Recent Developments on gMicroMC: Transport Simulations of Proton and Heavy Ions and Concurrent Transport of Radicals and DNA.

Mechanistic Monte Carlo (MC) simulation of radiation interaction with water and DNA is important for the understanding of biological responses induced by ionizing radiation. In our previous work, we employed the Graphical Processing Unit (GPU)-based parallel computing technique to develop a novel, highly efficient, and open-source MC simulation tool, gMicroMC, for simulating electron-induced DNA damages. In this work, we reported two new developments in gMicroMC: the transport simulation of protons and heavy ions and the concurrent transport of radicals in the presence of DNA. We modeled these transports based on electromagnetic interactions between charged particles and water molecules and the chemical reactions between radicals and DNA molecules. Various physical properties, such as Linear Energy Transfer (LET) and particle range, from our simulation agreed with data published by NIST or simulation results from other CPU-based MC packages. The simulation results of DNA damage under the concurrent transport of radicals and DNA agreed with those from nBio-Topas simulation in a comprehensive testing case. GPU parallel computing enabled high computational efficiency. It took 41 s to simultaneously transport 100 protons with an initial kinetic energy of 10 MeV in water and 470 s to transport 105 radicals up to 1 µs in the presence of DNA.

Virtual dosimetry study with three cone-beam breast computed tomography scanners using a fast GPU-based Monte Carlo code.

Objective. To compare the dosimetric performance of three cone-beam breast computed tomography (BCT) scanners, using real-time Monte Carlo-based dose estimates obtained with the virtual clinical trials (VCT)-BREAST graphical processing unit (GPU)-accelerated platform dedicated to VCT in breast imaging. Approach. A GPU-based Monte Carlo (MC) code was developed for replicatingin silicothe geometric, x-ray spectra and detector setups adopted, respectively, in two research scanners and one commercial BCT scanner, adopting 80 kV, 60 kV and 49 kV tube voltage, respectively. Our cohort of virtual breasts included 16 anthropomorphic voxelized breast phantoms from a publicly available dataset. For each virtual patient, we simulated exams on the three scanners, up to a nominal simulated mean glandular dose of 5 mGy (primary photons launched, in the order of 1011-1012per scan). Simulated 3D dose maps (recorded for skin, adipose and glandular tissues) were compared for the same phantom, on the three scanners. MC simulations were implemented on a single NVIDIA GeForce RTX 3090 graphics card.Main results.Using the spread of the dose distribution as a figure of merit, we showed that, in the investigated phantoms, the glandular dose is more uniform within less dense breasts, and it is more uniformly distributed for scans at 80 kV and 60 kV, than at 49 kV. A realistic virtual study of each breast phantom was completed in about 3.0 h with less than 1% statistical uncertainty, with 109primary photons processed in 3.6 s computing time.Significance. We reported the first dosimetric study of the VCT-BREAST platform, a fast MC simulation tool for real-time virtual dosimetry and imaging trials in BCT, investigating the dose delivery performance of three clinical BCT scanners. This tool can be adopted to investigate also the effects on the 3D dose distribution produced by changes in the geometrical and spectrum characteristics of a cone-beam BCT scanner.

Mechanistic modelling of relative biological effectiveness of carbon ion beams and comparison with experiments.

Objective.Relative biological effectiveness (RBE) plays a vital role in carbon ion radiotherapy, which is a promising treatment method for reducing toxic effects on normal tissues and improving treatment efficacy. It is important to have an effective and precise way of obtaining RBE values to support clinical decisions. A method of calculating RBE from a mechanistic perspective is reported.Approach.Ratio of dose to obtain the same number of double strand breaks (DSBs) between different radiation types was used to evaluate RBE. Package gMicroMC was used to simulate DSB yields. The DSB inductions were then analyzed to calculate RBE. The RBE values were compared with experimental results.Main results.Furusawa's experiment yielded RBE values of 1.27, 2.22, 3.00 and 3.37 for carbon ion beam with dose-averaged LET of 30.3 keVµm-1, 54.5 keVµm-1, 88 keVµm-1and 137 keVµm-1, respectively. RBE values computed from gMicroMC simulations were 1.75, 2.22, 2.87 and 2.97. When it came to a more sophisticated carbon ion beam with 6 cm spread-out Bragg peak, RBE values were 1.61, 1.63, 2.19 and 2.36 for proximal, middle, distal and distal end part, respectively. Values simulated by gMicroMC were 1.50, 1.87, 2.19 and 2.34. The simulated results were in reasonable agreement with the experimental data.Significance.As a mechanistic way for the evaluation of RBE for carbon ion radiotherapy by combining the macroscopic simulation of energy spectrum and microscopic simulation of DNA damages, this work provides a promising tool for RBE calculation supporting clinical applications such as treatment planning.

