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Presence of non-Newtonian fluid in invasive pulmonary mucinous adenocarcinomas impacts fluorescence during intraoperative molecular imaging of lung cancer

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Background

Intraoperative molecular imaging (IMI) with folate-targeted NIR tracers has been shown to improve lesion localization in more than 80% of lung adenocarcinomas. However, mucinous adenocarcinomas (MAs) and invasive mucinous adenocarcinomas (IMAs) of the lung, which are variants of adenocarcinoma, appear to have decreased fluorescence despite appropriate folate receptor expression on the tumor surface. We hypothesized that the etiology may be related to light excitation and emission through non-Newtonian fluid (mucin) produced by goblet and columnar cancer cells.

Methods

Intraoperative data for 311 subjects were retrospectively reviewed from a prospectively collected 6-year database. For standardization, all patients underwent infusion of the same targeted molecular optical contrast agent (pafolacianine, folate receptor-targeted NIR fluorochrome) for lung cancer resections. Then, the ratio of the mean fluorescence intensity of the tumors and background tissues (TBR) was calculated. Tumors were examined for mucin, FRa, FRb, and immunofluorescent tracer uptake by a board-certified pathologist. The optical properties of mucin analyzed by imaging software were used to create in vitro gel models to explore the effects on NIR tracer fluorescence intensity.

Results

A large proportion (192, 62%) of the patients were female, with an average of 62.8 years and a 34-year mean pack smoking history. There were no severe (Clavien–Dindo > III) complications related to pafolacianine infusion. A total of 195 lesions in the study were adenocarcinomas, of which 19 (6.1%) were of the mucinous subtype. A total of 14/19 of the patients had a smoking history, and more than 74% of the IMA lesions were in the lower lobes. IMA lesions had a lower in situ TBR than nonmucinous adenocarcinomas (2.64 SD 0.23) vs (3.45 SD 0.11), respectively (p < 0.05). Only 9/19 (47%) were localized in situ. Tumor bisection and removal of mucin from IMAs significantly increased pafolacianine fluorescence, with resultant TBR not being significantly different from the control group (4.67 vs 4.89) (p = 0.19). Of the 16 lesions that underwent FR expression analysis, 15/16 had FR presence on cancer cells or tumor-associated macrophages in the tumor microenvironment. There was no statistically significant difference in fluorescence intensity during immunofluorescence analysis (4.99 vs 5.08) (p = 0.16). Physical removal of mucin from IMAs improved the TBR from 3.11 to 4.67 (p < 0.05). In vitro analysis of the impact of synthetic non-Newtonian fluid (agarose 0.5%) on NIR tracer fluorescence showed a decrease in MFI by a factor of 0.25 regardless of the concentration for each 5 mm thickness of mucin.

Conclusion

The mucinous subtype of lung adenocarcinomas presents a unique challenge in pafolacianine-targeted IMI-guided resections. The presence of non-Newtonian fluids presents a physical barrier that dampens the excitation of the tracer and fluorescence emission detected by the camera. Knowledge of this phenomenon can allow the surgeon to critically analyze lesion fluorescence parameters during IMI-guided lung cancer resections.

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Abbreviations

IMI:

Intraoperative molecular imaging

IMA:

Invasive mucinous adenocarcinoma

FRa:

Folate receptor alpha

FRb:

Folate receptor beta

TBR:

Tumor to background ratio

NIR:

Near infrared

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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). Dr. Sullivan has an NIH T32 postdoctoral fellowship (NIH T32 CA009140).

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Authors and Affiliations

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

    Feredun Azari, Gregory Kennedy, Ashley Chang, Bilal Nadeem, Neil Sullivan, Isvita Marfatia, Azra Din, John Kucharczuk & Sunil Singhal

  2. Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Charuhas Desphande

  3. Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

    Edward J. Delikatny

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  1. Feredun Azari
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Correspondence to Sunil Singhal.

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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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Video Demonstration of mucin removal and its impact on fluorescence emission intensity change during pafolacianine-guided lung cancer resection of invasive mucinous adenocarcinoma. (MP4 284648 KB)

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Azari, F., Kennedy, G., Chang, A. et al. Presence of non-Newtonian fluid in invasive pulmonary mucinous adenocarcinomas impacts fluorescence during intraoperative molecular imaging of lung cancer. Eur J Nucl Med Mol Imaging 49, 4406–4418 (2022). https://doi.org/10.1007/s00259-022-05912-8

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