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

摘要 闪光照射，即剂量率为&40GY/S的照射，已被证明大大减少 在不影响肿瘤控制的同时，对正常组织进行辐射损伤。这种节省的效果是 在多个动物模型中进行了演示，主要使用电子闪光照射。前- 临床数据有力地推动了闪光放射治疗(RT)进入临床。 到目前为止，只有少数人类患者接受了闪光放射治疗。第一名患者是一名 对单个皮肤淋巴瘤病灶进行电子闪光放射治疗。最近，瓦里安- 宣布了质子闪光放射治疗(1期)的第一次临床试验，并治疗了第一批患者 有症状的骨转移。 然而，许多问题仍然没有得到回答。最重要的是， 闪光诱导的健康组织的保留仍然难以捉摸。作为推论，约束条件是- 根据临床参数(如剂量、剂量率和治疗内和治疗之间的时间)提出 场)来诱导闪光组织节约效应仍未确定。 虽然目前正在进行许多实验性的工作，但我的团队一直致力于 从实验和理论两个角度理解闪光灯。我们的前任- 周边初步数据显示，肠道、脑和皮肤中有质子闪光组织。 我们的理论初步数据包括模拟氧气消耗和模拟辐射辐射。 使用TOPAS-nBio的物理化学，这是我们小组开发的一个机械蒙特卡罗框架。 我们的中心假设是闪光效应是由体内的(干细胞)细胞组合引起的。 低氧利基和长寿命(从S到毫秒)的化学反应的子产物，包括 氧气。我们提出了一种实验和建模之间的相互作用来确定欠 应用Topas-nBio技术探讨Flash-RT组织保存的机制 根据其固有的时间特征，涉及化学反应。 我们建议检验假设并验证模型，目标如下： SA 1：研究质子闪光RT的机制 1.开展多尺度实验，指导建模工作。 2.在相应的时间尺度上模拟TOPAS-nBio的作用机理和化学过程。 SA 2：验证模型并确定闪光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.