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Rapid and Quantitative Intraoperative Pathology-Assisted Surgery by Paired-Agent Imaging-Derived Confidence Map

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Abstract

Purpose

In nonmetastatic head and neck cancer treatment, surgical margin status is the most important prognosticator of recurrence and patient survival. Fresh frozen sectioning (FFS) of tissue margins is the standard of care for intraoperative margin assessment. However, FFS is time intensive, and its accuracy is not consistent among institutes. Mapping the epidermal growth factor receptor (EGFR) using paired-agent imaging (PAI) has the potential to provide more consistent intraoperative margin assessment in a fraction of the time as FFS.

Procedures

PAI was carried out through IV injection of an anti-epidermal growth factor receptor (EGFR) affibody molecule (ABY-029, eIND 122,681) and an untargeted IRDye680LT carboxylate. Imaging was performed on 4 µm frozen sections from three oral squamous cell carcinoma xenograft mouse models (n = 24, 8 samples per cell line). The diagnostic ability and tumor contrast were compared between binding potential, targeted, and untargeted images. Confidence maps were constructed based on group histogram-derived tumor probability curves. Tumor differentiability and contrast by confidence maps were evaluated.

Results

PAI outperformed ABY-029 and IRDye 680LT alone, demonstrating the highest individual receiver operating characteristic (ROC) curve area under the curve (PAI AUC: 0.91, 0.90, and 0.79) and contrast-to-noise ratio (PAI CNR: 1, 1.1, and 0.6) for FaDu, Det 562, and A253. PAI confidence maps (PAI CM) maintain high tumor diagnostic ability (PAI CMAUC: 0.91, 0.90, and 0.79) while significantly enhancing tumor contrast (PAI CMCNR: 1.5, 1.3, and 0.8) in FaDu, Det 562, and A253. Additionally, the PAI confidence map allows avascular A253 to be differentiated from a healthy tissue with significantly higher contrast than PAI. Notably, PAI does not require additional staining and therefore significantly reduces the tumor delineation time in a 5 \(\times\) 5 mm slice from ~ 35 min to under a minute.

Conclusion

This study demonstrated that PAI improved tumor detection in frozen sections with high diagnostic accuracy and rapid analysis times. The novel PAI confidence map improved the contrast in vascular tumors and differentiability in avascular tumors. With a larger database, the PAI confidence map promises to standardize fluorescence imaging in intraoperative pathology-assisted surgery (IPAS).

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Acknowledgements

The authors would like to acknowledge the gift of ABY-029 (R01 CA167413). The IRDye 680LT NHS ester was graciously provided by LI-COR Biosciences, Inc. as part of an ongoing academic-industrial partnership. The authors thank Pathology Translational Research Program at Dartmouth-Hitchcock Medical Center and histotechnologist Scott M. Palisoul ASCP (HT), who performed the frozen sectioning, IHC, and H&E staining.

Funding

This work was funded by the grant R37 CA212187 (KSS). The production of ABY-029 was funded by R01 CA167413.

Author information

Authors and Affiliations

  1. Thayer School of Engineering, Dartmouth College, Hanover, NH, USA

    Cheng Wang, Sassan Hodge, P. Jack Hoopes & Kimberley S. Samkoe

  2. Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    Eunice Y. Chen, P. Jack Hoopes & Kimberley S. Samkoe

  3. Geisel School of Medicine, Dartmouth College, Hanover, NH, USA

    Divya Ravi, Eunice Y. Chen, P. Jack Hoopes & Kimberley S. Samkoe

  4. Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA

    Kenneth M. Tichauer

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Contributions

CW designed the research, performed the experiments, analyzed the data, and wrote the manuscript. SH, DR, and PJH helped perform the experiments, analyzed the data, and/or interpreted the data. EYC and KMT helped design the study and interpreted the data. KSS designed the research, provided the funding, interpreted the data, and supervised the experiments. All the authors read, edited, and approved the final version of the manuscript.

Corresponding author

Correspondence to Kimberley S. Samkoe.

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Conflict of Interest

Author KSS reports receiving the Odyssey M imaging system from LI-COR Biosciences, Inc. as a gift. All the other authors report no conflict of interest.

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Wang, C., Hodge, S., Ravi, D. et al. Rapid and Quantitative Intraoperative Pathology-Assisted Surgery by Paired-Agent Imaging-Derived Confidence Map. Mol Imaging Biol 25, 190–202 (2023). https://doi.org/10.1007/s11307-022-01780-8

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