RT Journal Article SR Electronic T1 Optimal [18]F-Misonidazole PET threshold to locate SCC7 tumor hypoxia using EPR pO2 as ground truth JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 12 OP 12 VO 62 IS supplement 1 A1 Inna Gertsenshteyn A1 Eugene Barth A1 Heejong Kim A1 Boris Epel A1 Lara Leoni A1 Hsiu-Ming Tsai A1 John Lukens A1 Subramanian Sundramoorthy A1 Mihai Giurcanu A1 Amandeep Ahluwalia A1 Xiaobing Fan A1 Erica Markiewicz A1 Marta Zamora A1 Mohammed Bhuiyan A1 Richard Freifelder A1 Anna Kucharski A1 Chien-Min Kao A1 Howard Halpern* A1 Chin-Tu Chen* YR 2021 UL http://jnm.snmjournals.org/content/62/supplement_1/12.abstract AB 12Objectives: Tumor hypoxia is associated with resistance to therapy and tumor progression, and correlates negatively with patient survival [1, 2, 3]. 18F-Misonidazole (FMISO) is frequently used in clinical PET trials to measure and treat tumor hypoxia [4], but there is no universally accepted threshold to define tumor hypoxia with FMISO. This study uses electron paramagnetic resonance (EPR) pO2 images as true hypoxia (pO2 < 10 mmHg) [5] to calculate the optimal corresponding FMISO PET threshold for identifying hypoxic tumors in SCC7 tumor murine models of squamous cell carcinoma. Methods: Imaging: Using SCC7 squamous cell carcinoma murine models (n=14), the tumor-bearing leg was immobilized in the plastic bed in a polysiloxane dental mold cast (GC America, Alsip, IL) with embedded fiducials to allow for co-registration between modalities. FMISO PET and EPR images were acquired in a hybrid PET/EPR system for simultaneous imaging [6], which gave the advantage of identical physiological conditions of the mouse. A tail-vein cannula was used to administer an oxygen-sensitive spin probe solution for EPR imaging. A bolus injection of ~230 uCi of FMISO (produced at the in-house cyclotron facility) was used for PET imaging; images were acquired 2-hours post-injection. T2-weighted images were acquired in a 9.4 Tesla small animal imager (Bruker, Erlangen, Germany) for registration and tumor/muscle contouring. Image analysis: Following MRI/EPR/PET registration in MATLAB, images were resampled to the PET image’s isotropic voxel resolution of [0.5 mm]3. The T2 MRI-based tumor and muscle contour were transformed to the PET and EPR images in units of tumor-to-muscle ratio (TMR) and pO2, respectively. Using a custom-written script in MATLAB, ROC curves were generated for each tumor across all thresholds of PET TMR > 0 to 5.6 in increments of 0.2, using EPR pO2 < 10 mmHg as true hypoxia. The accuracy (ACC) (fraction of true negatives and positives over all true/false negatives/positives), Dice Similarity Coefficient (DSC), and Hausdorff Distance (dH) were used to quantify overlap between hypoxic regions as defined by EPR and PET. Because maximum ACC and DSC are both between 0 and 1, with 1 corresponding to highest overlap, dH was normalized and subtracted from 1 (1 - || dH ||) so that the highest value would also show maximum overlap. The peak mean of ACC, DSC, and 1 - ||dH|| averaged over all tumors was used to determine the optimal PET threshold. The hypoxic fractions of tumor voxels based on resulting thresholds was also calculated to compare between modalities. Results: For all tumors, the area under the ROC curve using pO2 < 10 mmHg as gold standard was AUC = 0.739 (SE = 0.03). The peak ACC = 0.816 (SE = 0.02) corresponding to the PET threshold TMR > 2.4, and peak DSC = 0.485 (SE = 0.05) corresponding to a threshold TMR 2.0. At its minimum, mean dH = 3.40 (SE = 0.2) mm at TMR > 2.4. The average value of ACC, DSC, and 1-|| dH || showed a peak at TMR > 2.2 and pO2 < 10 mmHg. The mean hypoxic fraction of EPR images was 0.20 (SE = 0.05), and of PET images was 0.19 (SE = 0.03), which was not significant based on the two-sample t-test (p = 0.51). Conclusions: Based on this dataset of SCC7 squamous cell carcinoma murine models, the PET threshold of TMR > 2.2 has the highest ACC and DSC, and the lowest dH, when compared to hypoxic tumor regions defined by EPR pO2 < 10 mmHg. These results might help improve patient prognosis for more accurate hypoxia-based dose-painting treatment plans based on PET imaging. References: [1] Hockel, M et al. (1996). Cancer Res, 56(19): p. 4509-15.[2] Hockel, M and Vaupel, P (2001). J Natl Cancer Inst, 93(4): p. 266-76.[3] Brizel, DM et al. (1997). Int J Radiat Oncol Biol Phys, 38(2): p. 285-9.[4] Lopci, E et al. (2014). Am J Nucl Med Mol Imaging, 4: p. 365-384.[5] Epel, B et al. (2019). Int J Radiat Oncol Biol Phys, 103(4): p. 977-984.[6] Kim H et al. (2020). Nuclear Inst. and Methods in Physics Research Section, A, 959.