NIR Fluorescent SLN Mapping for Breast Cancer

描述（由申请人提供）：乳腺癌手术的标准治疗包括前哨淋巴结（SLN）的识别和评估。目前，SLN标测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SLN的灵敏检测，但需要核医学医师的参与，取决于所采用的药剂，在通过时间上变化很大，可能难以用手持式伽马探针定位，并且使患者和护理人员暴露于电离辐射。蓝色染料，如异硫蓝，透过皮肤和脂肪不容易看到，但可以帮助确定性的识别SLN时，手持伽玛探头给出模糊的结果。最后，使用当前可用的技术，与SLN过程中的专业知识相关的学习曲线相当长。在本申请中，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SLN的淋巴流，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，也没有移动部件。手术解剖结构以彩色显示，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NIR荧光团的化学方面也有相当多的经验，并开发了FDA批准的吲哚菁绿色（ICG）非共价吸附到人血清白蛋白（HSA）的简单制剂（ICG：HSA），其导致量子产率增加三倍，并在SLN中充分保留。使用大型动物模型系统，一些自发性肿瘤转移到区域淋巴结，我们已经验证了皮肤，乳腺组织，食管，胃，结肠，肺，胸膜腔和腹膜腔中的NIR荧光SLN映射。我们的研究表明，这项技术现在已经准备好进行临床转化。在这项临床研究中，我们将与Susan L. Troyan，医学博士，她是一名学术性乳腺癌外科医生，每年在我们机构进行100多例SLN标测手术。所有患者将接受使用过滤的99 mTc-硫胶体的标准治疗。在特定目标1中，我们提出了一项成像系统与ICG：HSA联合使用的设盲I期安全性研究;该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，我们提出了一项II期研究，在此期间，ICG：HSA将用于指导SLN的识别和切除，99 mTc-硫胶体将用于确认SLN。本研究将明确近红外荧光SLN定位乳腺癌的优点和局限性。如果被证明是成功的，该技术可以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患者护理。项目叙述：前哨淋巴结（SLN）定位是乳腺癌手术分期的标准治疗。我们提出了一种方法SLN映射的基础上使用不可见的近红外荧光灯，有显着的优势，为患者和外科医生。

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.