ART2Dose: A comprehensive dose verification platform for online adaptive radiotherapy.

BACKGROUND: Online adaptive radiotherapy (ART) involves the development of adaptable treatment plans that consider patient anatomical data obtained right prior to treatment administration, facilitated by cone-beam computed tomography guided adaptive radiotherapy (CTgART) and magnetic resonance image-guided adaptive radiotherapy (MRgART). To ensure accuracy of these adaptive plans, it is crucial to conduct calculation-based checks and independent verification of volumetric dose distribution, as measurement-based checks are not practical within online workflows. However, the absence of comprehensive, efficient, and highly integrated commercial software for secondary dose verification can impede the time-sensitive nature of online ART procedures. PURPOSE: The main aim of this study is to introduce an efficient online quality assurance (QA) platform for online ART, and subsequently evaluate it on Ethos and Unity treatment delivery systems in our clinic. METHODS: To enhance efficiency and ensure compliance with safety standards in online ART, ART2Dose, a secondary dose verification software, has been developed and integrated into our online QA workflow. This implementation spans all online ART treatments at our institution. The ART2Dose infrastructure comprises four key components: an SQLite database, a dose calculation server, a report generator, and a web portal. Through this infrastructure, file transfer, dose calculation, report generation, and report approval/archival are seamlessly managed, minimizing the need for user input when exporting RT DICOM files and approving the generated QA report. ART2Dose was compared with Mobius3D in pre-clinical evaluations on secondary dose verification for 40 adaptive plans. Additionally, a retrospective investigation was conducted utilizing 1302 CTgART fractions from ten treatment sites and 1278 MRgART fractions from seven treatment sites to evaluate the practical accuracy and efficiency of ART2Dose in routine clinical use. RESULTS: With dedicated infrastructure and an integrated workflow, ART2Dose achieved gamma passing rates that were comparable to or higher than those of Mobius3D. Additionally, it significantly reduced the time required to complete pre-treatment checks by 3-4 min for each plan. In the retrospective analysis of clinical CTgART and MRgART fractions, ART2Dose demonstrated average gamma passing rates of 99.61 ± 0.83% and 97.75 ± 2.54%, respectively, using the 3%/2 mm criteria for region greater than 10% of prescription dose. The average calculation times for CTgART and MRgART were approximately 1 and 2 min, respectively. CONCLUSION: Overall, the streamlined implementation of ART2Dose notably enhances the online ART workflow, offering reliable and efficient online QA while reducing time pressure in the clinic and minimizing labor-intensive work.

Mechanistic modelling of oxygen enhancement ratio of radiation via Monte Carlo simulation-based DNA damage calculation.

Objective.Oxygen plays an important role in affecting the cellular radio-sensitivity to ionizing radiation. The objective of this study is to build a mechanistic model to compute oxygen enhancement ratio (OER) using a GPU-based Monte Carlo (MC) simulation package gMicroMC for microscopic radiation transport simulation and DNA damage calculation.Approach.We first simulated the water radiolysis process in the presence of DNA and oxygen for 1 ns and recorded the produced DNA damages. In this process, chemical reactions among oxygen, water radiolysis free radicals and DNA molecules were considered. We then applied a probabilistic approach to model the reactions between oxygen and indirect DNA damages for a maximal reaction time oft0. Finally, we defined two parametersP0andP1, representing probabilities for DNA damages without and with oxygen fixation effect not being restored in the repair process, to compute the final DNA double strand breaks (DSBs). As cell survival fraction is mainly determined by the number of DSBs, we assumed that the same numbers of DSBs resulted in the same cell survival rates, which enabled us to compute the OER as the ratio of doses producing the same number of DSBs without and with oxygen. We determined the three parameters (t0,P0andP1) by fitting the OERs obtained in our computation to a set of published experimental data under x-ray irradiation. We then validated the model by performing OER studies under proton irradiation and studied model sensitivity to parameter values.Main results.We obtained the model parameters ast0= 3.8 ms,P0= 0.08, andP1= 0.28 with a mean difference of 3.8% between the OERs computed by our model and that obtained from experimental measurements under x-ray irradiation. Applying the established model to proton irradiation, we obtained OERs as functions of oxygen concentration, LET, and dose values, which generally agreed with published experimental data. The parameter sensitivity analysis revealed that the absolute magnitude of the OER curve relied on the values ofP0andP1, while the curve was subject to a horizontal shift when adjustingt0.Significance.This study developed a mechanistic model that fully relies on microscopic MC simulations to compute OER.

Small animal photon counting cone-beam CT on a preclinical radiation research platform to improve radiation dose calculation accuracy.

