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Prospective validation of tumor folate receptor expression density with the association of pafolacianine fluorescence during intraoperative molecular imaging–guided lung cancer resections

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Abstract

Purpose

Pafolacianine, a folate receptor alpha-targeted NIR tracer, has demonstrated clear efficacy in intraoperative molecular imaging–guided (IMI) lung cancer surgery. However, the selection of patients who would benefit from IMI remains challenging given the variability of fluorescence with patient-associated and histopathologic factors. Our goal in this study was to prospectively evaluate whether preoperative FRα/FRβ staining can predict pafolacianine-based fluorescence during real-time lung cancer resections.

Methods

This was a prospective study conducted between 2018 and 2022 that reviewed core biopsy and intraoperative data from patients with suspected lung cancer. A total of 196 patients were deemed eligible, of whom core biopsies were taken from 38 patients and assessed for FRα and FRβ expression by immunohistochemistry (IHC). All patients underwent infusion of pafolacianine 24 h prior to surgery. Intraoperative fluorescence images were captured with the VisionSense bandpass filter–enabled camera. All histopathologic assessments were performed by a board-certified thoracic pathologist.

Results

Of the 38 patients, 5 (13.1%) were found to have benign lesions (necrotizing granulomatous inflammation, lymphoid aggregates) and 1 had metastatic non-lung nodule. Thirty (81.5%) had malignant lesions, with the vast majority (23, 77.4%) being lung adenocarcinoma (7 (22.5%) SCC). None of the benign tumors (0/5, 0%) exhibited in vivo fluorescence (mean TBR of 1.72), while 95% of the malignant tumors fluoresced (mean TBR of 3.11 ± 0.31) compared to squamous cell carcinoma (1.89 ± 0.29) of the lung and sarcomatous lung metastasis (2.32 ± 0.09) (p < 0.01). The TBR was significantly higher in the malignant tumors (p = 0.009). The median FRα and FRβ staining intensities were both 1.5 for benign tumors, while the FRα and FRβ staining intensities were 3 and 2 for malignant tumors, respectively. Increased FRα expression was significantly associated with the presence of fluorescence (p = 0.01),

Conclusion

This prospective study sought to determine whether preoperative FRα and FRβ expression on core biopsy IHC correlates with intraoperative fluorescence during pafolacianine-guided surgery. These results, although of small sample size, including limited non-adenocarcinoma cohort, suggest that performing FRα IHC on preoperative core biopsies of adenocarcinomas as compared to squamous cell carcinomas could provide low-cost, clinically useful information for optimal patient selection which should be further explored in advanced clinical trials.

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Data availability

All data is available in the manuscript and the supplementary file. Additional data can be obtained by contacting the corresponding author.

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Acknowledgements

Figure panels edited with BioRender.

Funding

Dr. Azari was supported by the training grant in Surgical Oncology by the National Institutes of Health (T32CA251063-01), the Society of Thoracic Surgeons Thoracic Surgery Foundation Research Award, and the Stephen CC Cheung Fellowship in Surgical Oncology. Dr. Singhal was supported by the National Institutes of Health (NIH P01CA254859) and the State of Pennsylvania Health Research Formula Fund. Dr. Kennedy was supported by the American Philosophical Society and the National Institutes of Health (grant F32 CA254210-01).

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Author notes

  1. Feredun Azari and Kevin Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, 6 White Building, Philadelphia, PA, 19104, USA

    Feredun Azari, Gregory Kennedy, Patrick Bou-Samra, Ashley Chang, Austin Chang, Azra Din, John Kucharczuk, Jarrar Doraid, Taine Pechet & Sunil Singhal

  2. University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Kevin Zhang

  3. Ohio State University School of Medicine, Ohio, Columbus, USA

    Patrick Bou-Samra

  4. Ankara Yildirim Beyazit Faculty of Medicine, Ankara, Turkey

    Bilal Nadeem & Aysuna Galandarova

  5. Faculty of Medicine, Ankara University, Ankara, Turkey

    Arturan Ibrahimli

  6. Faculty of Medicine, Ege University, Izimir, Turkey

    Ziya Karimov

  7. Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Edward Delikatny

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  1. Feredun Azari
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Corresponding author

Correspondence to Sunil Singhal.

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Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and approved by the University of Pennsylvania Institutional Review Board. The study complies with the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Supplementary Information

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259_2023_6141_MOESM1_ESM.jpeg

Supplementary file1 Fig. 1: False-positive fluorescence of benign lymph nodes with IHC demonstrating strong FRβ density and minimal FRα presence. (JPEG 972 KB)

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Azari, F., Zhang, K., Kennedy, G. et al. Prospective validation of tumor folate receptor expression density with the association of pafolacianine fluorescence during intraoperative molecular imaging–guided lung cancer resections. Eur J Nucl Med Mol Imaging 50, 2453–2465 (2023). https://doi.org/10.1007/s00259-023-06141-3

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