We present a microscopic mechanism that accounts for the outward burst of "cold" ion species (IS) in a high-energy particle track due to coupling with ''hot" non-ion species (NIS). IS refers to radiolysis products of ionized molecules, whereas NIS refers to non-ionized excitations of molecules in a medium. The interaction is mediated by a quantized field of acoustic phonons, a channel that allows conversion of thermal energy of NIS to kinetic energy of IS, a flow of heat from the outer to the inner core of the track structure. We demonstrate the coexistence of "hot" NIS with "cold" IS in the radiation track structures right after their generation. NIS, concentrated within nano-scales volumes wrapping around IS, are the main source of intensive heat-waves and the outward burst of IS due to femto-second time scale IS-NIS coupling. By comparing the transport of IS coupled to NIS with identical configurations of non-interacting IS in thermal equilibrium at room temperature, we demonstrate that the energy gain of IS due to the surrounding hot nanoscopic volumes of NIS significantly increases their effective diffusion constants. The much higher diffusion constants predicted in the present model suggest higher inter-track chemical reaction rates at FLASH-UHDR, as well as lower intra-track reaction rates.
Current Views on Mechanisms of the FLASH Effect in Cancer Radiotherapy
Peking University（北京大学）；the Second Affiliated Hospital of Wenzhou Medical University（温州医科大学附属第二医院）；College of Chemistry and Molecular Engineering, Peking University（北京大学化学与分子工程学院）；Sun Yat-sen University（中山大学）；KIRI Precision Particle Therapy Flash Technologies Research Center（基锐精准粒子治疗闪速技术研究中心）；The University of Hong Kong-Shenzhen Hospital（香港大学深圳医院）
It has been postulated that the delivery of radiotherapy at ultra-high dose rates ("FLASH") reduces normal tissue toxicities by depleting them of oxygen. The fraction of normal tissue and cancer cells surviving radiotherapy depends on dose and oxygen levels in an exponential manner and even a very small fraction of tissue at low oxygen levels can determine radiotherapy response. The effect of FLASH on radiation-induced normal and tumour tissue cell killing was studied by simulating oxygen diffusion, metabolism, and radiolytic oxygen depletion over domains with simulated capillary architectures…
An in-silico study of conventional and FLASH radiotherapy iso-effectiveness: Radiolytic oxygen depletion and its potential impact on tumor control probability
While spatial dose conformity delivered to a target volume has been pushed to its practical limits with advanced treatment planning and delivery, investigations in novel temporal dose delivery are unfolding new mechanisms. Recent advances in ultra-high dose radiotherapy, abbreviated as FLASH, indicate the potential for reduction in healthy tissue damage while preserving tumor control. FLASH therapy relies on very high dose rate of > 40Gy/sec with sub-second temporal beam modulation, taking a seemingly opposite direction from the conventional paradigm of fractionated therapy. FLASH brings uniqu…
Beam monitoring for radiotherapy from conventional to FLASH dose rates using Low Gain Avalanche Silicon detectors
Universidad de Sonora（索诺拉大学）；University of Kansas（堪萨斯大学）；Washington University School of Medicine（华盛顿大学医学院）；Rice University（莱斯大学）；University of Kansas Cancer Center（堪萨斯大学癌症中心）；The University of Texas MD Anderson Cancer Center（德克萨斯大学安德森癌症中心）
FLASH is a new treatment modality that requires optimization of dose, dose rate, and LET. Here we validate these three quantities under FLASH conditions, which includes the quantum uncertainty in the time-dependent instantaneous dose rate (IDR) curves and LET spectra that underlie the newly proposed integrated optimization framework. Measurements of dose, IDR, and LET were performed at the Emory Proton Therapy Center using a FLASH proton beam with a nominal energy of 250 MeV and a 3D printed ridge filter. Because 3D printing resin is made from a proprietary chemical formula, we developed a met…
Review of oxygen measurement and relevance to the mechanisms of FLASH radiotherapy
Thayer School of Engineering at Dartmouth（达特茅斯学院泰耶尔工程学院）；Giesel School of Medicine at Dartmouth（达特茅斯学院吉塞尔医学院）；University of Wisconsin School of Medicine and Public Health（威斯康星大学医学院和公共卫生学院）
Purpose: A Monte Carlo (MC) beam model and its implementation in a clinical treatment planning system (TPS, Varian Eclipse) are presented for a modified ultra-high dose-rate electron FLASH radiotherapy (eFLASH-RT) LINAC. Methods: The gantry head without scattering foils or targets, representative of the LINAC modifications, was modelled in Geant4. The energy spectrum (σE) and beam source emittance cone angle (θcone) were varied to match the calculated and Gafchromic film measured central-axis percent depth dose (PDD) and lateral profiles. Its Eclipse configuration was validated with measured p…
