RESPONSE TO THERAPY FOR PATIENTS WITH GLIOMA USING HYPERPOLARIZED C-13 PYRUVATE

描述(由申请人提供)：这项建议的R21赠款的目的是展示超极化C-13磁共振代谢成像作为一种新的和独特的工具用于检测胶质瘤患者的早期治疗反应。将这项新颖而令人兴奋的技术转化到临床上对研究这些肿瘤特别有兴趣，因为这些肿瘤在传统的解剖图像上是不同的，而且通常很难解释治疗后发生的变化。被考虑的人群将包括20名成年患者，他们接受了大部手术切除，被诊断为4级胶质瘤(GBM)。无菌超极化C-13丙酮酸将使用我们研究的3T磁共振扫描仪旁边的DNP概念证明偏振器来制备。患者将在开始治疗前(基线)和开始治疗后4周内(早期随访)使用研究性磁共振成像方案进行扫描，其中包括解剖、扩散、灌注和乳酸编辑的H-1光谱图像，以及超极化C-13代谢数据的获取。后处理将使用定制设计的软件来估计乳酸/丙酮酸水平变化的时间进程，并将它们与在其他磁共振图像中观察到的异常联系起来。前10名患者将使用动态2-D C-13 EPSI序列进行扫描，以跟踪将C-13丙酮酸输送到肿瘤并将其转化为乳酸的时间过程。接下来的10名患者将接受单一3-D C-13 EPSI序列的研究，从预计与正常大脑相比，肿瘤中乳酸/丙酮酸的噪声对比度最高的时间开始。将对这些数据进行分析，以实现两个目标。具体目的1：比较肿瘤残留区与正常脑组织乳酸/丙酮酸的比值。我们假设，与正常脑组织相比，GBM患者在基线时残留T2高信号(T2L)区域的超极化C-13乳酸/丙酮酸水平升高。特定目标2：确定患者治疗后乳酸/丙酮酸水平是否降低。我们将验证这样一种假设，即接受放射治疗和替莫唑胺治疗的受试者在早期随访时，与他们的基线扫描相比，超极化的C-13乳酸/丙酮酸水平将会降低。这项研究的结果将是提供一种快速和灵敏的代谢成像方法，通过提供更可靠的治疗反应特征来帮助临床决策，这将有助于确定是否需要替代策略。 公共卫生相关性：优化胶质瘤患者的治疗是复杂的，因为病变内部和病变之间的异质性，以及使用标准成像方法解释治疗反应的模棱两可。这项拟议研究的目的是展示超极化C-13磁共振代谢成像作为检测GBM患者治疗早期反应的一种新的独特工具的应用。

DESCRIPTION (provided by applicant): The objective of this proposed R21 grant is to demonstrate the application of hyperpolarized C-13 MR metabolic imaging as a new and unique tool for detecting early response to therapy in patients with glioma. Translating this novel and exciting technology into the clinic is of particular interest for studying these tumors because the are heterogeneous on conventional anatomic images and it is often difficult to interpret changes that occur in response to therapy. The population being considered will comprise 20 adult patients who have received a subtotal surgical resection with a diagnosis of grade 4 glioma (GBM). Sterile hyperpolarized C-13 pyruvate will be prepared using the proof of concept DNP polarizer adjacent to our research 3T MR scanner. Patients will be scanned prior to initiating therapy (baseline) and within 4 weeks after starting therapy (early follow-up) using a research MR imaging protocol that includes anatomic, diffusion, perfusion and lactate-edited H-1 spectroscopic images, as well as the acquisition of hyperpolarized C-13 metabolic data. Post-processing will use custom-designed software to estimate the time course of changes in levels of lactate/pyruvate and to relate them to abnormalities observed in the other MR images. The first 10 patients will be scanned using a dynamic 2-D C-13 EPSI sequence in order to track the time course of delivering C-13 pyruvate to the tumor and its conversion to lactate. The next 10 patients will be studied with a single 3-D C-13 EPSI sequence starting at the time expected to give the highest contrast to noise for lactate/pyruvate in tumor versus normal brain. These data will be analyzed to address two aims. Specific Aim 1: To compare the ratio of lactate/pyruvate for regions of residual tumor vs normal brain. We hypothesize that patients with GBM have elevated hyperpolarized C-13 lactate/pyruvate at baseline in regions of the residual T2 hyperintensity (T2L) compared to levels in normal brain Specific Aim 2: To determine whether patients exhibit a reduction in lactate/pyruvate with therapy. We will test the hypothesis that subjects receiving treatment with radiation and temozolomide will exhibit a reduction in hyperpolarized C-13 lactate/pyruvate at early follow-up compared to their baseline scan. The outcome of this study will be the availability of a rapid and sensitive metabolic imaging method that will help in clinical decision-making by providing a more reliable characterization of response to therapy that will help to determine whether alternative strategies are required. PUBLIC HEALTH RELEVANCE: Optimizing treatment for patients with glioma is complicated by heterogeneity within and between lesions, as well as by the ambiguities in interpreting response to therapy using standard imaging methods. The goal of the proposed study is to demonstrate the application of hyperpolarized C-13 MR metabolic imaging as a new and unique tool for detecting early response to therapy for patients with GBM.