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

描述（由申请人提供）：这项R21拨款的目的是证明超极化C-13 MR代谢成像作为一种新的独特工具的应用，用于检测胶质瘤患者对治疗的早期反应。将这种新颖而令人兴奋的技术应用于临床对于研究这些肿瘤具有特别的意义，因为这些肿瘤在常规解剖图像上是异质的，并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名诊断为4级胶质瘤（GBM）并接受次全手术切除的成年患者。无菌超极化C-13丙酮酸将使用我们研究的3T MR扫描仪旁边的DNP偏振器进行概念验证。患者将在开始治疗前（基线）和开始治疗后4周内（早期随访）使用研究磁共振成像方案进行扫描，包括解剖，扩散，灌注和乳酸编辑的H-1光谱图像，以及获取超极化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联系起来。前10名患者将使用动态二维C-13 EPSI序列进行扫描，以跟踪将C-13丙酮酸输送到肿瘤及其转化为乳酸的时间过程。接下来的10例患者将使用单一的3-D C-13 EPSI序列进行研究，预计在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，以达到两个目的。特异性目的1：比较残余肿瘤区与正常脑区乳酸/丙酮酸比值。我们假设GBM患者在剩余T2高强度（T2L）区域的超极化C-13乳酸/丙酮酸水平在基线时高于正常脑水平。特异性目的2：确定患者是否表现出治疗后乳酸/丙酮酸水平的降低。我们将验证这样的假设，即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/丙酮酸水平会降低。这项研究的结果将是一种快速和敏感的代谢成像方法的可用性，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。

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.