Intraoperative confocal microscopy for quantitative delineation of low-grade glio

术中共聚焦显微镜定量描绘低级别胶质细胞

• 批准号: 9118107
• 负责人: Jonathan T.C. Liu
• 金额: $ 33.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118107
• 关键词: Aminolevulinic Acid; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Collection; Color; Complement; Confocal Microscopy; Contrast Sensitivity; Country; Decision Making; Development; Devices; Diagnostic Neoplasm Staging; Diffuse; Excision; Feasibility Studies; Figs - dietary; Fluorescence; Fresh Tissue; Future; Gadolinium; Glioma; Gold; Hand; Health; Histopathology; Human; Image; Image-Guided Surgery; Imaging Device; Imaging Techniques; Imaging technology; Infiltration; Institutes; Institution; Magnetic Resonance Imaging; Measures; Methodology; Microscope; Microscopy; Morbidity - disease rate; Morphologic artifacts; Motion; Neurologic; Neuronavigation; Normal tissue morphology; Operative Surgical Procedures; Optical Biopsy; Optics; Outcome; Patient-Focused Outcomes; Patients; Performance; Population; Proliferating; Publishing; Reporting; Resolution; Safety; Scanning; Site; Specimen; Speed; Spottings; Staging; Sterilization; Surface; Surgeon; Surgical margins; Techniques; Technology; Thick; Time; Tissues; Translating; Translations; Tumor Burden; Tumor stage; United States; Variant; Weight; base; clinically significant; contrast imaging; experience; fluorescence imaging; gadolinium oxide; human study; human tissue; image guided; imaging modality; improved; in vivo; in vivo imaging; instrument; instrumentation; neoplastic cell; neurosurgery; novel; operation; optical imaging; phase III trial; preclinical study; protoporphyrin IX; tissue fixing; translational study; tumor

DESCRIPTION (provided by applicant): In recent years, fluorescence image-guided surgery (FIGS) with contrast provided by 5-aminolevulinic acid (5- ALA)-induced protoporphyrin IX (PpIX) has been demonstrated to improve surgical outcomes for glioma patients. However, there are limitations to this wide-field (low-resolution) imaging method. Specifically, it is diffiult to accurately identify a surgical margin based on subtle variations of fluorescence intensity in gliomas, which are diffuse and lack a distinct transition from tumor to normal tissue. Furthermore, wide-field (low- resolution) approaches, such as FIGS and MRI, provide pixel intensities that represent an average value from many cells, resulting in a diminished ability to detect the sparse tumor cell populations at the glioma periphery. This problem is exacerbated in low-grade gliomas, where 5-ALA-induced PpIX fluorescence is only generated by rare proliferating cell populations and is typically undetectable via wide-field FIGS. Recently, Dr. Nader Sanai, a collaborator on this project, has shown that intraoperative cellular-resolution confocal microscopy can be used to visualize these sparse fluorescent cells in low-grade glioma patients treated with 5-ALA. The implications of this finding are highly significant since reported rates of gross-total resection (GTR) have been suboptimal for low-grade gliomas (14% to 46%), suggesting a need for improved image-guidance techniques. Here, we propose to develop a hand-held intraoperative confocal microscope to visualize 5-ALA-induced PpIX expression in low-grade glioma tissues. Ex vivo imaging studies with clinical specimens will demonstrate that this real-time in vivo imaging technique 1) quantifies PpIX expression accurately compared to gold-standard histopathology, 2) has the sensitivity to identify tumor infiltration beyond conventional radiographic margins based on T2-weighted MRI, and 3) provides superior image quality compared to the only existing optical- sectioning microscope in neurosurgical use, the Zeiss Optiscan(R) confocal microscope. Finally, a first-in-human study is proposed to demonstrate the feasibility of incorporating our device into the operative workflow, providing a real-time quantitative "optical biopsy" that complements existing wide-field imaging techniques in neurosurgery and helps to calibrate surgical decision-making at the final stages of tumor resection. Preclinical and clinical studies will leverage the existing expertise of Dr. Nader Sanai at the Barrow Neurological Institute (BNI), which is the highest-volume operative center for glioma resection in the United States and the only institution with extensive experience using both wide-field FIGS and intraoperative confocal microscopy. The results of these technological developments and translational studies will justify future clinical trials investigating quantitatie intraoperative confocal microscopy as a surgical strategy to maximize extent of resection, minimize operative morbidity, and improve overall survival for low-grade glioma patients.

描述（由申请人提供）：近年来，已经证明，荧光图像引导的手术（图2）已被证明是5-氨基乙烯酸（5- ALA）诱导的原核IX（PPIX）提供的对比度，可以改善胶质瘤患者的术语。但是，这种广阔的（低分辨率）成像方法存在局限性。具体而言，很难准确地基于神经胶质瘤中荧光强度的细微变化来准确识别手术缘，这些变化是弥漫性的，缺乏从肿瘤到正常组织的明显过渡。此外，宽场（低分辨率）方法（例如无花果和MRI）提供的像素强度代表了许多细胞的平均值，从而导致检测神经胶质瘤外围稀疏肿瘤细胞群体的能力降低。在低级神经胶质瘤中，此问题加剧了，其中5-ALA诱导的PPIX荧光仅由罕见的增殖细胞群体产生，通常无法通过广阔的无花果发现。最近，该项目的合作者纳德·萨奈（Nader Sanai）博士表明，术中细胞分辨率共聚焦显微镜可用于可视化5-ALA治疗的低级神经胶质瘤患者中这些稀疏的荧光细胞。自报道以来，这一发现的含义非常重要 对于低级神经胶质瘤（14％至46％）的总体切除率（GTR）的速率是次优的，这表明需要改善图像鉴定技术。在这里，我们建议开发手持术内共聚焦显微镜，以可视化低度神经胶质瘤组织中5-ALA诱导的PPIX表达。带有临床标本的体内成像研究将证明，这种实时体内成像技术1）与金色标准的组织病理学相比，准确量化PPIX表达，2）具有敏感性，具有识别肿瘤渗透的敏感性，而超越常规的放射线照相率，基于T2守流的MRI和3）与现有的图像质量相比，与现有的图像质量相比，将其分为较高的分割序列，以分割为分割的分段，以分割为分割的分割序列。 Optiscan（R）共聚焦显微镜。最后，提出了第一项人类研究，以证明将我们的设备纳入手术工作流程的可行性，从而提供了实时定量的“光学活检”，该实时定量“光学活检”补充了神经外科手术中现有的宽视野成像技术，并有助于在肿瘤切除术的最后阶段校准表面决策。临床前和临床研究将利用Barrow神经学研究所（BNI）的Nader Sanai博士的现有专业知识，该研究所是美国胶质瘤切除术和唯一具有广泛经验的胶质瘤切除术中心，使用广阔的无花果和室内共摄影显微镜。这些技术发展和转化研究的结果将证明未来研究量定术内共聚焦显微镜作为一种手术策略，以最大程度地切除范围，最大程度地减少手术发病率并提高低度胶质瘤患者的整体存活率。