Mediastinal Lymph Node Identification in Lung Cancer using NIR Fluorescent VATS

7.项目总结/摘要 非小细胞肺癌的分期需要综合评估肺淋巴结 通过肺切除术期间的完全淋巴结切除术或通过淋巴结取样 使用纵隔镜检查（术前或术中）。前瞻性随机对照试验Z 0030， 2011年报告，报告完全纵隔淋巴结清扫术（MLND）和 更有限的纵隔淋巴结采样（MLNS），前提是至少18个淋巴结 找到并切除然而，即使在纵膈找到18个淋巴结也是一项艰巨的任务，特别是 当最新的ACOSOG建议包括来自2 R、4 R、7、8、9站的特定淋巴结时， 右胸10 R，左胸4L、5、6、7、8、9和10 L。目前，淋巴结取样 肺是耗时和技术上具有挑战性的，这反过来又增加了并发症的风险， 遗漏的淋巴结理想的NSCLC分期技术将提供敏感和实时的 通过直径5 mm的胸腔镜识别肺淋巴结，无需电离辐射。 Curadel开发了这样一种技术。FLARE®（荧光辅助切除术和 勘探）成像平台使用低水平的安全，不可见，近红外（NIR）荧光灯，以突出 一个或多个目标。我们的两项最新创新包括微创FLARE®系统 与视频辅助胸腔镜手术（VATS）和靶向NIR荧光造影剂兼容 （CUR-PS327），在单次低剂量给药后数小时内突出显示纵隔中的每个淋巴结 静脉注射由于近红外光能穿透活体组织和血液几毫米， 该技术使MLNS治疗NSCLC能够以高灵敏度实时进行。 我们的长期目标是最大限度地减少麻醉时间，减少并发症发生率， NSCLC患者的淋巴结采样。为了实现这一目标，我们组建了一个国际团队， 来自学术界的经验丰富的研究者（荷兰莱顿大学医学中心; LUMC） （Curadel，LLC）。每个机构都有经过验证的核心能力和独特的基础设施， 结合起来，并发挥杠杆作用，以完成赠款的目标。具体来说，我们将优化5毫米直径 胸腔镜能够同时进行彩色视频、700 nm NIR荧光和800 nm荧光， 开发符合cGMP的泛淋巴结剂CUR-PS327的合成和无菌灌装-成品（800 nm峰 排放），进行临床试验申请（IND等效），启用毒理学，并进行1A期试验 （正常人类志愿者）和1B期（接受MLNS的NSCLC患者）首次人体临床试验， LUMC药物研究中心的技术。 具体目标的完成将使这项新技术对护理产生重大影响， 肺癌患者。

7. PROJECT SUMMARY/ABSTRACT The staging of non-small cell lung cancer (NSCLC) requires comprehensive evaluation of lung lymph nodes, either via complete lymphadenectomy during pulmonary resection or via sampling of lymph nodes using mediastinoscopy (preoperatively or intraoperatively). Prospective randomized controlled trial Z0030, reported in 2011, reported no difference between a complete mediastinal lymph node dissection (MLND) and a more limited mediastinal lymph node sampling (MLNS), provided that a minimum of 18 lymph nodes were found and resected. However, finding even 18 lymph nodes in the mediastinum is a daunting task, especially when the latest ACOSOG recommendations include specific lymph nodes from stations 2R, 4R, 7, 8, 9, and 10R in the right chest and stations 4L, 5, 6, 7, 8, 9, and 10L in the left chest. Currently, lymph node sampling of the lung is time-consuming and technically challenging, which in turn increases the risk of complications and missed lymph nodes. The ideal technology for NSCLC staging would provide sensitive and real-time identification of lung lymph nodes via a 5-mm diameter thoracoscope, without the need for ionizing radiation. Curadel has developed such a technology. The FLARE® (FLuorescence-Assisted Resection and Exploration) imaging platform uses low levels of safe, invisible, near-infrared (NIR) fluorescent light to highlight one or more targets during surgery. Our two newest innovations include a minimally-invasive FLARE® system compatible with video-assisted thoracoscopic surgery (VATS) and a targeted NIR fluorescent contrast agent (CUR-PS327) that highlights every lymph node in the mediastinum for several hours after a single low-dose intravenous injection. Because NIR light penetrates several millimeters through living tissue and blood, this technology enables MLNS for NSCLC to be performed in real-time and with high sensitivity. Our long-term goal is to minimize anesthesia time, minimize complication rate, and maximize lymph node sampling for patients with NSCLC. To accomplish this goal, we have assembled an international team of highly experienced investigators from academia (Leiden University Medical Center in The Netherlands; LUMC) and industry (Curadel, LLC). Each institution has proven core competencies and unique infrastructures that will be combined and leveraged to complete the aims of the grant. Specifically, we will optimize a 5-mm diameter thoracoscope capable of simultaneous color video, 700 nm NIR fluorescence, and 800 nm fluorescence, develop cGMP-compliant synthesis and aseptic fill-finish of pan lymph node agent CUR-PS327 (800 nm peak emission), perform Clinical Trial Application (IND equivalent) enabling toxicology, and perform Phase 1A (normal human volunteers) and Phase 1B (NSCLC patients undergoing MLNS) first-in-human clinical trials of the technology at the LUMC Centre for Drug Research. Completion of the Specific Aims will position this new technology to have a major impact on the care of patients with lung cancer.