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

Inna Gertsenshteyn; Boris Epel; Amandeep Ahluwalia; Heejong Kim; Xiaobing Fan; Eugene Barth; Marta Zamora; Erica Markiewicz; Hsiu Ming Tsai; Subramanian Sundramoorthy; Lara Leoni; John Lukens; Mohammed Bhuiyan; Richard Freifelder; Anna Kucharski; Mihai Giurcanu; Brian B. Roman; Gregory Karczmar; Chien Min Kao; Howard Halpern; Chin Tu Chen

doi:10.1007/s00259-022-05889-4

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

Inna Gertsenshteyn, Boris Epel, Amandeep Ahluwalia, Heejong Kim, Xiaobing Fan, Eugene Barth, Marta Zamora, Erica Markiewicz, Hsiu Ming Tsai, Subramanian Sundramoorthy, Lara Leoni, John Lukens, Mohammed Bhuiyan, Richard Freifelder, Anna Kucharski, Mihai Giurcanu, Brian B. Roman, Gregory Karczmar, Chien Min Kao, Howard HalpernChin Tu Chen^*

^*Corresponding author for this work

Radiology

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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≤ 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 K^trans and v_e 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 (ρ) 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 ± 0.2) were SUV ≥ 1.4 × SUV_mean and SUV ≥ 0.6 × SUV_max. Weak-to-moderate correlations (|ρ|< 0.70) were observed between PET/EPRI hypoxia images with vascular permeability (K^trans) or fractional extracellular-extravascular space (v_e) 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.

Original language	English (US)
Pages (from-to)	4014-4024
Number of pages	11
Journal	European Journal of Nuclear Medicine and Molecular Imaging
Volume	49
Issue number	12
DOIs	https://doi.org/10.1007/s00259-022-05889-4
State	Published - Oct 2022

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. 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. 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 pO imaging technology; HH and BE are also members of a start-up company O2M to market the pO 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. 2 2

Keywords

DCE-MRI
EPRI
FMISO PET
Tumor hypoxia

ASJC Scopus subject areas

Radiology Nuclear Medicine and imaging

Access to Document

10.1007/s00259-022-05889-4

Cite this

Gertsenshteyn, I., Epel, B., Ahluwalia, A., Kim, H., Fan, X., Barth, E., Zamora, M., Markiewicz, E., Tsai, H. M., Sundramoorthy, S., Leoni, L., Lukens, J., Bhuiyan, M., Freifelder, R., Kucharski, A., Giurcanu, M., Roman, B. B., Karczmar, G., Kao, C. M., ... Chen, C. T. (2022). The optimal ¹⁸F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO₂ electron paramagnetic resonance imaging as reference truth. European Journal of Nuclear Medicine and Molecular Imaging, 49(12), 4014-4024. https://doi.org/10.1007/s00259-022-05889-4

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

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≤ 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 (ρ) 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 ± 0.2) were SUV ≥ 1.4 × SUVmean and SUV ≥ 0.6 × SUVmax. Weak-to-moderate correlations (|ρ|< 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.",

keywords = "DCE-MRI, EPRI, FMISO PET, Tumor hypoxia",

author = "Inna Gertsenshteyn and Boris Epel and Amandeep Ahluwalia and Heejong Kim and Xiaobing Fan and Eugene Barth and Marta Zamora and Erica Markiewicz and Tsai, {Hsiu Ming} and Subramanian Sundramoorthy and Lara Leoni and John Lukens and Mohammed Bhuiyan and Richard Freifelder and Anna Kucharski and Mihai Giurcanu and Roman, {Brian B.} and Gregory Karczmar and Kao, {Chien Min} and Howard Halpern and Chen, {Chin Tu}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2022",

month = oct,

doi = "10.1007/s00259-022-05889-4",

language = "English (US)",

volume = "49",

pages = "4014--4024",

journal = "European Journal of Nuclear Medicine and Molecular Imaging",

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Gertsenshteyn, I, Epel, B, Ahluwalia, A, Kim, H, Fan, X, Barth, E, Zamora, M, Markiewicz, E, Tsai, HM, Sundramoorthy, S, Leoni, L, Lukens, J, Bhuiyan, M, Freifelder, R, Kucharski, A, Giurcanu, M, Roman, BB, Karczmar, G, Kao, CM, Halpern, H & Chen, CT 2022, 'The optimal ¹⁸F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO₂ electron paramagnetic resonance imaging as reference truth', European Journal of Nuclear Medicine and Molecular Imaging, vol. 49, no. 12, pp. 4014-4024. https://doi.org/10.1007/s00259-022-05889-4

The optimal ¹⁸F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO₂ electron paramagnetic resonance imaging as reference truth. / Gertsenshteyn, Inna; Epel, Boris; Ahluwalia, Amandeep et al.
In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 49, No. 12, 10.2022, p. 4014-4024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - The optimal 18F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO2 electron paramagnetic resonance imaging as reference truth

AU - Gertsenshteyn, Inna

AU - Epel, Boris

AU - Ahluwalia, Amandeep

AU - Kim, Heejong

AU - Fan, Xiaobing

AU - Barth, Eugene

AU - Zamora, Marta

AU - Markiewicz, Erica

AU - Tsai, Hsiu Ming

AU - Sundramoorthy, Subramanian

AU - Leoni, Lara

AU - Lukens, John

AU - Bhuiyan, Mohammed

AU - Freifelder, Richard

AU - Kucharski, Anna

AU - Giurcanu, Mihai

AU - Roman, Brian B.

AU - Karczmar, Gregory

AU - Kao, Chien Min

AU - Halpern, Howard

AU - Chen, Chin Tu

PY - 2022/10

Y1 - 2022/10

N2 - 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≤ 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 (ρ) 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 ± 0.2) were SUV ≥ 1.4 × SUVmean and SUV ≥ 0.6 × SUVmax. Weak-to-moderate correlations (|ρ|< 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.

AB - 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≤ 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 (ρ) 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 ± 0.2) were SUV ≥ 1.4 × SUVmean and SUV ≥ 0.6 × SUVmax. Weak-to-moderate correlations (|ρ|< 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.

KW - DCE-MRI

KW - EPRI

KW - FMISO PET

KW - Tumor hypoxia

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