NIR Fluorescent SLN Mapping for Breast Cancer

描述（由申请人提供）：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制图利用伽马射线发射放射性示踪剂和/或蓝色染料。放射性示踪剂提供了对sln的灵敏检测，但需要核医学医生的参与，其传输时间因所用药剂而异，难以用手持式伽马探针定位，并且使患者和护理人员暴露在电离辐射中。蓝色染料，如异硫丹蓝，不容易通过皮肤和脂肪被发现，但当手持式伽马探针给出模糊的结果时，可以帮助确定SLN。最后，使用当前可用的技术，与SLN程序中的专业知识相关的学习曲线相当长。在本应用中，我们描述了一种光学成像技术，该技术使外科医生能够实时跟踪从注射部位到淋巴结转移的淋巴流动，并在敏感的图像引导下切除淋巴结转移。作为美国国立卫生研究院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、不可见的近红外光，不与患者接触，也没有活动部件。手术解剖以彩色同时显示，并覆盖近红外荧光，以客观地评估手术视野。我们的实验室在近红外荧光团的化学方面也有相当的经验，并开发了一种简单的配方（ICG:HSA）， FDA批准的吲哚菁绿（ICG:HSA）非共价吸附到人血清白蛋白（HSA）上，导致量产率增加三倍，并在SLN中充分保留。使用大型动物模型系统，一些自发肿瘤转移到区域淋巴结，我们已经验证了近红外荧光SLN在皮肤、乳腺组织、食道、胃、结肠、肺、胸膜间隙和腹膜间隙中的定位。我们的研究表明，这项技术现在已经准备好进行临床应用。在这项临床研究中，我们将与医学博士Susan L. Troyan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定位手术。所有患者将接受标准护理，使用过滤后的99mtc -硫胶体。在Specific Aim 1中，我们提出了一项成像系统联合ICG:HSA的盲法I期安全性研究；此特定目标将确定最佳剂量，光激发通量和相机曝光时间。在Specific Aim 2中，我们提出了一项II期研究，其中ICG:HSA将用于指导SLN的识别和切除，99mtc -硫胶体将用于确认SLN。本研究将明确近红外荧光SLN定位乳腺癌的优势和局限性。如果被证明是成功的，这项技术有可能通过消除对电离辐射和蓝色染料的需要、缩短学习曲线和缩短手术时间来改善病人的护理。项目描述：前哨淋巴结（SLN）定位是乳腺癌手术分期的标准护理。我们提出了一种基于使用不可见近红外荧光的SLN映射方法，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.