Highly Sensitive Detection of Occult Pancreatic Cancer Using Intraoperative Molecular Imaging

项目总结/摘要 手术未能为胰腺癌切除患者提供长期的无病生存期， 癌症与不能识别转移或局部部位的隐匿性肿瘤病灶有关。为 为了使手术有效，迫切需要实时检测小的亚临床转移（如果 目前）和可视化的肿瘤的不可见的浸润沿着边界的计划 切除术本申请的总体目标是在临床上验证荧光标记的使用 抗EGFR抗体，帕尼单抗-IRDye 800 CW（pan 800），用于术中检测低容量 (1-3 mm 3）胰腺癌肿瘤病灶。核心假设是近红外（NIR） 使用PAN 800的术中成像将能够超灵敏地检测肿瘤沉积物， 否则使用当前的成像技术和外科检查/触诊来逃避检测。在 在一项拟议的研究中，符合手术条件的胰腺癌患者将接受 在手术前2-5天使用pan 800，术中使用NIR摄像机检测1-3 mm³肿瘤 焦点本研究的主要目的是：1）确定pan 800诊断的准确性 术中荧光成像以检测放射学上隐匿的（即，放射科医生看不见） 胰腺癌转移;和2）确定pan 800荧光成像对 识别明显的隐匿性（即，外科医生看不见）手术后切除床的残留肿瘤病灶， 体内或离体切除标本的边缘。在第一个目标下， 这种术中成像模式，以确定小，亚放射腹膜转移，将 记录在案。对于第二个目标，这种模式的增量产量超过传统的明场 在切除床或标本边缘进行检查以识别不可见的肿瘤病灶， 演示。将现成的治疗性EGFR抗体重新用于外科成像剂 在申请人看来，不仅安全和成本有效，而且高度创新，因为它可以挑战 与术中胰腺癌检测相关的现状，尚未从根本上改变 在几十年里。拟议的研究是重要的，因为它将建立在以前的 证明了pan 800在体内检测胰腺癌的有效性，为其 作为一种工具持续发展，以加强术中分期，支持决策，增加 完全切除肿瘤的可能性，并最终改善这种高度恶性肿瘤患者的临床结局。 致命的恶性肿瘤

PROJECT SUMMARY/ABSTRACT The failure of surgery to provide a long-disease free survival interval to patients with resected pancreatic cancer is related to the inability to recognize occult tumor foci at metastatic or locoregional sites. For surgery to be effective, there is a critical need for real-time detection of small, sub-clinical metastases (if present) and for visualization of the tumor’s invisible infiltration along the boundaries of the planned resection. The overall objective of this application is to clinically validate the use of a fluorescently labeled anti-EGFR antibody, panitumumab-IRDye800CW (pan800), for the intraoperative detection of low-volume (1-3 mm3) pancreatic cancer tumor foci in vivo. The central hypothesis is that Near InfraRed (NIR) intraoperative imaging with pan800 will enable ultrasensitive detection of tumor deposits that would otherwise escape detection using current imaging technology and surgical inspection/palpation. In the proposed study, patients with pancreatic adenocarcinoma eligible for surgery will undergo infusion of pan800 2-5 days prior to surgery and NIR cameras will be used intraoperatively to detect 1-3 mm³ tumor foci. The following two specific aims will be pursued: 1) Determine the diagnostic accuracy of pan800 intraoperative fluorescent imaging to detect radiographically occult (i.e., unseen by the radiologist) pancreatic adenocarcinoma metastases; and 2) Determine the efficacy of pan800 fluorescent imaging to identify visibly occult (i.e., unseen by the surgeon) residual tumor foci at the post-surgical resection bed in vivo or at the margin of the resected specimen ex vivo. Under the first aim, the sensitivity and specificity of this intraoperative imaging modality to identify small, sub-radiologic peritoneal metastases will be documented. For the second aim, the incremental yield of this modality over conventional bright-field inspection in identifying otherwise invisible tumor foci at the resection bed or specimen margin will be demonstrated. The repurposing of readily available therapeutic EGFR antibodies to surgical imaging agents is not only safe and cost effective, but also highly innovative, in the applicant’s opinion, as it can challenge the status quo related to intraoperative pancreatic cancer detection, which has not fundamentally changed over several decades. The proposed research is significant because it will build upon the previously demonstrated efficacy of pan800 to detect pancreatic cancer in vivo, providing new opportunities for its continued development as a tool to enhance intraoperative staging, support decision making, increase the likelihood of complete tumor resection, and eventually improve clinical outcomes for patients with this highly lethal malignancy.