Objective.Cone beam CT (CBCT) in preclinical small animal irradiation platforms provides essential information for image guidance and radiation dose calculation for experiment planning. This project developed a photon-counting detector (PCD)-based multi(3)-energy (ME-)CBCT on a small animal irradiator to improve the accuracy of material differentiation and hence dose calculation, and compared to conventional flat panel detector (FPD)-based CBCT.Approach.We constructed a mechanical structure to mount a PCD to an existing preclinical irradiator platform and built a data acquisition pipeline to acquire x-ray projection data with a 100 kVp x-ray beam using three different energy thresholds in a single gantry rotation. We implemented an energy threshold optimization scheme to determine optimal thresholds to balance signal-to-noise ratios (SNRs) among energy channels. Pixel-based detector response calibration was performed to remove ring artifacts in reconstructed CBCT images. Feldkamp-Davis-Kress method was employed to reconstruct CBCT images and a total-variance regularization-based optimization model was used to decompose CBCT images into bone and water material images. We compared dose calculation results using PCD-based ME-CBCT with that of FPD-based CBCT.Main results.The optimal nominal energy thresholds were determined as 26, 56, and 90 keV, under which SNRs in a selected region-of-interest in the water region were 6.11, 5.91 and 5.93 in the three energy channels, respectively. Compared with dose calculation results using FPD-based CBCT, using PCD-based ME-CBCT reduced the mean relative error from 49.5% to 16.4% in bone regions and from 7.5% to 6.9% in soft tissue regions.Significance.PCD-based ME-CBCT is beneficial in improving radiation dose calculation accuracy in experiment planning of preclinical small animal irradiation researches.

Development and implementation of a metaphase DNA model for ionizing radiation induced DNA damage calculation.

Objective. To develop a metaphase chromosome model representing the complete genome of a human lymphocyte cell to support microscopic Monte Carlo (MMC) simulation-based radiation-induced DNA damage studies.Approach. We first employed coarse-grained polymer physics simulation to obtain a rod-shaped chromatid segment of 730 nm in diameter and 460 nm in height to match Hi-C data. We then voxelized the segment with a voxel size of 11 nm per side and connected the chromatid with 30 types of pre-constructed nucleosomes and 6 types of linker DNAs in base pair (bp) resolutions. Afterward, we piled different numbers of voxelized chromatid segments to create 23 pairs of chromosomes of 1-5µm long. Finally, we arranged the chromosomes at the cell metaphase plate of 5.5µm in radius to create the complete set of metaphase chromosomes. We implemented the model in gMicroMC simulation by denoting the DNA structure in a four-level hierarchical tree: nucleotide pairs, nucleosomes and linker DNAs, chromatid segments, and chromosomes. We applied the model to compute DNA damage under different radiation conditions and compared the results to those obtained with G0/G1 model and experimental measurements. We also performed uncertainty analysis for relevant simulation parameters.Main results. The chromatid segment was successfully voxelized and connected in bps resolution, containing 26.8 mega bps (Mbps) of DNA. With 466 segments, we obtained the metaphase chromosome containing 12.5 Gbps of DNA. Applying it to compute the radiation-induced DNA damage, the obtained results were self-consistent and agreed with experimental measurements. Through the parameter uncertainty study, we found that the DNA damage ratio between metaphase and G0/G1 phase models was not sensitive to the chemical simulation time. The damage was also not sensitive to the specific parameter settings in the polymer physics simulation, as long as the produced metaphase model followed a similar contact map distribution.Significance. Experimental data reveal that ionizing radiation induced DNA damage is cell cycle dependent. Yet, DNA chromosome models, except for the G0/G1 phase, are not available in the state-of-the-art MMC simulation. For the first time, we successfully built a metaphase chromosome model and implemented it into MMC simulation for radiation-induced DNA damage computation.

Virtual Clinical Trials in 2D and 3D X-ray Breast Imaging and Dosimetry: Comparison of CPU-Based and GPU-Based Monte Carlo Codes.

Computational reproductions of medical imaging tests, a form of virtual clinical trials (VCTs), are increasingly being used, particularly in breast imaging research. The accuracy of the computational platform that is used for the imaging and dosimetry simulation processes is a fundamental requirement. Moreover, for practical usage, the imaging simulation computation time should be compatible with the clinical workflow. We compared three different platforms for in-silico X-ray 3D breast imaging: the Agata (University & INFN Napoli) that was based on the Geant4 toolkit and running on a CPU-based server architecture; the XRMC Monte Carlo (University of Cagliari) that was based on the use of variance reduction techniques, running on a CPU hardware; and the Monte Carlo code gCTD (University of Texas Southwestern Medical Center) running on a single GPU platform with CUDA environment. The tests simulated the irradiation of cylindrical objects as well as anthropomorphic breast phantoms and produced 2D and 3D images and 3D maps of absorbed dose. All the codes showed compatible results in terms of simulated dose maps and imaging values within a maximum discrepancy of 3%. The GPU-based code produced a reduction of the computation time up to factor 104, and so permits real-time VCT studies for X-ray breast imaging.

