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

MRI 造影剂的光学类似物用于脑肿瘤切除手术指导

• 批准号: 10530702
• 负责人: Scott C Davis
• 金额: $ 57.71万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530702
• 关键词: Address; Aftercare; Anatomy; Animal Model; Animals; Behavior; Biodistribution; Brain; Brain Neoplasms; Caring; Characteristics; Clinical; Clinical Management; Compensation; Contrast Media; Couples; Craniotomy; Custom; Data; Data Sources; Development; Devices; Diagnosis; Diagnostic; Dose; Drug Kinetics; Evaluation; Excision; Family suidae; Fluorescence; Fluorescent Dyes; Gadolinium; Glioma; Head; Human; Human Biology; Image; Incubated; Intracranial Neoplasms; Investigation; Kinetics; Label; Lead; Literature; Magnetic Resonance Imaging; Malignant Neoplasms; Managed Care; Microscope; Modality; Modeling; Modernization; Molecular; Molecular Abnormality; Monitor; Monitoring for Recurrence; Normal tissue morphology; Operative Surgical Procedures; Optics; PPIX; Patient-Focused Outcomes; Patients; Play; Preparation; Procedures; Progression-Free Survivals; Protocols documentation; Recurrence; Reference Standards; Resolution; Role; Signal Transduction; Structure; Surgeon; Surgical Instruments; Time; Tissues; Tumor Tissue; Update; Vision; Visual; Visual Fields; Xenograft Model; alternative treatment; analog; brain tumor resection; candidate identification; clinical imaging; clinical translation; contrast enhanced; design; experience; fluorescence-guided surgery; follow-up; image registration; improved; improved outcome; lead candidate; neoplastic cell; neurosurgery; novel; novel strategies; optical imaging; prognostic indicator; standard of care; targeted agent; tomography; tool; tumor; tumor heterogeneity; tumor xenograft; ultrasound; uptake; whole body imaging

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.

抽象的 手术切除是治疗颅内肿瘤的固定方法，越来越多的数据表明 与次全切除相比，大体全切除的总体生存率和无进展生存率有所提高 切除。目前治疗颅内肿瘤的护理标准在很大程度上依赖于 MRI 钆基造影剂（Gd-MRI），在诊断、手术计划、 术中指导和后续监测。在手术过程中，患者在空间上进行配准 术前 MRI 和 MRI 衍生的肿瘤轮廓投射到手术视野内 显微镜指导切除。尽管这些复杂的工具被广泛部署 手术中，次全切除率仍然居高不下。罪魁祸首包括困难 视觉识别肿瘤以及由于大脑变形导致术前配准准确性下降 随着手术的进展。在此背景下，人们做出了广泛的努力来寻求缓解这些缺点， 包括使用术中立体视觉和/或超声与脑变形模型来 更新术前 MRI 并使用荧光剂标记视野中的肿瘤。虽然 虽然这两种方法都有希望，但都有已知的缺点。具体来说，所使用的数据源 更新术前 MRI 仅与 MRI 相关，并且大多数当前的荧光引导 手术（FGS）的重点是设计用于标记肿瘤细胞分子特征的靶向药物， 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 在管理颅内肿瘤方面的现有临床理解 肿瘤。具体来说，我们将识别和评估模仿动力学行为的荧光剂 常规基于 MRI 的造影剂指导颅内肿瘤手术。这种方法将转移 众所周知，Gd-MRI 直接进入视野，可实现快速的手术内检查 剂的管理，并为手术期间更新术前 MRI 提供理想的数据输入。 我们的方法的前提是小动物神经胶质瘤模型中令人信服的初步数据显示出高度 Gd-MRI 和几种非靶向光学制剂之间的相关摄取。为了推进这一战略，我们 将，(1) 严格验证这些结果并使用 MRI 检查其他候选光学制剂， 我们定制的高光谱全身成像冷冻切片机，(2) 建立之间的一致性 使用我们的术中 MRI 设备在新的猪神经胶质瘤模型中使用候选光学制剂和 Gd-MRI 和 FGS 仪器，以及 (3) 评估使用光学试剂数据更新术前数据的能力 核磁共振成像。我们还将定量比较候选药物 Gd-MRI 和 ALA-PPIX 的吸收情况， 神经胶质瘤 FGS 的现行标准。完成该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，并为临床转化奠定了基础。