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续期，以支持荧光成像(FI)在指导颅内肿瘤切除方面的开发和评估。利用在第一个资助期发展并以术中探针的形式实现的定量荧光(QFI)概念，在活体内定量测量了d-氨基酮丙酸(ALA)诱导的人脑肿瘤中原卟啉IX(PpIX)的浓度。这些结果具有深远的临床意义，因为它们首次表明，具有诊断意义的PPIX浓度存在低于人类视觉检测阈值的脑肿瘤--即使是在低级别胶质瘤(LGG)中--以前通过视觉FI(VFI)无法接触到的肿瘤，尽管通过FI技术提高手术切除的完整性将获得显著的临床影响。我们继续的整体研究计划概述了将并行进行的临床和技术/临床前研究--这一战略已被证明在当前的资助期内是成功的，并创建了一个迭代交流的框架，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)，旨在实现广域定量FI(QFI)和广域深度探测FI(DFI)。我们还将招募患者参加ALA诱导的PpIX FI(人工智能)的临床研究 2)生成确定给定PpIX浓度量化值的肿瘤概率所需的数据。这些研究将为预期的临床登记(目标3)奠定基础，旨在评估在用传统方法评估术中和术后手术准确性时，在视觉荧光成像(VFI)中添加QFI和DFI。我们将实现QFI和DFI的结合(在目标4中)，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的PpIX浓度。这些技术还将扩展到激发/发射光谱覆盖近红外波长的新兴荧光团，这最终可能比PpIX更有潜力，并能够同时对多个荧光团的浓度进行定量成像。到拟议的资助期结束时，我们将在人类手术中实施和评估广域QFI和DFI技术，并期望在恶性胶质瘤患者的预期登记中加入VFI时，证明这些创新可以改善手术结果。

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.