NIR Imaging of Sentinel Nodes in Lung Cancer: Finding Micrometastases

描述（由申请人提供）：肺癌是美国癌症死亡的主要原因，每年有超过16万人死亡。手术切除后生存的最佳预测指标是区域淋巴结是否存在转移性疾病。然而，即使早期患者被认为是阴性的淋巴结疾病（N0），显示40%的总复发率。回顾性分析表明，在组织学上仔细检查时，大量早期肺癌患者存在“隐匿性”转移，就像乳腺癌和黑色素瘤的前哨淋巴结（sln）一样，这些患者的生存率较低，复发风险增加。鉴别和切除肺癌的单细胞转移网络将允许进行必要的组织学检查，以检测微转移性疾病，并允许微转移性疾病与肺癌复发风险的准确关联。不幸的是，由于巨大的技术困难，以往的SLN制图技术在肺癌中的应用受到严重限制，使得SLN制图基本上无法用于肺癌患者。因此，SLN分析是否能改善临床结果尚不清楚。我们开发了一种光学成像平台，利用不可见的近红外（NIR）荧光结合彩色视频，为外科医生提供实时的术中图像指导，从而实现精确的SLN映射和切除。广泛的优化和成功的大型动物临床前验证导致需要进行临床可行性研究，特别是关于设备和造影剂组合的安全性和有效性。已经获得了IRB批准，可以使用FDA批准的近红外荧光团吲哚菁绿（ICG）进行临床试验，我们描述了一个系统的计划，以评估该设备和荧光团在人类肺癌手术中的安全性和有效性。本研究的总体目标是在早期肺癌手术切除期间通过图像引导最大限度地检测肿瘤特异性SLN，未来的目标是改善目前方法每年错过的约15,000例转移性淋巴结疾病的早期肺癌患者的预后。具体目的是优化ICG注射技术、荧光团浓度和SLN制图过程中的激发光通量。特异性目的2将确定近红外荧光成像是否可以改善当前淋巴结切除术中SLN的识别和分析。特异性目的3将确定近红外图像引导下的SLN切除是否能增强对转移性疾病的检测，以及微转移性疾病的存在是否能预测疾病复发。这些特定目标的完成将导致一种新型光学成像技术从临床前到临床应用的转化，将确保未来利用近红外荧光在肺癌中的临床研究能够使用优化的成像参数安全地进行，并开始评估SLN分析对早期肺癌患者的治疗益处。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the United States, accounting for over 160,000 deaths each year. The best predictor of survival following surgical resection is the presence or absence of metastatic disease in regional lymph nodes. However, even early stage patients believed to be negative for nodal disease (N0), exhibit a 40% overall recurrence rate. Retrospective analysis has demonstrated that a significant number of early stage lung cancer patients harbor "occult" metastases when histologically scrutinized as is done for sentinel lymph nodes (SLNs) in breast cancer and melanoma, and these patients demonstrate poorer survival and an increased risk of recurrence. The identification and excision of SLNs for lung cancer would permit the histologic scrutiny necessary to detect micrometastatic disease and allow accurate correlation of micrometastatic disease with the risk of lung cancer recurrence. Unfortunately, previous SLN mapping techniques have been severely limited in lung cancer due to formidable technical difficulties, making SLN mapping essentially unavailable for patients with lung cancer. As such, it remains unknown if SLN analysis can improve clinical outcomes. We have developed an optical imaging platform that utilizes invisible near-infrared (NIR) fluorescent light combined with color video, to provide the surgeon with real-time, intraoperative image guidance that permits accurate SLN mapping and resection to be performed. Extensive optimization and successful pre-clinical validation in large animals has lead to the need for clinical feasibility studies, especially with regard to safety and efficacy of the device and contrast agent combination. IRB approval has been obtained to conduct a clinical trial with the FDA- approved NIR fluorophore indocyanine green (ICG) and we describe a systematic plan to assess safety and efficacy of the device and fluorophore during human lung cancer surgery. The overall goal of this study is to maximize the detection of tumor-specific SLN via image-guidance during operative resection of early lung cancer, with the future goal of improving outcomes for the estimated 15,000 early lung cancer patients with metastatic nodal disease missed each year by current methods. Specific Aim I is focused on optimizing ICG injection technique, fluorophore concentration and excitation light fluence rate during SLN mapping. Specific Aim 2 will determine whether NIR fluorescence imaging can improve identification and analysis of SLN over current lymphadenectomy. Specific Aim 3 will determine if NIR image-guided SLN excision enhances detection of metastatic disease and whether the presence of micrometastatic disease is a predictor of disease recurrence. Completion of these specific aims will result in translation of a novel optical imaging technology from pre-clinical to clinical use, will ensure that future clinical studies utilizing NIR fluorescence in lung cancer are conducted safely using optimized imaging parameters, and begin to assess the therapeutic benefit of SLN analysis in patients with early stage lung cancer. The clinical evaluation of the feasibility, safety and efficacy of novel near-infrared (NIR) guidance for sentinel lymph node (SLN) dissection for early lung cancer in an intraoperative setting has the potential to change the current standard-of-care for patients with surgically resectable lung cancer. NIR fluorescent imaging represents a significant advance in SLN identification for lung cancer patients and promises to substantially improve the detection of the occult metastatic disease currently missed in local lymph nodes of an estimated 15,000 patients with potentially curable lung cancer each year in the US. Given that previously undetected micrometastatic disease results in a significant decrease in survival and a nearly 3 fold increase in recurrence, accurate and safe identification of a subset of early lung cancer patients that could potentially benefit from adjuvant therapy, is of vital importance in the ongoing battle against lung cancer.