S2582
Radiobiology – Normal tissue radiobiology
ESTRO 2026
Digital Poster 4306
maintaining tumor control. We investigated the biological response of lung tissue to helium ion irradiation delivered at conventional (CONV) and FLASH dose rates, and assessed tumor control as a secondary endpoint. Material/Methods: Clockwise irradiation of whole-thoracic irradiation of C57BL/6 mice was performed in 4sec (interspill) intervals using four fields (81 spots each in ~170 msec each) at the Heidelberg Ion-Beam Therapy Center using raster-scanned helium beams. Single-fraction 12.5 Gy exposures were delivered either at CONV ( ≈ 4.5 Gy/s) or FLASH ( ≈ 145 Gy/s) dose rate in the plateau area (LET ≈ 2.3 keV/ μ m). Lung fibrosis was assessed 24 weeks post-irradiation by computed tomography (CT) using mean lung density (LD) and volume (LV) as well as a well-established radiomics feature (the fibrosis index, FI) as surrogates.Radiological features were correlated with blood gas and clinical chemistry parameters (ipH, BE, HCO3, SvO2% and PCO2) and detailed quantitative histopathological examination (lung architecture, ECM deposition and macrophage influx/polarization). To evaluate possible differences in tumor response, A549 xenografts (KEAP1-deficient and KEAP1-reconstituted) were irradiated with the same helium configuration. Tumor growth kinetics were monitored by serial calliper measurements and survival analysis. Results: Lungs exposed to FLASH helium irradiation showed a significant reduction in parenchymal LD and preserved LV as well as reduced FI compared with CONV. These data correlated with clinical blood gas and chemistry as well as histopathological readouts. In A549 xenografts tumor-bearing models, KEAP1- reconstituted tumor exhibited slower growth pattern and lower response to irradiation as compared with KEAP1-reconstituted counterparts, indicating enhanced radiosensitivity upon KEAP1-reconstitution. In both genotypes, FLASH and CONV irradiated tumors revealed significant delayed tumor progression relative to non-irradiated controls (p<0.05), but no significant differences were observed between FLASH and CONV within each genotype (p>0.05). Conclusion: Helium FLASH irradiation significantly reduces late fibrotic lung changes while preserving tumor control, supporting its translational potential for future thoracic particle-therapy applications. Ongoing work aims to define the underlying molecular mechanisms through transcriptomic and spatial analyses. Keywords: ion therapy, Lung fibrosis, mouse model
Salsalate to improve the therapeutic ratio of radiotherapy in Hepatocellular Carcinoma Evangelia Tsakiridis 1 , Simon Wang 2 , Elham Ahmadi 2 , Olga-Demetra Biziotis 2 , Amr Ali 2 , Daniel Del Rosso 2 , Gregory Steinberg 1 , Theodoros Tsakiridis 2 1 Medicine, McMaster, Hamilton, Canada. 2 Oncology, McMaster, Hamilton, Canada Purpose/Objective: Conventional fractionation external beam and stereotactic body radiotherapy are standard of care options for unresectable hepatocellular carcinoma (HCC), offering local tumor control. However, their clinical utility is limited by the risk of acute radiation- induced liver disease (RILD) and progressive fibrosis in the surrounding liver tissue. Identifying agents to protect normal liver parenchyma while maintaining the anti-tumor efficacy of radiotherapy remains a critical unmet need. In this study, we investigated the potential of the anti-inflammatory drug salicylate and its non-acetylated dimersalsalate to improve radiotherapy response and mitigate radiation-induced fibrosis in xenograft models of human HCC. Material/Methods: In vitro, human hepatocellular carcinoma (HCC) cell lines (SK-HEP-1, PLC/PRF/5, HepG2, and Hep3B) were treated with salsalate (100–1000 μ M) in combination with radiotherapy (2–8 Gy) to assess effects on cell growth and gene expression. Transcriptomic profiling was performed to identify pathways altered by the combined treatment. In vivo validation was conducted using two mouse models: an ectopic Hep3B xenograft model treated with vehicle, salsalate (2.5 g/kg salsalate diet), radiotherapy (5 Gy), or both; and a radiation- induced liver disease (RILD) model exposed to 10 or 20 Gy abdominal irradiation with or without dietary salsalate. Tumor growth, hepatic fibrosis, macrophage infiltration, and survival outcomes were evaluated. Results: In vitro, salsalate (100–1000 μ M) combined with radiotherapy (2–8 Gy) synergistically or additively suppressed cell growth across all HCC cell lines. Transcriptomic profiling showed upregulation of fatty acid oxidation and G2–M checkpoint pathways, with concurrent downregulation of tumor growth, epithelial-mesenchymal transition, and fibrosis-related signaling (TGF β , IL-2/STAT5). In vivo, the combination treatment significantly enhanced anti-tumor efficacy in the Hep3B xenograft model and reduced radiation- induced hepatic fibrosis in the RILD model. At six months post-irradiation, salsalate co-treatment decreased fibrosis by ~40% after 10 Gy and showed similar protection at 20 Gy, accompanied by reduced hepatic macrophage infiltration and a trend toward improved survival.
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