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: 8171636
• 负责人: Changho Choi
• 金额: $ 2.09万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171636
• 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; Computer Retrieval of Information on Scientific Projects Database; 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; Institution; Investments; Liquid substance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measurement; Measures; Metastatic malignant neoplasm to brain; Methods; Neoplasm Metastasis; Operating Rooms; Patients; Pattern; Phase; Positron-Emission Tomography; Progressive Disease; Protocols documentation; Protons; Radiation; Radiation therapy; Recovery; Recurrence; Renal Cell Carcinoma; Research; Research Personnel; Resources; Serine; Signal Transduction; Source; Spectrum Analysis; System; Techniques; Therapeutic; Time; Uncertainty; United States National Institutes of Health; Validation; Weight; base; clinical application; follow-up; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 质子磁共振波谱（1H-MRS）为体内无创测量人脑代谢物提供了有效的工具。 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 7T 下，通过标准 1H-MRS 精确测量几种临床上重要的低丰度代谢物通常也难以实现。 该研究的目标是开发 MRS 技术，以改进代谢物间区分，以在 7T 和 3T 下检测甘氨酸、丝氨酸、N-乙酰天冬氨酰谷氨酸 (NAAG)、谷氨酰胺、γ-氨基丁酸等。 具体的临床目标是开发更好的脑部癌症诊断工具。 患有脑肿瘤（无论是胶质母细胞瘤（GBM）还是全身性癌症转移瘤）的患者，尽管采取了积极的多学科治疗，但仍面临着毁灭性的临床病程，包括在一年多的时间内进行性身体和认知能力下降。诊断、治疗和随访各个阶段的管理决策都依赖于 MR 成像，该成像基于对钆增强和 T2/FLAIR（流体衰减反转恢复）信号从一个时间点到另一个时间点的变化的解释。然而，这充满了相互矛盾的解释，可能会改变治疗方法并对预后产生深远影响。不确定性通常集中在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大小的增加以及相关的 T2 加权 FLAIR 的增加有关。然而，相同的成像特征被归因于经典的放射性坏死，并且在 GBM 中被称为“假性进展”，因为不可能通过可用的成像来区分真实的肿瘤进展。因此，神经肿瘤治疗团队依赖于基于临床情况的“最佳猜测”。由于根据肿瘤进展或治疗效果，预后和治疗有很大不同，因此患者经常被带回手术室重复开颅手术和活检以做出诊断。类似重要的是临床情况，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无法区分。因此，总的来说，迫切需要开发新的成像技术来帮助在这些关键决策点进行非侵入性诊断。 基于 MRI 与其他技术的集成，例如正电子发射断层扫描 (MR-PET)、 23Na MR 成像以及 31P 或 13C MR 波谱，人们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很有吸引力，但由于需要大量投资额外设备，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，例如 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，并且这两种方法都通过 7T 下化学位移色散的增加而得到了本质上的改进，并且可以在标准 1H 成像系统。在本提案中，我们利用了项目 2 中描述的用于 GBM 和 MT 的良好表征的人类原位小鼠模型、动物和人类高场成像的可用性以及针对脑肿瘤患者的 7T 开放招募临床成像方案。总体目标是通过 1H-MRS 和 CEST 成像识别特征模式，从而区分肿瘤进展与治疗效果，并检测标准 T2/FLAIR 和钆描绘的边界以外区域的早期进展。 目标 1：使用人类原位小鼠模型，在放射之前和之后表征 GBM 以及转移到大脑的四种最常见肿瘤（黑色素瘤、肺癌、乳腺癌和肾细胞癌）中的每一种的 1H MR 谱和 7T 的 CEST 图像治疗。将在目标 2 中进行患者验证。 目标 2：表征低级别神经胶质瘤患者的 1H MR 谱和 7T 的 CEST 图像，并识别与 GBM 的差异，这些差异可用于生成特征模式，该模式预示着在常用的临床或治疗之前从低级别进展到 GBM。标准MR指标。 目标 3：使用目标 1 和 2 中确定的特征代谢物以及 7T CEST 成像的特征模式绘制低级别胶质瘤、胶质母细胞瘤和脑转移瘤患者的大脑图谱，以识别胶质瘤中的浸润性肿瘤和转移性肿瘤的早期复发/进展疾病。