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

描述（由申请人提供）：这项拟议的R21赠款的目的是证明超极化C-13 MR代谢成像作为一种新的和独特的工具，用于检测神经胶质瘤患者对治疗的早期反应的应用。将这种新颖而令人兴奋的技术转化为临床研究这些肿瘤特别感兴趣，因为传统的解剖图像是异质的，并且通常很难解释治疗后发生的变化。考虑的人群将包括20名接受过次全手术切除并诊断为4级胶质瘤（GBM）的成年患者。无菌超极化C-13丙酮酸盐将使用与我们的研究3 T MR扫描仪相邻的概念验证DNP偏振器来制备。将使用研究MR成像协议在开始治疗前（基线）和开始治疗后4周内（早期随访）对患者进行扫描，该协议包括解剖、扩散、灌注和乳酸盐编辑的H-1光谱图像，以及超极化的采集C-13代谢数据。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过程，并将其与其他MR图像中观察到的异常相关联。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丙酮酸递送至肿瘤及其转化为乳酸的时间过程。接下来的10名患者将使用单个3-D C-13 EPSI序列进行研究，该序列从预计肿瘤与正常大脑中乳酸/丙酮酸的噪音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：比较残留肿瘤与正常脑区域的乳酸/丙酮酸比值。我们假设GBM患者在基线时剩余T2高信号（T2 L）区域的超极化C-13乳酸/丙酮酸水平高于正常大脑中的水平。具体目标2：确定患者治疗后乳酸/丙酮酸水平是否降低。我们将检验接受放疗和替莫唑胺治疗的受试者在早期随访时与基线扫描相比超极化C-13乳酸盐/丙酮酸盐减少的假设。本研究的结果将是一种快速灵敏的代谢成像方法的可用性，该方法将通过提供更可靠的治疗反应表征来帮助临床决策，从而有助于确定是否需要替代策略。 公共卫生相关性：胶质瘤患者的优化治疗因病变内和病变间的异质性以及使用标准成像方法解释治疗反应的模糊性而变得复杂。本研究的目的是证明超极化C-13 MR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.