Highly Sensitive Detection of Occult Pancreatic Cancer Using Intraoperative Molecular Imaging

项目摘要/摘要 手术未能为胰腺切除患者提供长期无病生存间隔 癌症与无法识别转移或局部区域的隐匿性肿瘤灶有关。为 手术要有效，迫切需要实时检测微小的亚临床转移(如果 目前)和可视化的肿瘤的不可见的渗透沿计划的边界 切除手术。这项应用的总体目标是在临床上验证荧光标记的 抗EGFR抗体Panitumab-IRDye800CW(Pan800)用于术中低容量检测 (1-3mm~3)活体胰腺癌肿瘤灶。中心假设是近红外(NIR) 术中使用Pan800进行成像将能够对肿瘤沉积物进行超灵敏的检测， 否则，使用当前的成像技术和外科检查/触诊进行逃逸检测。在 建议的研究，符合手术条件的胰腺癌患者将接受输注 Pan800将在手术前2-5天使用，术中使用近红外摄像机检测1-3 mm的肿瘤 焦点。将追求以下两个具体目标：1)确定Pan800的诊断准确性 术中荧光成像以检测放射学上的隐匿性(即放射科医生看不到的) 胰腺癌转移；以及2)确定Pan800荧光成像对 确定手术后切除床上可见的隐蔽(即外科医生看不见)的残留肿瘤灶 活体或在体外切除标本的边缘。在第一个目标下，检测的敏感性和特异性 这种术中用来识别小的、放射下腹膜转移的成像方式将是 有记录在案。对于第二个目标，这种模式的增量产量比传统的亮场 在切除床或标本边缘发现其他看不见的肿瘤病灶的检查将 演示了。外科显像剂的易得性治疗性EGFR抗体的再利用 在申请人看来，不仅安全和成本效益高，而且极具创新性，因为它可以挑战 与术中胰腺癌检测相关的现状没有根本改变 几十年来。拟议的研究具有重要意义，因为它将建立在先前 Pan800在体内检测胰腺癌的有效性，为其提供了新的机会 持续发展作为加强术中分期、支持决策、增加 完全切除肿瘤的可能性，并最终改善高度患有这种疾病的患者的临床结果 致命的恶性疾病。

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.