Author: Denise Dunn, Scott R. Floyd, Tyler V. Kay, Anna Lynnette-Price, Eric L. Martin, Stepan Mikhailov, Taylor Nguyen, Mark Oldham, Victoria J. P. Radosova, Zachary J. Reitman, Ramona Rodriguiz, Andrew Thompson, William Wetsel, Seth Wilcox, Ying Wu 👨🔬
Affiliation: Duke University Mouse Behavior Core, Department of Physics, Duke University, Medical Physics Graduate Program, Duke University, Duke University Medical Physics Program, Duke University, Duke University Mouse Behavioral and Neuroendocrine Analysis Core Facility, Department of Radiation Oncology, Duke University Medical Center 🌍
Purpose: FLASH radiation therapy (RT) shows promise for reducing normal tissue damage, though its mechanisms remain unclear. Using an in-vivo model with the High Intensity Gamma-ray Source (HIGS) linac, we assess tissue response and cognitive effects across varying FLASH dose rates.
Methods: C57BL/6J mice were divided into four treatment groups (TG) and exposed to different mean dose rates (MDR) for a total dose of ~20 Gy with a 35MeV electron beam from the HIGS linac at Triangle Universities Nuclear Laboratory. Dosimetry was performed using EBT-XD gafchromic film. Body weight was recorded regularly post-irradiation following with evaluations at Duke’s Behavioral Core. Subsets were sacrificed four days post-irradiation for analysis, including immunofluorescence staining (IBA-1, DAPI, GFAP) and cytokine profiling. Confocal imaging of immunofluorescence staining was taken and analyzed using CellProfiler, while cytokine data was processed with Eve Technologies. Statistical analyses were conducted in GraphPad.
Results: TGs received treatments with MDRs of 2.07E+07±5.72E+06, 56.11±0.72, 0.83±0.2, and 0.15±0.0015 Gy/s. Initial behavioral assessments showed no significant differences between NoIR and MDR 2.07E+07±5.56E+06 Gy/s in most tasks, except for the Radial Arm assessment that revealed mild working memory deficits (p<0.01) in high-dose rate TGs. Mice in MDR 0.15±0.0015 Gy/s group did not survive beyond 9 days post-irradiation, precluding them from behavioral testing. A comparative weight analysis revealed significant divergence for MDR:0.15±0.0015 Gy/s compared to other TGs, while NoIR and MDR 2.07E+07±5.56E+06 Gy/s showed minimal weight changes.
Conclusion: FLASH dose rates demonstrated very pronounced and significant cognitive sparing and increased survival when compared to conventional dose rates, highlighting the potential benefits of FLASH irradiation. Conversely, lower dose rates caused rapid mortality, preventing further study. Future work will leverage HIGS' extreme MDR capabilities (up to 20 MGy/s) to study tumor control in in-vivo models. These findings highlight dose rates' role in survival and cognitive outcomes, guiding FLASH-RT optimization.