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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 质子磁共振光谱（1H-MRS）为在体内无创的人脑中的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，因此即使在7T时，标准1H-MRS的几种临床重要，低实现代谢产物的精确测量也常常难以捉摸。 这项研究的目标是开发MRS技术，这些技术可提供改进的甘氨酸，丝氨酸，N-乙酰基体甲基 - 谷氨酸（NAAG），谷氨酰胺，γ-氨基丁酸等，以7T和3T的速度检测。 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。 脑瘤（GBM）或全身性癌症转移的患者面临着毁灭性的临床病程，尽管多模型疗法具有侵略性的多模式疗法，但几乎不到一年的临床临床病程。诊断，治疗和随访的各个阶段的管理决策取决于MR成像，基于对gadolinium增强的变化的解释和T2/FLAIR（流体减弱的反转恢复）信号从一个时间点到另一个时间点。但是，这充满了矛盾的解释，这些解释可以改变管理，并可能对预后产生深远的影响。不确定性最常见于辐射后的肿瘤进展与治疗效果的区分，这是GBM和转移患者的常见情况。经典的肿瘤进展与增加的质量增强质量的尺寸增加，而T2加权的能力增加。然而，相同的成像特征归因于经典的放射性疾病，在GBM中被称为“伪雌性”，因为不可能通过可用的成像与真正的肿瘤进展区分开。因此，治疗神经肿瘤的团队依赖于基于临床环境的“最佳猜测”。由于预后和管理取决于肿瘤的进展还是治疗效果，因此经常被带回手术室进行重复的颅骨切开术和活检以进行诊断。同样重要的是临床情况，其中T2/Flair信号的变化可能会在增强肿瘤增强之前预示早期进行性疾病，但与周围的水肿或反应性神经胶质病无法区分。因此，总体而言，迫切需要开发新型的成像技术，这将有助于在这些关键决策点上进行非侵入性诊断。 基于MRI与其他技术的整合，例如正电子发射断层扫描（MR-PET），23NA的MR成像以及31p或13c的MR光谱法，已经提出了改善脑肿瘤表征的许多方法。尽管所有这些方法对于研究该疾病的基本生物学都是有吸引力的，但由于对所需的其他设备进行了大量投资，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可用的1H设备（例如1H光谱和化学交换饱和转移（CEST））提供了相对简单的对临床研究的进展，并且两种方法固有地通过7T的化学变化分散体固有地改进，并且可以在标准1H成像系统中实现。在此提案中，我们利用了项目2中描述的GBM和MT的人类原位小鼠模型，对动物和人类的高野外成像以及7T的脑肿瘤患者的开放式临床成像方案。总体目标是通过1H-MRS和CEST成像鉴定签名模式，以区分肿瘤的进展与治疗效果并检测到由标准T2/Flair和Gadolinium划定的边界以外地区的早期进展。 目的1：使用人类原始小鼠模型，在GBM和四个最常见的肿瘤中表征1H MR Spectra和Cest图像，以及在辐射疗法之前和之后，使用人类原始小鼠模型转移到大脑（黑色素瘤，肺，乳房和肾细胞癌）中的四个最常见的肿瘤。患者的验证将在AIM 2中进行。 AIM 2：在低级神经胶质瘤患者中表征1H MR Spectra和7T的CEST图像，并确定与GBM的差异，该差异可用于生成一种签名模式，该模式将在常用的临床或标准MR指标之前从低年级到GBM的进展。 目标3：使用AIMS 1和2中鉴定的签名代谢物以及7T的CEST成像的特征模式来鉴定胶质膜中的肿瘤肿瘤和转移性疾病的早期再生/进展。