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.

摘要 手术切除是治疗颅内肿瘤的固定方法，有越来越多的数据表明， 与次全切除相比， 切除术目前治疗颅内肿瘤的标准治疗严重依赖于MRI， 钆基造影剂（Gd-MRI），在诊断、手术计划 术中指导和随访监测。在手术期间，患者在空间上配准到 术前MRI和MRI衍生的肿瘤轮廓投影在手术视野内， 显微镜引导切除。尽管这些复杂的工具广泛部署在 手术，次全切除率仍然居高不下。主要原因包括： 视觉上识别肿瘤以及由于脑变形而导致的术前配准精度降低 随着手术的进行在这种情况下，已经作出了广泛的努力来寻求减轻这些缺点， 包括使用具有脑变形模型的术中立体视觉和/或超声， 更新术前MRI和荧光剂标记视野中肿瘤的使用。虽然 这两种方法都有已知的缺点。具体而言，用于 更新术前MRI仅是MRI的替代相关性，大多数当前荧光引导 外科手术（FGS）的努力集中在设计用于标记肿瘤细胞分子特征的靶向药物上， 显示出高的患者内/肿瘤异质性。该项目旨在解决这两个问题 直接利用Gd-MRI在颅内动脉瘤治疗中的现有临床认识， 肿瘤的具体地说，我们将鉴定和评估荧光剂，模拟的动力学行为， 传统的基于MRI的造影剂，以指导颅内肿瘤手术。这种方法将转移 Gd-MRI直接进入视野的众所周知的行为， 这是一个理想的数据输入，用于在手术期间更新术前MRI。 我们的方法基于小动物胶质瘤模型中令人信服的初步数据，显示出高度的 Gd-MRI与几种非靶向光学剂之间的相关摄取。为了推进这一战略，我们 将，（1）严格验证这些结果，并使用MRI检查其他光学试剂候选物， 我们定制的高光谱全身成像冷冻切片机，（2）建立 使用我们的术中MRI设备在新的猪胶质瘤模型中进行候选光学试剂和Gd-MRI 和FGS仪器，以及（3）评估使用光学代理数据更新术前 核磁共振我们还将定量比较候选药物Gd-MRI和ALA-PPIX的摄取， 胶质瘤FGS的现行标准。完成本项目的目标将建立光学模拟 战略作为一个引人注目的方法，手术指导和奠定基础的临床翻译。