Ultrahigh Dose Rate Helium Ion Beams: Minimizing Brain Tissue Damage while Preserving Tumor Control.

Ultrahigh dose rate radiotherapy (RT) with electrons and protons has shown potential for cancer treatment by effectively targeting tumors while sparing healthy tissues (FLASH effect). This study aimed to investigate the potential FLASH sparing effect of ultrahigh dose rate helium ion irradiation, focusing on acute brain injury and subcutaneous tumor response in a preclinical in vivo setting. Raster-scanned helium ion beams were used to compare the effects of standard dose rate (SDR; at 0.2 Gy/second) and FLASH (at 141 Gy/second) RT on healthy brain tissue. Irradiation-induced brain injury was studied in C57BL/6 mice via DNA damage response, using nuclear γH2AX as a marker for double-strand breaks. The integrity of neurovascular and immune compartments was assessed through CD31+ microvascular density and activation of microglia/macrophages. IBA1+ ramified and CD68+ phagocytic microglia/macrophages were quantified, along with the expression of inducible nitric oxide synthetase. Tumor response to SDR (0.2 Gy/second) and FLASH (250 Gy/second) RT was evaluated in an A549 carcinoma model, using tumor volume and Kaplan-Meier survival as endpoints. The results showed that helium FLASH RT significantly reduced acute brain tissue injury compared with SDR, evidenced by lower levels of double-strand breaks and preserved the neurovascular endothelium. Additionally, FLASH RT reduced neuroinflammatory signals compared with SDR, as indicated by fewer CD68+ inducible nitric oxide synthetase-positive microglia/macrophages. FLASH RT achieved tumor control comparable with that of SDR RT. To the best of our knowledge, this is the first study to report the FLASH sparing effect of raster scanning helium ion RT in vivo, highlighting its potential for neuroprotection and effective tumor control.