Intraoperative Label-Free Optical Molecular Imaging of Breast Tumor Margins

描述(申请人提供)：实体肿瘤手术治疗过程中的边缘状态是决定局部复发率的最关键因素。对于乳腺癌，乳房 保留性手术或肿块切除术是常规手术。目前，外科医生无法直观地看到肿瘤边缘的微观结构，传统上依赖手术后边缘的组织学评估来验证肿瘤是否被完全切除。然而，术中必须作出关键的决定，以确定必须切除多少原发肿瘤周围的组织，或者必须确定手术边缘的位置。因此，迫切需要在手术室中对手术切缘进行实时的显微评估，使空间分辨率和病理精度与术后组织学相适应，以便在手术干预期间获得术中反馈。由合作的学术、临床和工业机构和研究人员组成的合作伙伴关系将通过非线性干涉振动成像(NIVI)解决这一关键需求。NIVI可以对各种固有振动的生物分子进行成像，深度可达1毫米，无需标记。对定量拉曼光谱的灵敏干涉检测使NIVI能够作为拉曼显微光谱的高速成像模拟物。通过我们光学实验室获得的初步结果，我们证明了NIVI结合了相干反斯托克斯拉曼散射(CARS)光谱和光学相干断层扫描(OCT)的优势，并成功地利用NIVI通过内源性生物标志物分子的特定异常来检测乳腺癌的肿瘤边缘。因此，这一合作伙伴关系将致力于将NIVI转化为术中成像工具。这一伙伴关系的目标将通过系统的方法实现。首先，光纤组件的广泛使用将提高系统的健壮性和便携性，因此NIVI将在很大程度上保持标准光纤OCT系统的简单性。此外，先进的基于MEMS扫描仪的手持式成像探头将被整合到系统中，以便在手术中灵活地接触切除组织的手术边缘。最后，将确定检测阳性边缘的敏感性和特异性，以筛选和标记可疑的边缘位置以发现残留的乳房肿瘤。该项目的成功完成将带来一种经过统计验证的高分辨率分子成像技术，能够在乳腺癌手术期间进行图像引导的外科干预。术中对肿瘤边缘状态的评估有可能实时更新和指导手术干预，减少或消除再手术，最大限度地减少成本，最重要的是，降低局部复发的风险。尽管Nivi在术中的成像 乳腺癌手术是这个项目的主要重点，我们预计这项技术将使外科肿瘤学的许多其他领域受益。

DESCRIPTION (provided by applicant): Margin status during the surgical treatment of solid tumors is the most critical factor in determining local recurrence rates. For breast cancer, breast conserving surgeries or lumpectomies are routinely performed. Currently, the surgeon is unable to visualize the microscopic structure at the margin, and conventionally relies on post-operative histological assessment of surgical margins to verify complete resection of the tumor. However, a critical intraoperative decision must be made to determine how much tissue around the primary tumor must be removed, or, where one must define the surgical margin. Therefore, a critical need exists to assess the surgical margin microscopically in real-time in the operating room, with spatial resolutions and pathological accuracies commensurate with post-operative histology, so that intraoperative feedback can be obtained during the surgical intervention. A partnership composed of collaborating academic, clinical, and industrial institutions and investigators will address this critical need by nonlinear interferometric vibrational imaging (NIVI). NIVI can images a wide variety of intrinsically vibrating biomolecules at a depth up to 1 mm with no labeling. The sensitive interferometric detection of quantitative Raman spectra allows NIVI to perform as a high-speed imaging analogue to Raman micro-spectroscopy. Through preliminary results obtained in our optical laboratory, we have demonstrated NIVI to have combined advantages of coherent anti-Stokes Raman scattering (CARS) spectroscopy and optical coherence tomography (OCT), and have successfully employed NIVI to detect tumor margins of breast cancer through specific abnormalities of endogenous biomarker molecules. This partnership will thus pursue the clinical translation of NIVI into an intraoperative imaging tool. The goal of this partnership will be achieved through a systematic approach. First, the extensive use of fiber-optic components will improve the robustness and the portability of the system, so that NIVI will largely retain the simplicity of a standard fiber-based OCT system. Also, an advanced handheld MEMS-scanner- based imaging probe will be incorporated into the system to flexibly access the surgical margin intraoperatively on resected tissue. Finally, the sensitivity and specificity of detecting positive margins will be determined to screen and flag margin locations suspicious for residual breast tumor. The successful completion of this project will result in a statistically-validated high-resolution molecular imaging technology capable of performing image-guided surgical interventions during breast cancer surgery. The intraoperative assessment of surgical tumor margin status has the potential to update and direct the surgical intervention in real-time, to reduce or eliminate reoperations, to minimize costs, and most importantly, to reduce the risk of local recurrence. Although the intraoperative imaging by NIVI in breast cancer surgery is the main focus of this project, we envision that this technique will benefit many other areas of surgical oncology.