Coregistered Fluorescence-Enhanced Resection of Malignant Glioma

描述（由申请人提供）：本申请是第二个资助期的修订竞争性更新，以支持荧光成像（FI）在指导颅内肿瘤切除术中的开发和评价。利用定量FI（qFI）的概念，在第一个资助期内开发，并实现了在术中探针的形式，浓度的d-氨基乙酰丙酸（ALA）诱导的原卟啉IX（PpIX）已在体内定量测量人脑肿瘤。这些结果在临床上意义深远，因为它们首次表明，诊断上显著的PpIX浓度存在于低于人类视觉检测阈值的脑肿瘤中-即使在低级别胶质瘤（LGG）中-先前发现用视觉FI（vFI）不可接近的肿瘤，尽管通过FI技术改善其手术切除的完整性获得了显著的临床影响。我们的总体研究计划概述了将并行进行的临床和技术/临床前研究-这一策略在当前资助期间已被证明是成功的，并创建了一个迭代交流框架，为解决外科医生面临的切除挑战提供了临床和技术要求。在该项目的第二个资助阶段，我们实施和评估临床前技术进步（目标1），旨在实现宽场定量FI（qFI）和宽场深度检测FI（dFI）。我们还将招募患者参加ALA诱导的PpIX FI的临床研究（在Ai 2)以产生对于给定的PpIX浓度定量值确定肿瘤概率所需的数据。这些研究将为前瞻性临床入组（目标3）奠定基础，旨在评价在使用常规方法评价术中和术后手术准确性时，将qFI和dFI添加到视觉荧光成像（vFI）中。我们将实现qFI和dFI（目标4）的组合，通过在荧光和反射模式中结合空间光调制成像来定量检测深度处的PpIX浓度。这些技术还将扩展到具有覆盖近红外波长的激发/发射光谱的新兴荧光团，其最终可能比PpIX具有更大的潜力，并且能够同时定量成像多个荧光团的浓度。到拟议的资助期结束时，我们将在人类手术中实施和评估宽场qFI和dFI技术，并期望在恶性胶质瘤患者的前瞻性招募中将这些创新添加到vFI中时，能够改善手术结局。

DESCRIPTION (provided by applicant): This application is a revised competing renewal for a second funding period to support the development and evaluation of fluorescence imaging (FI) in guiding the resection of intracranial tumor. Utilizing quantitative FI (qFI) concepts developed during the first funding period, and realized in the form of an intraoperative probe, concentrations of d-aminolevulinic acid (ALA) induced protoporphyrin IX (PpIX) have been measured quantitatively in vivo in human brain tumors. These results are clinically profound because they indicate for the first time that diagnostically significant PpIX concentrations exist brain tumors which are below the threshold of human visual detection - even in low grade glioma (LGG) - tumors previously found inaccessible with visual FI (vFI), despite the significant clinical impact to be gained from improving their completeness of surgical resection through FI technique. Our overall research plan for continuation outlines clinical and technical/ preclinical studies that will be pursued in parallel - a strategy that has proved to be successful during the current funding period and creates a framework for iterative exchange that informs the clinical and technical requirements for solving the resection challenges facing the surgeon. In the second funding phase of the project, we implement and evaluate preclinically technical advances (in Aim 1) designed to achieve wide-field quantitative FI (qFI) and wide-field depth-detected FI (dFI). We will also enroll patients into clinical studies of ALA-induced PpIX FI (in Ai 2) to generate the data required to determine the probability of tumor for a given quantitative value of PpIX concentration. These studies will set the stage for prospective clinical enrollments (in Aim 3) designed to evaluate the addition of qFI and dFI to visual fluorescence imaging (vFI) when surgical accuracy is evaluated intra- and post-operatively with conventional methods . We will realize the combination of qFI and dFI (in Aim 4) to quantitatively detect PpIX concentration at depth by incorporating spatial light modulation imaging in fluorescence as well as reflectance modes. These techniques will also be extended to emerging fluorophores with excitation/emission spectra covering near-infrared wavelengths, which may ultimately have more potential than PpIX, and to enable simultaneous quantitative imaging of concentrations of multiple fluorophores. By the end of the proposed funding period, we will have implemented and evaluated wide-field qFI and dFI techniques in human surgeries and expect to demonstrate that these innovations improve surgical outcomes when added to vFI in a prospective enrollment of patients with malignant glioma.