流量(CBF)及平均通过时间(MTT)等血流灌注参数。在SM1具有最高T值的运动任务激活区内绘制1cm3的感兴趣区(ROI),提取血流灌注及BOLD反应参数,采用两侧参数的比值考察其不对称性。结果：HGG及脑膜瘤患者肿瘤侧SM1运动任务激活程度显著下降,且与SM1到肿瘤的距离相关。肿瘤侧SM1的CBV在HGG患者较对侧下降,在脑膜瘤患者则保持正常。局部基础血流灌注的改变不能解释SM1区的激活程度下降。Carbogen吸入激发的BOLD反应是SM1运动任务激活程度不对称性的最有价值的预测因子(R=0.51)。94.9+4.9%的运动任务相关的激活体积被纳入Carbogen吸入激发的BOLD反应区域内。结论：Carbogen吸入激发的BOLD反应参数图能更好地解释脑肿瘤患者功能区运动任务激活程度的改变。
这两项研究结果均显示,MRI技术在检测与评价脑肿瘤的血管生成具有良好的应用前景。
Glioma is the most frequent primary brain tumor in adults. Tumoral vascularization by means of the mechanism of angiogenesis not only correlates closely to tumoral growth, but also has been proven as a new approach to cancer treatment using recent developed anti-angiogenic agents. Modern magnetic resonance imaging (MRI) is able to noninvasively investigate the tumoral vascularization in vivo. It plays a more important role in diagnostic and treatment of glioma as well as in the estimation of new drugs created for tumoral medications, including anti-angiogenic therapy. This thesis consists two parts:
PartⅠ:OBJECTIVE:To evaluate retrospectively whether cerebral blood volume measurement based on pretreatment perfusion MRI is a prognostic biomarker for survival in patients with oligodendroglioma or mixed oligoastrocytoma. MATERIALS AND METHODS:Between 1998 and 2004,54 patients (23 females and 31 males), aged 21-73 years, with oligodendroglioma (or mixed tumour) were examined prior to beginning treatment with dynamic susceptibility-weighted contrast (DSC) perfusion MRI with gadolinium first-pass technique. The relative cerebral blood volume (rCBV) was calculated by dividing the measurement within the tumour by the measurement of the normal-appearing contralateral region. Patients were classified in two groups, grade A and grade B, according to the St. Anne Hospital classification and followed-up clinically by means of MRI until their death or for a minimum of 5 years. Patients were also classified in gradeⅡand gradeⅢ-Ⅳ, according to the World Health Organisation (WHO) classification, and were analyzed with the same methods. Age, sex, treatment, tumor grade, contrast agent uptake, and rCBV were tested using survival curves with Kaplan-Meier method, and their differences were analysed using the log-rank test. RESULTS:In this population, median survival was 3 years. A rCBV threshold value of 2.2 was validated as a prognostic factor, for survival in these patients with oligodendrogliomas. Age, sex, contrast uptake, and maximum rCBV were found to be prognostic factors in univariate analysis. Multivariate analysis revealed that tumour grade (grade A/grade B), rCBV, age, and sex were prognostic factors independent of the other factors. The tumour grade according to the WHO classification (ⅡversusⅢ-Ⅳ) was also detected as an independent prognostic factor. CONCLUSION:Pretreatment rCBV measured by DSC perfusion MRI was found to be a prognostic factor for survival in patients with oligodendroglioma or mixed tumour, by using the St. Anne Hospital classification, which separate the IIB from the IIA.
PartⅡ:OBJECTIVE:To identify pathophysiological mechanisms associated with impaired peritumoral BOLD signal. MATERIALS AND METHODS:25 patients referred for resection of primary frontal or parietal neoplasms (low grade glioma (LGG) (n=8); high grade glioma (HGG) (n=7); meningioma (n=10)) without macroscopic tumoral infiltration of the primary sensorimotor cortex (SM1) were examined preoperatively using BOLD fMRI during simple motor tasks. Overall cerebral BOLD signal was estimated using vasoreactivity to carbogen inhalation. Using bolus of gadolinium, cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP) were estimated. In a lcm3 region-of-interest centered on maximal T-value in SMI contralateral to movements, interhemispheric asymmetry was evaluated using interhemispheric ratios for BOLD and perfusion parameters. RESULTS:During motor tasks contralateral to the tumor, ipsitumoral sensorimotor activations were decreased in HGG and meningiomas, correlated to the distance between the tumor and SMI. Whereas CBV was decreased in ipsitumoral SMI for HGG, it remained normal in meningiomas. Changes in basal perfusion could not explain motor activation impairment in SMI. Decreased interhemispheric ratio of the BOLD response to carbogen was the best predictor to model the asymmetry of motor activation (R=0.51). Moreover,94.9±4.9% of all motor activations overlapped significant BOLD response to carbogen inhalation. CONCLUSION:The map of BOLD response to carbogen inhalation could be able to better interpret the alterations of SM1 activation in patients with brain tumor.
These two studies indicated that MRI techniques in testing and evaluation of tumoral vascularisation have a good application prospect.
引文
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