S2504
Radiobiology - Biology of novel irradiation techniques
ESTRO 2026
p=0.0005)). However, no histopathologic difference between CONV and UHDR was seen (epidermal p=0.9977; dermal p=0.3467). No hindlimb contracture of irradiated mice was observed up to 50 Gy. At 55 Gy, both CONV and UHDR induced significant contracture (CONV:+17%, p=0.0079; UHDR:+23%, p=0.0079), but no difference between dose rates was seen (p=0.286). Conclusion: Unlike single-fraction electron UHDR-RT, 5-fraction UHDR-RT did not confer a protective effect against skin toxicity in a C57Bl/6 hindlimb model. These findings suggest that the normal tissue-sparing component of the FLASH effect may be adversely affected by fractionation. A 3-fraction regimen is under investigation to assess whether fewer fractions can preserve the FLASH effect while remaining clinically relevant. Keywords: FLASH, ultra-high dose rate, fractionation Poster Discussion 950 Cuproptosis Enhances FLASH Radiotherapy Efficacy in Radio-Resistant HNSCC through cGAS-STING Pathway Activation Hong-Shuai Li 1 , Wen Yang 2 , Ruo Tang 2 , Yun-Fei Sun 2 , Chao-Fan Ma 2 , Yi Zhang 1 , Xuan-Lu He 3 , Li-Li Zhu 1 , Liu Yang 2 , Ye Chen 4 , Zhuo Zhang 2 , Shu-Qing Liao 2 , Jin-Shui Shi 2 , Jian-Jun Deng 2 , Xiao-Zhong He 2 , Xing-Chen Peng 1 1 Department of Biotherapy, West China Hospital of Sichuan University, Chengdu, China. 2 Institute of Fluid Physics, Chinese Academy of Engineering Physics, Mianyang, China. 3 School of Clinical Medicine, Zunyi Medical University, Zunyi, China. 4 Department of Abdominal Oncology, West China Hospital of Sichuan University, Chengdu, China Purpose/Objective: FLASH radiotherapy (RT) using high-energy X-rays has shown significant potential in overcoming radioresistance in head and neck squamous cell carcinoma (HNSCC). Cuproptosis, a regulated form of cell death, has been implicated in the modulation of tumor radiosensitivity. This study aims to further explore the role of cuproptosis in reversing radioresistance induced by FLASH-RT and to elucidate the underlying molecular mechanisms. Material/Methods: Established RT-resistant HNSCC cell lines and mouse models were exposed to FLASH-RT or conventional RT (Conv-RT) using a rhodotron accelerator. Stable cell lines with overexpression or knockdown of key cuproptosis-related molecules were generated by lentiviral transduction. Expression levels of these key molecules were assessed using immunohistochemistry, western blotting, or quantitative PCR (qPCR). Intracellular copper ion
Proffered Paper 857
Five-fraction ultra-high dose rate (FLASH) radiotherapy does not mitigate skin toxicity compared to conventional dose rate in a mouse hindlimb model Elise Konradsson 1 , Lucy Whitmore 1 , Edgardo Aguilar 1 , Denae Neill 1 , Luke Connell 1 , Nolan Esplen 1 , Emil Schüler 1 , Devarati Mitra 2 1 Department of Radiation Physics, The University of Texas MD Andeson Cancer Center, Houston, USA. 2 Department of Radiation Oncology, The University of Texas MD Andeson Cancer Center, Houston, USA Purpose/Objective: Ultra-high dose rate (UHDR) radiotherapy (RT) has potential to reduce normal tissue toxicity without compromising tumor control, a phenomenon known as the “FLASH effect”. While we, and others, have shown that single-fraction electron UHDR-RT significantly reduces acute skin toxicity relative to conventional dose rate (CONV)-RT, clinical translation is limited by the normal tissue toxicity often associated with single-fraction regimens. Fractionated delivery, which aligns more closely with standard clinical practice, may offer a more feasible path for implementation. This study evaluates whether a 5- fraction UHDR-RT regimen mitigates skin and soft tissue toxicity compared to CONV-RT in a mouse hindlimb model. Material/Methods: Cohorts of 5-10 female C57Bl/6 mice received 5- fraction RT (7-12 Gy/fraction) to the right hindlimb using either CONV-RT (0.2-0.3 Gy/s) or single-pulse UHDR-RT (6-7 MGy/s) delivered by 7 MeV electron beam from a UHDR-capable linear accelerator (2-cm diameter field). Skin toxicity was graded weekly over 9 weeks using a 6-point scale ranging from fur color change only to moist desquamation/ulceration in >50% of the irradiated field. Histologic analysis of hematoxylin-and-eosin (H&E) stained sections were used to assess epidermal (10 measurements/mouse) and dermal thickness (5 measurements/mouse). Hindlimb contracture was measured at 5 weeks post- RT, using the contralateral limb as control. Results: No significant differences in skin toxicity grade were observed between CONV and UHDR at any total dose from 35-60 Gy (p ≥ 0.444). Animals receiving 35-40 Gy developed only minor toxicity (fur color change and hair loss), while most animals receiving ≥ 50 Gy developed severe moist desquamation/ulcers. Therefore, 45 Gy total dose was selected for histologic analysis. Compared to sham treated mice, irradiated mice showed significant thickening of the epidermis (CONV:+332%, p<0.0001; UHDR:+274%, p<0.0001) and dermis (CONV:+28%, p=0.0005; UHDR:+18%,
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