7T MRS AND CEST IMAGING OF BRAIN TUMORS: BIOMARKERS OF THERAPEUTIC RESPONSE

脑肿瘤的 7T MRS 和 CEST 成像：治疗反应的生物标志物

• 批准号: 8363887
• 负责人: Changho Choi
• 金额: $ 3.22万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363887
• 关键词: Animals; Attenuated; Back; Biological Markers; Biology; Biopsy; Brain; Brain Mapping; Brain Neoplasms; Breast; Characteristics; Chemicals; Clinical; Clinical Research; Combined Modality Therapy; Common Neoplasm; Conflict (Psychology); Coupling; Craniotomy; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Discrimination; Disease; Edema; Enrollment; Equipment; Face; Funding; Gadolinium; Glioblastoma; Glioma; Gliosis; Glutamates; Glutamine; Glycine; Goals; Grant; Human; Image; Imaging Techniques; Impaired cognition; Investments; Liquid substance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measurement; Measures; Metabolism; Metastatic malignant neoplasm to brain; Methods; National Center for Research Resources; Neoplasm Metastasis; Operating Rooms; Patients; Pattern; Phase; Positron-Emission Tomography; Principal Investigator; Progressive Disease; Protocols documentation; Protons; Radiation; Radiation therapy; Recovery; Recurrence; Renal Cell Carcinoma; Research; Research Infrastructure; Resources; Serine; Signal Transduction; Source; Spectrum Analysis; System; Techniques; Therapeutic; Time; Uncertainty; United States National Institutes of Health; Validation; Weight; base; clinical application; cost; follow-up; gadolinium oxide; gamma-Aminobutyric Acid; improved; in vivo; lung melanoma; macromolecule; mouse model; neuro-oncology; novel; outcome forecast; response; tool; treatment effect; tumor; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Proton magnetic resonance spectroscopy (1H-MRS) provides an effective tool for measuring metabolites in the human brain noninvasively in vivo. Precise measurement of several clinically-important, low-abundance metabolites by standard 1H-MRS is often elusive even at 7T, due to the spectroscopic complexities arising from the scalar coupling effects and macromolecule baseline signals. The objectives of the research are to develop MRS techniques that provide improved inter-metabolite discrimination for detection of glycine, serine, N-acetylaspartyl-glutamate (NAAG), glutamine, gamma-aminobutyric acid, etc., at both 7T and 3T. The specific clinical goal is to develop better diagnostic tools for cancer involving the brain. Patients with brain tumors, either a glioblastoma (GBM) or a metastasis from systemic cancer, face a devastating clinical course consisting of progressive physical and cognitive decline over little more than a year, despite aggressive multimodality therapy. Management decisions in all phases of diagnosis, treatment and follow up rely on MR imaging based on interpretation of changes in gadolinium enhancement and T2/FLAIR (fluid attenuated inversion recovery) signal from one time point to another. However, this is fraught with conflicting interpretations which can alter management and can have profound impact on prognosis. The uncertainty is most commonly centered around differentiating tumor progression from treatment effect following radiation, a common scenario for both GBMs and metastases patients. Classic tumor progression is associated with increased size of a gadolinium enhancing mass with associated increased T2-weighted FLAIR. However, the identical imaging characteristic are ascribed to classic radionecrosis and in GBM is called "pseudoprogression" because it is impossible to differentiate from true tumor progression by available imaging. Thus the treating neuro-oncology team relies on "best guess" based on the clinical context. Since the prognosis and management is vastly different depending on whether it is tumor progression or treatment effect, patients are often taken back to the operating room for a repeat craniotomy and biopsy to make the diagnosis. Of similar importance is the clinical scenario in which changes in T2/FLAIR signal may