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

基本信息

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
项目类别：
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

项目摘要

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，利用5-氨基乙酰丙酸（5-ALA）诱导的原卟啉IX（PpIX）提供的对比度的荧光图像引导手术（FIGS）已被证明可以改善神经胶质瘤患者的手术结果。然而，这种宽视场（低分辨率）成像方法存在局限性。具体来说，很难根据神经胶质瘤中荧光强度的细微变化准确识别手术切缘，神经胶质瘤是弥漫性的并且缺乏从肿瘤到正常组织的明显过渡。此外，宽视场（低分辨率）方法，例如无花果和MRI，提供代表许多细胞平均值的像素强度，导致检测神经胶质瘤外围稀疏肿瘤细胞群的能力下降。这个问题在低级别神经胶质瘤中更为严重，其中 5-ALA 诱导的 PpIX 荧光仅由罕见的增殖细胞群产生，并且通常通过宽视野图无法检测到。最近，该项目的合作者 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接受 5-ALA 治疗的低级别神经胶质瘤患者中的这些稀疏荧光细胞。自报告以来，这一发现的意义非常重大低级别胶质瘤的总切除率 (GTR) 并不理想（14% 至 46%），这表明需要改进的图像引导技术。在这里，我们建议开发一种手持式术中共聚焦显微镜，以可视化低级别胶质瘤组织中 5-ALA 诱导的 PpIX 表达。对临床标本进行的体外成像研究将证明，这种实时体内成像技术 1) 与金标准组织病理学相比可以准确量化 PpIX 表达，2) 具有基于 T2 加权 MRI 识别超出常规放射线边缘的肿瘤浸润的敏感性，3) 与神经外科领域唯一现有的光学切片显微镜 Zeiss Optiscan(R) 共焦显微镜相比，可提供卓越的图像质量。最后，提出了一项首次人体研究，以证明将我们的设备纳入手术工作流程的可行性，提供实时定量“光学活检”，补充神经外科现有的广域成像技术，并有助于校准手术决策-在肿瘤切除的最后阶段进行。临床前和临床研究将利用巴罗神经研究所 (BNI) 的 Nader Sanai 博士的现有专业知识，该研究所是美国规模最大的神经胶质瘤切除手术中心，也是唯一一家在使用宽视野技术方面拥有丰富经验的机构图和术中共聚焦显微镜。这些技术发展和转化研究的结果将证明未来临床试验的合理性，研究定量术中共聚焦显微镜作为一种手术策略，以最大限度地扩大切除范围，最大限度地减少手术发病率，并提高低级别神经胶质瘤患者的总体生存率。