House Broderick J, Schaefer Jasmin M, Barth Connor W, Davis Scott C, Gibbs Summer L
Biomedical Engineering Department, Oregon Health & Science University, Portland, OR 97201.
Thayer School of Engineering, Dartmouth College, Hanover, NH 03755.
Proc SPIE Int Soc Opt Eng. 2019 Feb;10862. doi: 10.1117/12.2510625. Epub 2019 Mar 7.
Identification of tumor margins in the operating room in real time is a critical challenge for surgical procedures that serve as cancer cure. Breast conserving surgery (BCS) is particularly affected by this problem, with current re-excision rates above 25%. Due to a lack of clinically available methodologies for detection of involved or close tumor margins, much effort is focused on developing intraoperative margin assessment modalities that can aid in addressing this unmet clinical need. BCS provides a unique opportunity to design contrast-based technologies that are able to assess tumor margins independent from the patient, providing a rapid pathway from bench to bedside at a much lower cost. Since resected tissue is removed from the patient's blood supply, non-specific contrast agent uptake becomes a challenge due to the lack of clearance. Therefore, a dual probe, ratiometric fluorescence imaging approach was taken in an effort to reduce non-specific signal, and provide a modality that could demonstrate rapid, robust margin assessment on resected patient samples. Termed, dual-stain difference specimen imaging (DDSI), DDSI includes the use of spectrally unique, and fluorescently labeled target-specific, as well as non-specific biomarkers. In the present study, we have applied epidermal growth factor receptor (EGFR) targeted DDSI to tumor xenografts with variable EGFR expression levels using a previously optimized staining protocol, allowing for a quantitative assessment of the predictive power of the technique under biologically relevant conditions. Due to the presence of necrosis in the model tumors, ring analysis was employed to characterize diagnostic accuracy as measured by receiver operator characteristic (ROC) curve analysis. Our findings demonstrate the robust nature of the DDSI technique even in the presence of variable biomarker expression and spatial patterns. These results support the continued development of this technology as a robust diagnostic tool for tumor margin assessment in resected specimens during BCS.
在手术室实时识别肿瘤边缘是癌症根治性手术面临的一项关键挑战。保乳手术（BCS）尤其受此问题影响，目前再次切除率超过25%。由于缺乏用于检测肿瘤边缘受累或接近情况的临床可用方法，大量精力集中在开发术中边缘评估方法上，以满足这一未得到满足的临床需求。BCS提供了一个独特的机会来设计基于对比的技术，该技术能够独立于患者评估肿瘤边缘，以低得多的成本提供从实验室到床边的快速途径。由于切除的组织已脱离患者的血液供应，缺乏清除机制导致非特异性造影剂摄取成为一个挑战。因此，采用了双探针比率荧光成像方法，以减少非特异性信号，并提供一种能够对切除的患者样本进行快速、可靠边缘评估的方法。双染差异标本成像（DDSI）使用光谱独特、荧光标记的靶向特异性以及非特异性生物标志物。在本研究中，我们使用先前优化的染色方案，将表皮生长因子受体（EGFR）靶向的DDSI应用于具有不同EGFR表达水平的肿瘤异种移植模型，从而在生物学相关条件下对该技术的预测能力进行定量评估。由于模型肿瘤中存在坏死，采用环形分析通过受试者操作特征（ROC）曲线分析来表征诊断准确性。我们的研究结果表明，即使存在可变的生物标志物表达和空间模式，DDSI技术仍具有强大的性能。这些结果支持将该技术继续开发为一种强大的诊断工具，用于BCS期间切除标本的肿瘤边缘评估。
