No abstract

The aim of this work is to develop and validate a computational model to investigate direct and indirect DNA damage by directly quantifying DNA strand breaks. A detailed geometrical target model was created in the Monte Carlo toolkit Geant4 to represent the nucleus of a single human cell with complete human genome. A calculation framework to simulate double-strand breaks (DSBs) was implemented using this single cell model in the Geant4-DNA extension. A detailed ellipsoidal single cell model was implemented using a compacted DNA structure representing the fibroblast cell in the G0/G1 phase of the cycle using a total of 6 Gbp within the nucleus to represent the complete human genome. This geometry was developed from the publicly available Geant4-DNA example (wholeNuclearDNA), and modified to record DNA damage for both the physical and chemical stages. A clustering algorithm was implemented in the analysis process in order to quantify direct, indirect, and mixed DSBs. The model was validated against published experimental and computational results for DSB Gy−1Gbp−1 and the relative biological effectiveness (RBE) values for 250 kVp and Co-60 photons, as well as 2–100 MeV mono-energetic protons. A general agreement was observed over the whole simulated proton energy range, Co-60 beam, and 250 kVp in terms of the yield of DSB Gy−1Gbp−1 and RBE. The DSB yield was 8.0 ± 0.3 DSB Gy−1Gbp−1 for Co-60, and 9.2 ± 0.2 DSB Gy−1Gbp−1 for 250 kVp, and between 11.1 ± 0.9 and 8.1 ± 0.5 DSB Gy−1Gbp−1 for 2–100 MeV protons. The results also show mixed DSBs composed of direct and indirect SSBs make up more than half of the total DSBs. The results presented indicate that the current model reliably predicts the DSB yield and RBE for proton and photon irradiations, and allows for the detailed computational investigation of direct and indirect effects in DNA damage.

No abstract

Understanding and designing clinical radiation therapy is one of the most important areas of state-of-the-art oncological treatment regimens. Decades of research have gone into developing sophisticated treatment devices and optimization protocols for schedules and dosages. In this paper, we presented a comprehensive computational platform that facilitates building of the sophisticated multi-cell-based model of how radiation affects the biology of living tissue. We designed and implemented a coupled simulation method, including a radiation transport model, and a cell biology model, to simulate the tumor response after irradiation. The radiation transport simulation was implemented through Geant4 which is an open-source Monte Carlo simulation platform that provides many flexibilities for users, as well as low energy DNA damage simulation physics, Geant4-DNA. The cell biology simulation was implemented using CompuCell3D (CC3D) which is a cell biology simulation platform. In order to couple Geant4 solver with CC3D, we developed a ‘bridging’ module, RADCELL, that extracts tumor cellular geometry of the CC3D simulation (including specification of the individual cells) and ported it to the Geant4 for radiation transport simulation. The cell dose and cell DNA damage distribution in multicellular system were obtained using Geant4. The tumor response was simulated using cell-based tissue models based on CC3D, and the cell dose and cell DNA damage information were fed back through RADCELL to CC3D for updating the cell properties. By merging two powerful and widely used modeling platforms, CC3D and Geant4, we delivered a novel tool that can give us the ability to simulate the dynamics of biological tissue in the presence of ionizing radiation, which provides a framework for quantifying the biological consequences of radiation therapy. In this introductory methods paper, we described our modeling platform in detail and showed how it can be applied to study the application of radiotherapy to a vascularized tumor.

Purpose: The objective of this study was to investigate the dosimetric impact of range uncertainty in a large cohort of patients receiving passive scatter proton therapy.Methods: A cohort of 120 patients were reviewed in this study retrospectively, of which 61 were brain, 39 lung, and 20 prostate patients. Range uncertainties of ±3.5% (overshooting and undershooting by 3.5%, respectively) were added and recalculated on the original plans, which had been planned according to our clinical planning protocol while keeping beamlines, apertures, compensators, and dose grids intact. Changes in the coverage on CTV and DVH for critical organs were compared and analyzed. Correlation between dose change and minimal distance between CTV and critical organs were also investigated.Results: Although CTV coverages and maximum dose to critical organs were largely maintained for most brain patients, large variations over 5% were still observed sporadically. Critical organs, such as brainstem and chiasm, could still be affected by range uncertainty at 4 cm away from CTV. Coverage and OARs in lung and prostate patients were less likely to be affected by range uncertainty with very few exceptions. Conclusion:The margin recipe in modern TPS leads to clinically acceptable OAR doses in the presence of range uncertainties. However, range uncertainties still pose a noticeable challenge for small but critical serial organs near tumors, and occasionally for large parallel organs that are located distal to incident proton beams.