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Abstract: Cancer remains the second leading cause of death in the US, and more than 50% of all cancer patients receive radiation therapy (RT), often in combination with surgery, chemotherapy and/or immunotherapy. However, the fundamental limit on radiotherapy treatment efficacy is that radiation also damages healthy tissue. One potential way to overcome this limitation is through ultra-high dose rate radiation (FLASH RT). FLASH radiation has been shown to damage cancerous tissue while sparing healthy tissue. However, several obstacles stand in the way of clinical translation of FLASH, namely that the FLASH biological effect has been inconsistent between institutions and there is no commercially available device for robust and accurate radiation dosimetry at ultra high dose rates.

We sought to make an improved and more reproducible mouse model to better characterize and understand the FLASH effect. A likely source of inconsistency among FLASH studies is that there are no standard treatment conditions or dosimetry technology among FLASH researchers. We devised a large-scale animal study to identify how treatment parameters alter the FLASH effect and developed an accessible and robust real time dosimetry platform for in vivo experiments. A novel set-up was used to ensure reproducible total abdominal irradiation of mice. The animal study included 96 mice to identify the effects of gender, anesthesia, and beam structure on mouse weight loss and survival. Assays to measure the change in microbiome, histology, and fecal occult blood of mice was also studied to explore sensitive, qualitative metrics of FLASH sparing effect. 

To overcome the dearth of available FLASH dosimetry technology, we developed our own scintillation-based system to monitor the delivered entrance and exit dose in real time. This system was in agreement with 24 hour film and allowed real time confirmation of beam positioning, beam structure, and delivered dose. 

Using these methods, we established a foundation for more reproducible FLASH radiation research. We identified that gender of mouse and treatment anesthesia significantly alter mouse survival and weight loss. Furthermore, our scintillation system allowed us to better characterize our beam structure to determine when dosimetry was incorrect, which can pollute data analysis.

Thesis Committee: P. Jack Hoopes (Chair), Brian Pogue, David Gladstone, Benjamin Ross