Modeling the effect of oxygen on the chemical stage of water radiolysis using GPU-based microscopic Monte Carlo simulations, with an application in FLASH radiotherapy.

Oxygen plays a critical role in determining the initial DNA damages induced by ionizing radiation. It is important to mechanistically model the oxygen effect in the water radiolysis process. However, due to the computational costs from the many body interaction problem, oxygen is often ignored or treated as a constant continuum radiolysis-scavenger background in the simulations using common microscopic Monte Carlo tools. In this work, we reported our recent progress on the modeling of the chemical stage of the water radiolysis with an explicit consideration of the oxygen effect, based upon our initial development of an open-source graphical processing unit (GPU)-based MC simulation tool, gMicroMC. The inclusion of oxygen mainly reduces the yields of [Formula: see text] and [Formula: see text] chemical radicals, turning them into highly toxic [Formula: see text] and [Formula: see text] species. To demonstrate the practical value of gMicroMC in large scale simulation problems, we applied the oxygen-simulation-enabled gMicroMC to compute the yields of chemical radicals under a high instantaneous dose rate [Formula: see text] to study the oxygen depletion hypothesis in FLASH radiotherapy. A decreased oxygen consumption rate (OCR) was found associated with a reduced initial oxygen concentration level due to reduced probabilities of reactions. With respect to dose rate, for the oxygen concentration of 21% and electron energy of 4.5 [Formula: see text], OCR remained approximately constant (∼0.22 [Formula: see text]) for [Formula: see text]'s of [Formula: see text], [Formula: see text] and reduced to 0.19 [Formula: see text] at [Formula: see text], because the increased dose rate improved the mutual reaction frequencies among radicals, hence reducing their reactions with oxygen. We computed the time evolution of oxygen concentration under the FLASH irradiation setups. At the dose rate of [Formula: see text] and initial oxygen concentrations from 0.01% to 21%, the oxygen is unlikely to be fully depleted with an accumulative dose of 30 Gy, which is a typical dose used in FLASH experiments. The computational efficiency of gMicroMC when considering oxygen molecules in the chemical stage was evaluated through benchmark work to GEANT4-DNA with simulating an equivalent number of radicals. With an initial oxygen concentration of 3% (∼105 molecules), a speedup factor of 1228 was achieved for gMicroMC on a single GPU card when comparing with GEANT4-DNA on a single CPU.

Improving dose calculation accuracy in preclinical radiation experiments using multi-energy element resolved cone-beam CT.

Objective.Cone-beam CT (CBCT) in modern pre-clinical small-animal radiation research platforms provides volumetric images for image guidance and experiment planning purposes. In this work, we implemented multi-energy element-resolved (MEER) CBCT using three scans with different kVps on a SmART platform (Precision x-ray Inc.) to determine images of relative electron density (rED) and elemental composition (EC) that are needed for Monte Carlo-based radiation dose calculation.Approach.We performed comprehensive calibration tasks to achieve sufficient accuracy for this quantitative imaging purpose. For geometry calibration, we scanned a ball bearing phantom and used an analytical method together with an optimization approach to derive gantry angle specific geometry parameters. Intensity calibration and correction included the corrections for detector lag, glare, and beam hardening. The corrected CBCT projection images acquired at 30, 40, and 60 kVp in multiple scans were used to reconstruct CBCT images using the Feldkamp-Davis-Kress reconstruction algorithm. After that, an optimization problem was solved to determine images of rED and EC. We demonstrated the effectiveness of our CBCT calibration steps by showing improvements in image quality and successful material decomposition in cases with a small animal CT calibration phantom and a plastinated mouse phantom.Main results.It was found that artifacts induced by geometry inaccuracy, detector lag, glare, and beam hardening were visually reduced. CT number mean errors were reduced from 19% to 5%. In the CT calibration phantom case, median errors in H, O, and Ca fractions for all the inserts were below 1%, 2%, and 4% respectively, and median error in rED was less than 5%. Compared to the standard approach deriving material type and rED via CT number conversion, our approach improved Monte Carlo simulation-based dose calculation accuracy in bone regions. Mean dose error was reduced from 47.5% to 10.9%.Significance.The MEER-CBCT implemented on an existing CBCT system of a small animal irradiation platform achieved accurate material decomposition and significantly improved Monte Carlo dose calculation accuracy.