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The optimal 18F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO2 electron paramagnetic resonance imaging as reference truth

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

Abstract

Purpose

To identify the optimal threshold in 18F-fluoromisonidazole (FMISO) PET images to accurately locate tumor hypoxia by using electron paramagnetic resonance imaging (pO2 EPRI) as ground truth for hypoxia, defined by pO2 \(\le\) 10 mmHg.

Methods

Tumor hypoxia images in mouse models of SCCVII squamous cell carcinoma (n = 16) were acquired in a hybrid PET/EPRI imaging system 2 h post-injection of FMISO. T2-weighted MRI was used to delineate tumor and muscle tissue. Dynamic contrast enhanced (DCE) MRI parametric images of Ktrans and ve were generated to model tumor vascular properties. Images from PET/EPR/MRI were co-registered and resampled to isotropic 0.5 mm voxel resolution for analysis. PET images were converted to standardized uptake value (SUV) and tumor-to-muscle ratio (TMR) units. FMISO uptake thresholds were evaluated using receiver operating characteristic (ROC) curve analysis to find the optimal FMISO threshold and unit with maximum overall hypoxia similarity (OHS) with pO2 EPRI, where OHS = 1 shows perfect overlap and OHS = 0 shows no overlap. The means of dice similarity coefficient, normalized Hausdorff distance, and accuracy were used to define the OHS. Monotonic relationships between EPRI/PET/DCE-MRI were evaluated with the Spearman correlation coefficient (\(\rho\)) to quantify association of vasculature on hypoxia imaged with both FMISO PET and pO2 EPRI.

Results

FMISO PET thresholds to define hypoxia with maximum OHS (both OHS = 0.728 \(\pm\) 0.2) were SUV \(\ge\) 1.4 \(\times\) SUVmean and SUV \(\ge\) 0.6 \(\times\) SUVmax. Weak-to-moderate correlations (|\(\rho\)|< 0.70) were observed between PET/EPRI hypoxia images with vascular permeability (Ktrans) or fractional extracellular-extravascular space (ve) from DCE-MRI.

Conclusion

This is the first in vivo comparison of FMISO uptake with pO2 EPRI to identify the optimal FMISO threshold to define tumor hypoxia, which may successfully direct hypoxic tumor boosts in patients, thereby enhancing tumor control.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the first author or corresponding author on reasonable request.

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Acknowledgements

We would like to thank the University of Chicago’s Cyclotron Facility, the Integrated Small Animal Imaging Research Resource, and the Human Tissue Resource Center. We would also like to thank Dr. Scott Trinkle for his helpful comments after reading over the manuscript, Dr. Nicole Cipriani’s expertise in pathology, and Dr. Hannah Zhang’s advice in early histological imaging sample preparation.

Funding

This study was funded by National Institutes of Health grants R01 CA098575, R01 CA 236385, P30 CA014599, P41 EB002034, F31 CA254223, S10 OD025265, and R01 EB029948.

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Authors and Affiliations

  1. Department of Radiology, The University of Chicago, Chicago, IL, USA

    Inna Gertsenshteyn, Amandeep Ahluwalia, Heejong Kim, Xiaobing Fan, Marta Zamora, Mohammed Bhuiyan, Richard Freifelder, Anna Kucharski, Brian B. Roman, Gregory Karczmar, Chien-Min Kao & Chin-Tu Chen

  2. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA

    Inna Gertsenshteyn, Boris Epel, Eugene Barth, Subramanian Sundramoorthy, John Lukens & Howard Halpern

  3. Center for EPR Imaging In Vivo Physiology, The University of Chicago, Chicago, IL, USA

    Inna Gertsenshteyn, Boris Epel, Eugene Barth, Subramanian Sundramoorthy, John Lukens & Howard Halpern

  4. Integrated Small Animal Imaging Research Resource, OSRF, The University of Chicago, Chicago, IL, USA

    Xiaobing Fan, Marta Zamora, Erica Markiewicz, Hsiu-Ming Tsai, Lara Leoni, Brian B. Roman, Gregory Karczmar, Chien-Min Kao & Chin-Tu Chen

  5. Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA

    Mihai Giurcanu

Authors
  1. Inna Gertsenshteyn
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Contributions

The following authors contributed to acquiring data: Inna Gertsenshteyn, Boris Epel, Eugene Barth, John Lukens, Xiaobing Fan, Hsui-Ming Tsai, Lara Leoni, Heejong Kim, Marta Zamora, Erica Markiewicz, Subramanian Sundramoorthy, Richard Freifelder, Mohammed Bhuiyan, and Anna Kucharski. The following authors contributed to the conception and design of the data: Inna Gertsenshteyn, Boris Epel, Brian Roman, Gregory Karczmar, Chien-Min Kao, Howard Halpern, Chin-Tu Chen. The following authors contributed to analyzing and interpreting data: Inna Gertsenshteyn, Amandeep Ahluwalia, Mihai Giurcanu, Brian Roman, Gregory Karczmar, Howard Halpern, Chin-Tu Chen. The first draft of the manuscript was written by Inna Gertsenshteyn, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chin-Tu Chen.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

Conflict of interest

Author Chin-Tu Chen (CTC) is a PI for the following grants from NIH/NIBIB (R01 EB022388 and R01 EB029948), NIH/NIDA (R01 DA044760), and NIH/NCI (P30 CA14599 facility). CTC receives a personal fee from the American Institute of Physics for editorial responsibilities. Other relationships include institute licenses patents (CTC is a co-inventor) to RefleXion Medical, Inc. and Incom. CTC is a co-founder and on the board of directors of EVO Worldwide LLC and AEPX Imaging, Inc. Author Howard Halpern (HH) is a PI for the following grants from NIH/NCI (R01 CA098575 and P30 CA014599) and NIH/NIBIB (P41 EB002034). HH also holds two US patents (8,664,955 and 9,392,957) to him and one (9,392,957) to author Boris Epel (BE) for aspects of the pO2 imaging technology; HH and BE are also members of a start-up company O2M to market the pO2 imaging technology in preclinical models. No other potential conflicts of interest relevant to this article exist. The rest of the authors have no relevant financial or non-financial interests to disclose.

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Gertsenshteyn, I., Epel, B., Ahluwalia, A. et al. The optimal 18F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO2 electron paramagnetic resonance imaging as reference truth. Eur J Nucl Med Mol Imaging 49, 4014–4024 (2022). https://doi.org/10.1007/s00259-022-05889-4

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  • DOI: https://doi.org/10.1007/s00259-022-05889-4

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