We present a first-principles molecular dynamics (MD) simulation and expound upon a mechanism of oxygen depletion hypothesis to explain the mitigation of normal tissue injury observed in ultra-high-dose-rate (UHDR) FLASH radiotherapy. We simulated damage to a segment of DNA (also representing other bio-molecules such as RNA and proteins) in a simulation box filled with H$_2$O and O$_2$ molecules. Attoseconds physical interactions (ionizations, electronic and vibrational excitations) were simulated by using the Monte Carlo track structure code Geant4-DNA. Immediately after ionization, {\it ab i…
Treatment with high energy ionizing radiation is one of the main methods in modern cancer therapy that is in clinical use. During the last decades, two main approaches to dose calculation were used, Monte Carlo simulations and semi-empirical models based on Fermi-Eyges theory. A third way to dose calculation has only recently attracted attention in the medical physics community. This approach is based on the deterministic kinetic equations of radiative transfer. Starting from these, we derive a macroscopic partial differential equation model for electron transport in tissue. This model involve…
Ultra high dose rate electron beams also known as FLASH radiotherapy is becoming of importance in several preclinial cancer treatment studies. However, due to the dose rate used during the irradiation sessions, no real time dose monitoring device exists to date. In this work, we present the development of a beam current transformer (BCT), from the choice of the ferromagnetic component and the realisation of the shielding to the design of a front-end electronics based on a trans-impedance circuit in order to perform a low noise optimization of the detector. The BCT prototype is able to monitor …
Model of biological effects of ionizing particles, especially of protons and other ions, is proposed. The model is based on distinguishing the single-particle and collective effects of the underlying radiobiological mechanism. The probabilities of individual particles to form severe damages to DNA, their synergetic or saturation combinations, and the effect of cellular repair system are taken into account. The model enables to describe linear, parabolic and more complex curves, including those exhibiting low-dose hypersensitivity phenomena, in a systematic way. Global shape as well as detailed…
Purpose: To investigate experimentally, if FLASH irradiation depletes oxygen within water for different radiation types such as photons, protons and carbon ions. Methods: This study presents measurements of the oxygen consumption in sealed, 3D printed water phantoms during irradiation with X-rays, protons and carbon ions at varying dose rates up to 340 Gy/s. The oxygen measurement was performed using an optical sensor allowing for non-invasive measurements. Results: Oxygen consumption in water only depends on dose, dose rate and linear energy transfer (LET) of the irradiation. The total amount…
In oncology, treating cancer with a beam of photons is a well established therapeutic technique, developed over 100 years, and today over 50% of cancer patients will undergo traditional X-ray radiotherapy. However, ionizing radiation therapy is not the only option, as the high-energy photons delivering their cell-killing radiation energy into cancerous tumor can lead to significant damage to healthy tissues surrounding the tumor, located throughout the beam's path. Therefore, in nowadays, advances in ionizing radiation therapy are competitive to non-ionizing ones, as for example the laser ligh…
Ultrashort electron beams with femtosecond to picosecond bunch durations offer unique opportunities to explore active research areas ranging from ultrafast structural dynamics to ultra-high dose-rate radiobiological studies. We present a straightforward method to generate MeV-ranged electron beams in ambient air through the tight focusing of a few-cycle, mJ-class femtosecond IR laser. At one meter from the source, the highest measured dose rate of 0.15 Gy/s exceeds the yearly dose limit in less than one second and warrants the implementation of radiation protection. Two-dimensional Particle-In…
An Integrated Biological Optimization framework for proton SBRT FLASH treatment planning allows dose, dose rate, and LET optimization using patient-specific ridge filters
Charge Collection Efficiency in Air-Vented Plane-Parallel Ionisation Chambers at Ultra-High Dose Rates: A Self-Consistent Garfield++ Monte Carlo Model Including Space-Charge Effects and Ion Recombination
Université libre de Bruxelles (ULB)（布鲁塞尔自由大学）；Ion Beam Applications SA（离子束应用公司）
Presently 4T-1 luc cells were irradiated with proton under ultra-high dose rate FLASH or with gamma-ray with conventional dose rate, and then subcutaneous vaccination with or without Mn immuno-enhancing adjuvant into the mice for three times. One week later, we injected untreated 4T-1 luc cells on the other side of the vaccinated mice, and found that the untreated 4T-1 luc cells injected later nearly totally did not grow tumor (1/17) while controls without previous vaccination all grow tumors (18/18). The result is very interesting and the findings may help to explore in situ tumor vaccination…
Circulating Lymphocytes Preservation in Lung Cancer Stereotactic Body Radiation Therapy with Ultra-Fast Proton Delivery Using Modularized Pin Ridge Filters
