NIR Fluorescent SLN Mapping for Breast Cancer

描述(申请人提供)：乳腺癌手术的护理标准包括前哨淋巴结(SLN)的识别和评估。目前，SLN测绘使用伽马射线发射的放射性示踪剂和/或蓝色染料。放射性示踪剂可提供对SLN的灵敏检测，但需要核医学医生的参与，传输时间根据所用试剂的不同而变化很大，使用手持伽马探头很难定位，并将患者和护理人员暴露在电离辐射中。蓝色染料，如异硫氰蓝，不容易通过皮肤和脂肪看到，但当手持伽马探头给出模棱两可的结果时，可以帮助确定SLN。最后，使用目前可用的技术，与SLN程序的专业知识相关的学习曲线相当长。在这项应用中，我们描述了一种光学成像技术，它使外科医生能够实时跟踪从注射部位到SLN的淋巴流动，并在敏感的图像引导下切除SLN。作为NIH资助的生物工程研究伙伴关系的一部分，我们的实验室已经开发出一种近红外(NIR)荧光成像系统，该系统使用无害的、不可见的NIR光，不与患者接触，并且没有活动部件。手术解剖以彩色显示，同时覆盖近红外荧光，以客观地评估手术野。我们的实验室在近红外荧光团的化学方面也有丰富的经验，并开发了一种FDA批准的吲哚青绿(ICG)的简单配方(ICG：HSA)，它以非共价吸附到人血清白蛋白(HSA)上，导致量子产率增加三倍，并在SLN中有足够的保留。使用大型动物模型系统，其中一些自发性肿瘤转移到区域淋巴结，我们验证了皮肤、乳房组织、食道、胃、结肠、肺、胸膜和腹膜腔的近红外荧光SLN映射。我们的研究表明，这项技术现在已经准备好用于临床翻译。在这项临床研究中，我们将与苏珊·L·特洛扬医学博士合作，她是一位学术乳腺癌外科医生，每年在我们机构进行100多次SLN标测程序。所有患者都将接受使用过滤后的99mTc-硫磺胶体的标准护理。在具体目标1中，我们建议结合ICG：HSA对成像系统进行I期盲法安全性研究；这一特定目标将确定最佳剂量、光激发注量率和相机曝光时间。在具体目标2中，我们提出了第二阶段的研究，在此期间，将使用ICG：HSA来指导SLN的识别和切除，并将使用99mTc-硫胶体来确定SLN。这项研究将明确近红外荧光SLN定位在乳腺癌中的优势和局限性。如果被证明是成功的，这项技术可能会通过消除对电离辐射和蓝色染料的需求，缩短学习曲线，并缩短程序的长度，潜在地改善患者的护理。项目简介：前哨淋巴结(SLN)测绘是乳腺癌外科分期的标准护理。我们提出了一种基于不可见的近红外荧光灯的SLN标测方法，该方法对患者和外科医生都有显著的优势。

DESCRIPTION (provided by applicant): The standard of care in breast cancer surgery includes identification and assessment of the sentinel lymph node (SLN). At the present time, SLN mapping utilizes a gamma ray-emitting radiotracer and/or a blue dye. Radiotracers provide sensitive detection of SLNs, but require involvement of a nuclear medicine physician, vary widely in transit time depending on the agent employed, can be difficult to localize with a handheld gamma probe, and expose both patient and caregivers to ionizing radiation. Blue dyes, such as isosulfan blue, cannot be seen easily through skin and fat, but can aid in definitive identification of the SLN when the handheld gamma probe gives ambiguous results. Finally, the learning curve associated with expertise in the SLN procedure is quite long using currently available techniques. In this application, we describe an optical imaging technology that enables the surgeon to follow lymphatic flow in real-time from the injection site to the SLN, and to resect the SLN under sensitive image- guidance. As part of an NIH-funded Bioengineering Research Partnership, our laboratory has already developed a near-infrared (NIR) fluorescence imaging system that uses harmless, invisible NIR light, makes no contact with the patient, and has no moving parts. Surgical anatomy is displayed in color simultaneously with an overlay of NIR fluorescence to assess the surgical field objectively. Our laboratory also has considerable experience with the chemistry of NIR fluorophores and has developed a simple formulation (ICG:HSA) of FDA- approved indocyanine green (ICG) adsorbed non-covalently to human serum albumin (HSA) that results in a three-fold increase in quantum yield, and adequate retention in the SLN. Using large animal model systems, some with spontaneous tumors metastatic to regional lymph nodes, we have validated NIR fluorescent SLN mapping in the skin, mammary tissue, esophagus, stomach, colon, lung, pleural space, and peritoneal space. Our studies suggest that the technology is now ready for clinical translation. In this clinical study we will collaborate with Susan L. Troyan, M.D., an academic breast cancer surgeon who performs more than 100 SLN mapping procedures annually at our institution. All patients will receive the standard of care using filtered 99mTc-sulfur colloid. In Specific Aim 1, we propose a blinded Phase I safety study of the imaging system in combination with ICG:HSA; this Specific Aim will determine optimal dose, light excitation fluence rate, and camera exposure time. In Specific Aim 2, we propose a Phase II study during which ICG:HSA will be used to guide SLN identification and resection, and 99mTc-sulfur colloid will be used to confirm the SLN. This study will define the advantages and limitations of NIR fluorescent SLN mapping for breast cancer. If proven successful, the technology could potentially improve patient care by eliminating the need for ionizing radiation and blue dye, shortening the learning curve, and reducing the length of the procedure.7. PROJECT NARRATIVE: Sentinel lymph node (SLN) mapping is the standard of care for the surgical staging of breast cancer. We propose a method of SLN mapping based on the use of invisible near-infrared fluorescent light that has significant advantages for both patient and surgeon.