herald early progressive disease prior to the development of tumor enhancement but is indistinguishable from peritumoral edema or reactive gliosis. Thus, overall, there is an urgent need for the development of novel imaging techniques that would aid in non-invasive diagnosis at these critical decision points. Numerous methods to improve the characterization of brain tumors have been proposed based on the integration of MRI with other techniques such as positron emission tomography (MR-PET), MR imaging of 23Na, and MR spectroscopy of 31P or 13C. While all of these methods are attractive for studying the basic biology of the disease, they are limited in clinical application because of the substantial investment in additional equipment needed. Improved diagnostic methods that rely on widely-available 1H equipment such as 1H spectroscopy and chemical exchange saturation transfer (CEST) offer a relatively simple progression to clinical research and both methods are inherently improved by the increased chemical shifts dispersion at 7T and can be implemented in a standard 1H imaging system. In this proposal we take advantage of the well characterized human orthotopic mouse models for GBM and MT, described in Project 2, the availability of high field imaging for animals and humans, and the open enrolling clinical imaging protocol for brain tumor patients at 7T. The overarching goal is to identify signature patterns by 1H-MRS and CEST imaging that can differentiate tumor progression from treatment effect and detect early progression in regions beyond the borders delineated by standard T2/FLAIR and gadolinium. Aim 1: To characterize the 1H MR spectra and CEST images at 7T in GBM and each of the four most common tumors that metastasize to the brain (melanoma, lung, breast and renal cell cancer) using human orthotopic mouse models, before and after radiation therapy. Validation in patients will be performed in Aim 2. Aim 2: To characterize the 1H MR spectra and CEST images at 7T in patients with low grade gliomas and identify differences with GBM that could be used to generate a signature pattern that would herald progression from low grade to GBM prior to the commonly used clinical or standard MR indicators. Aim 3: To map the brain in patients with low grade glioma, glioblastoma and brain metastases using the signature metabolites identified in Aims 1 and 2 and the characteristic patterns on CEST imaging at 7T to identify infiltrating tumor in gliomas and early recurrence/progression in metastatic disease.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 质子磁共振波谱（1H-MRS）提供了一种有效的工具，测量代谢物在人脑中的非侵入性体内。 由于标量耦合效应和大分子基线信号引起的光谱复杂性，即使在7 T下，通过标准1H-MRS对几种临床重要的低丰度代谢物的精确测量也常常是难以实现的。 本研究的目的是开发MRS技术，该技术提供用于检测甘氨酸、丝氨酸、N-乙酰基-谷氨酸（NAAG）、谷氨酰胺、γ-氨基丁酸等的改进的代谢物间区分，在7 T和3 T下。 具体的临床目标是为涉及大脑的癌症开发更好的诊断工具。 脑肿瘤患者，无论是胶质母细胞瘤（GBM）或全身性癌症转移，面临着一个毁灭性的临床过程，包括进行性的身体和认知能力下降超过一年，尽管积极的多模态治疗。诊断、治疗和随访的所有阶段的管理决策都依赖于基于钆增强和T2/FLAIR（液体衰减反转恢复）信号从一个时间点到另一个时间点的变化解释的MR成像。然而，这是充满了相互矛盾的解释，可以改变管理，并可能对预后产生深远的影响。不确定性最常见的是围绕区分肿瘤进展与放疗后的治疗效果，这是GBM和转移患者的常见情况。典型的肿瘤进展与钆增强肿块的大小增加相关，并伴有T2加权FLAIR的增加。然而，相同的成像特征归因于经典的放射性坏死，并且在GBM中被称为“假进展”，因为通过可用的成像不可能与真实的肿瘤进展区分开。因此，治疗神经肿瘤的团队依赖于基于临床背景的“最佳猜测”。由于预后和管理取决于肿瘤进展或治疗效果，因此患者通常被带回手术室进行重复开颅手术和活检以做出诊断。同样重要的是临床情况，其中T2/FLAIR信号的变化可能预示着肿瘤增强发展之前的早期进展性疾病，但与瘤周水肿或反应性神经胶质增生难以区分。因此，总体而言，迫切需要开发新的成像技术，以帮助在这些关键决策点进行非侵入性诊断。 基于MRI与其他技术（如正电子发射断层扫描（MR-PET）、23 Na的MR成像和31 P或13 C的MR光谱）的整合，已经提出了许多改善脑肿瘤表征的方法。虽然所有这些方法对于研究疾病的基础生物学都是有吸引力的，但由于需要大量投资于额外的设备，因此它们在临床应用中受到限制。改进的诊断方法依赖于广泛使用的1H设备，如1H光谱和化学交换饱和转移（CEST），为临床研究提供了相对简单的进展，这两种方法都通过在7 T下增加化学位移分散而得到了固有的改进，并且可以在标准1H成像系统中实现。在该提案中，我们利用了项目2中描述的GBM和MT的良好表征的人类原位小鼠模型，动物和人类的高场成像的可用性，以及7 T下脑肿瘤患者的开放招募临床成像协议。总体目标是通过1H-MRS和CEST成像识别特征模式，可以区分肿瘤进展与治疗效果，并检测标准T2/FLAIR和钆划定边界以外区域的早期进展。 目标1：在放射治疗前后，使用人类原位小鼠模型，表征GBM和四种最常见的脑转移肿瘤（黑色素瘤、肺癌、乳腺癌和肾细胞癌）在7 T下的1H MR光谱和CEST图像。将在目标2中进行患者确认。 目标二：表征低级别胶质瘤患者在7 T下的1H MR光谱和CEST图像，并识别与GBM的差异，这些差异可用于生成特征模式，该特征模式预示在常用临床或标准MR指标之前从低级别进展至GBM。 目标3：使用目的1和2中鉴定的特征代谢物和7 T CEST成像的特征模式，对低级别胶质瘤、胶质母细胞瘤和脑转移瘤患者的脑进行标测，以鉴定胶质瘤中的浸润性肿瘤和转移性疾病中的早期复发/进展。