Optical Analogs to MRI Contrast Agents for Surgical Guidance of Brain Tumor Resection

摘要 手术切除是治疗颅内肿瘤的一种固定方法，越来越多的数据表明 与次全切除组相比，大部切除组的总体和无进展生存率有所提高 切除手术。目前治疗颅内肿瘤的标准严重依赖于脑部肿瘤的磁共振成像。 格拉基造影剂(Gd-MRI)在诊断、手术计划、 术中指导和随访监测。在手术期间，患者在空间上注册到 术前MRI和MRI衍生的肿瘤轮廓在手术视野上的投影 显微镜引导切除。尽管这些复杂的工具在 手术后，次全切除率仍然居高不下。主要罪魁祸首包括 肿瘤的视觉识别和因脑变形而导致的术前配准准确性下降 随着手术的进展。在这方面，作出了广泛的努力，试图缓解这些缺点， 包括使用术中立体视觉和/或超声和脑变形模型来 更新术前MRI和使用荧光剂标记视野中的肿瘤。虽然 这两种方法前景看好，但都有已知的缺点。具体而言，用于 术前MRI更新仅与MRI替代相关，并且大多数当前的荧光引导 外科手术(FGS)的努力集中在旨在标记肿瘤细胞分子特征的靶向药物上，这 已经显示出高度的患者内/肿瘤异质性。该项目旨在解决这两个问题 直接利用Gd-MRI在处理颅内疾病中的现有临床认识的缺点 肿瘤。具体地说，我们将识别和评估模拟动力学行为的荧光剂 以常规MRI为基础的造影剂指导颅内肿瘤手术。这种方法将转移到 Gd-MRI的广为人知的行为直接进入了视野，使快速、术中 代理的管理，并为术中更新术前MRI提供理想的数据输入。 我们的方法是以令人信服的初步数据为前提的，在小动物胶质瘤模型中显示出 几种非靶向光学试剂与Gd-MRI的相关摄取为了推进这一战略，我们 将，(1)严格验证这些结果，并使用MRI和 我们定制的高光谱全身成像冷冻大基因组，(2)建立了 使用我们的术中MRI设备在新的猪脑胶质瘤模型中应用候选光学试剂和Gd-MRI 和FGS仪器，以及(3)评估使用光学代理数据更新手术前的能力 核磁共振检查。我们还将定量比较候选试剂Gd-MRI和ALA-PPIX、 胶质瘤FGS的现行标准。完成本项目的目标将建立光学模拟 战略作为一种引人注目的手术指导方法，并为临床翻译奠定了基础。

ABSTRACT Surgical resection is a fixture in the treatment of intracranial tumors, and there is mounting data indicating that overall and progression-free survival improve for gross total resection compared to subtotal resection. The current standard of care for managing intracranial tumors relies heavily on MRI of gadolinium-based contrast agents (Gd-MRI), which plays a central role in diagnosis, surgical planning, intra-surgical guidance, and follow-up monitoring. During surgery, patients are spatially registered to the pre-operative MRI and MRI-derived tumor contours projected over the visual field within the surgical microscope to guide resection. Despite the widespread deployment of these sophisticated tools in surgery, subtotal resection rates remain stubbornly high. The primary culprits include difficulty in identifying tumor visually and the diminishing accuracy of the pre-op registration due to brain deformation as the surgery progresses. In this context, expansive efforts have sought to alleviate these shortcomings, including the use of intra-operative stereovision and/or ultrasound with brain deformation models to update the pre-op MRI and the use of fluorescent agents to label tumor in the visual field. Although promising, both of these approaches have known shortcomings. Specifically, the data sources used for updating pre-op MRI are only surrogate correlates with MRI, and most current fluorescence guided surgery (FGS) efforts focus on targeted agents designed to mark molecular features of tumor cells, which have shown high intra-patient/tumoral heterogeneity. This project aims to solve both of these shortcomings directly by leveraging the existing clinical understanding of Gd-MRI in managing intracranial tumors. Specifically, we will identify and evaluate fluorescent agents that mimic the kinetic behavior of conventional MRI-based contrast agents to guide intracranial tumor surgery. This approach will transfer the well-understood behavior of Gd-MRI directly into the visual field, enable rapid, intra-surgical administration of the agent, and provide an ideal data input for updating of pre-op MRI during surgery. Our approach is premised on compelling preliminary data in small animal glioma models showing highly correlative uptake between Gd-MRI and several untargeted optical agents. To advance this strategy we will, (1) rigorously validate these results and examine additional optical agent candidates using MRI and our custom hyperspectral whole-body imaging cryomacrotome, (2) establish concordance between candidate optical agents and Gd-MRI in a new porcine glioma model using our intra-operative MRI facility and FGS instruments, and (3) assess the capacity to use the optical agent data to update the pre-op MRI. We will also quantitatively compare uptake of the candidate agents, Gd-MRI and ALA-PPIX, the current standard for FGS of glioma. Completing the aims of this project will establish the optical analog strategy as a compelling approach for surgical guidance and lay the groundwork for clinical translation.