Using experimentally-guided multi-scale modeling to determining the mechanism of FLASH tissue sparing

摘要 FLASH辐照，即剂量率>40戈伊/s的辐照，已经显示出极大地降低了 辐射损伤正常组织而不影响肿瘤控制。这种节省效应是 在多个动物模型中证实，主要使用电子闪光照射。前- 临床数据产生了将FLASH放射治疗（RT）转化为临床的强大推动力。 到目前为止，只有少数人类患者接受了FLASH-RT治疗。 一个单一的皮肤淋巴瘤病灶用电子FLASH-RT治疗。最近，Varian和 宣布了质子FLASH-RT的第一个临床试验（第一阶段），并治疗了第一批患者， 有症状的骨转移 然而，许多问题仍然没有答案。最重要的是， FLASH诱导的健康组织的保留仍然是难以捉摸的。作为推论，约束条件是- 根据临床参数（例如，剂量、剂量率和治疗内和治疗间的时间）设定 场）诱导FLASH组织保护效应的方法仍然没有确定。 虽然目前有许多实验性的努力正在进行中，我的团队一直致力于 从实验和理论的角度来理解FLASH。我们的前- 实验初步数据显示质子FLASH在肠、脑和皮肤中的组织保留。 我们的理论初步数据包括建模氧消耗和模拟的放射性， 化学使用TOPAS-nBio，由我们的小组开发的机械蒙特卡罗框架。 我们的中心假设是，FLASH效应是由细胞中的（干）细胞组合引起的。 低氧环境和长寿命（µs至ms）的化学反应子产物， 氧气我们提出了实验和建模之间的相互作用，以确定下- 应用TOPAS-nBio研究FLASH-RT组织保留的躺卧机制， 涉及基于其内在时间特征的化学反应。 我们建议测试假设并验证模型，目标如下： SA 1：研究质子FLASH-RT的机制 1.进行多尺度实验以指导建模工作。 2.在TOPAS-nBio中对相关时间尺度的机制和化学过程进行建模。 SA 2：验证模型并确定FLASH组织保留的临床参数。

Abstract FLASH irradiations, irradiations with dose rates >40 Gy/s, have been shown to greatly reduce radiation damage for normal tissue while not affecting tumor control. This sparing effect was demonstrated in multiple animal models, mostly using electron FLASH irradiations. The pre- clinical data generated a strong push to translate FLASH radiation therapy (RT) into the clinic. Only a few human patients have so far been treated with FLASH-RT. The first patient, a single cutaneous lymphoma lesion was treated with electron FLASH-RT. Recently, Varian an- nounced the first clinical trial of proton FLASH-RT (phase 1) and treated the first patients with symptomatic bone metastases. Yet many questions remain unanswered. Most significantly, the underlying mechanism of FLASH induced sparing of healthy tissue still remain elusive. As corollary, the constraints im- posed on the clinical parameters (e.g. dose, dose rate and time within and between treatment fields) to induce the FLASH tissue sparing effect are still not determined. While there are many experimental efforts currently being pursued, my team has worked on understanding FLASH both from an experimental as well as theoretical point of view. Our ex- perimental preliminary data show proton FLASH tissue sparing in intestine, brain and skin. Our theoretical preliminary data include modeling oxygen depletion and simulations of radi- ochemistry using TOPAS-nBio, a mechanistic Monte Carlo framework developed by our group. Our central hypothesis is that the FLASH effect is caused by a combination of (stem) cells in a low-oxygen niche and long-lived (µs to ms) daughter products of chemical reactions involving oxygen. We propose an interplay between experiments and modeling to determine the under- lying mechanism of FLASH-RT tissue sparing by employing TOPAS-nBio to investigate the involved chemical reactions based on their intrinsic time features. We propose to test the hypothesis and validate the model with the following aims: SA 1: Investigate the mechanisms of proton FLASH-RT 1. Conduct multi-scale experiments to guide the modeling efforts. 2. Model the mechanism and chemical processes at relevant time scales in TOPAS-nBio. SA 2: Validate the model and determine clinical parameters for FLASH tissue sparing.