Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA.

PURPOSE: Track structure Monte Carlo (MC) codes have achieved successful outcomes in the quantitative investigation of radiation-induced initial DNA damage. The aim of the present study is to extend a Geant4-DNA radiobiological application by incorporating a feature allowing for the prediction of DNA rejoining kinetics and corresponding cell surviving fraction along time after irradiation, for a Chinese hamster V79 cell line, which is one of the most popular and widely investigated cell lines in radiobiology. METHODS: We implemented the Two-Lesion Kinetics (TLK) model, originally proposed by Stewart, which allows for simulations to calculate residual DNA damage and surviving fraction along time via the number of initial DNA damage and its complexity as inputs. RESULTS: By optimizing the model parameters of the TLK model in accordance to the experimental data on V79, we were able to predict both DNA rejoining kinetics at low linear energy transfers (LET) and cell surviving fraction. CONCLUSION: This is the first study to demonstrate the implementation of both the cell surviving fraction and the DNA rejoining kinetics with the estimated initial DNA damage, in a realistic cell geometrical model simulated by full track structure MC simulations at DNA level and for various LET. These simulation and model make the link between mechanistic physical/chemical damage processes and these two specific biological endpoints.

Implementation of the EPICS2017 database for photons in Geant4.

This paper describes in detail the implementation of Geant4 Livermore electromagnetic physics models based on the EPICS2017 database for the low energy transport of photons. These models describe four photon processes: gamma conversion, Compton scattering, photoelectric effect and Rayleigh scattering. New parameterizations based on EPICS2017 were performed for scattering functions of Compton effect, subshell cross-sections of the photoelectric effect and form factors of Rayleigh scattering, in order to improve the precision of fitted values compared to tabulated values. Comparisons between new and old parameterizations were also carried out to evaluate the precision of the new parameterizations. The models were tested through a comparative study, in which the mass attenuation coefficient was calculated for both total photon interaction and each process using Geant4 simulations based on EPICS2017 and EPDL97 respectively. The results obtained from the simulations were found in good agreement with the XCOM reference data.

A benchmarking study of Geant4 for Auger electrons emitted by medical radioisotopes.

Auger emitting radioisotopes are of great interest in targeted radiotherapy because, once internalised in the tumour cells, they can deliver dose locally to the radiation sensitive targets, while not affecting surrounding cells. Geant4 is a Monte Carlo code widely used to characterise the physics mechanism at the basis of targeted radiotherapy. In this work, we benchmarked the modelling of the emission of Auger electrons in Geant4 deriving from the decay of 123I, 124I, 125I radionuclides against existing theoretical approaches. We also compared Geant4 against reference data in the case of 131Cs, which is of interest for brachytherapy. In the case of 125I and 131Cs, the simulation results are compared to experimental measurements as well. Good agreement was found between Geant4 and the reference data. As far as we know, this is the first study aimed to benchmark against experimental measurements the emission of Auger electrons in Geant4 for radiotherapy applications.

Fully integrated Monte Carlo simulation for evaluating radiation induced DNA damage and subsequent repair using Geant4-DNA.

Ionising radiation induced DNA damage and subsequent biological responses to it depend on the radiation's track-structure and its energy loss distribution pattern. To investigate the underlying biological mechanisms involved in such complex system, there is need of predicting biological response by integrated Monte Carlo (MC) simulations across physics, chemistry and biology. Hence, in this work, we have developed an application using the open source Geant4-DNA toolkit to propose a realistic "fully integrated" MC simulation to calculate both early DNA damage and subsequent biological responses with time. We had previously developed an application allowing simulations of radiation induced early DNA damage on a naked cell nucleus model. In the new version presented in this work, we have developed three additional important features: (1) modeling of a realistic cell geometry, (2) inclusion of a biological repair model, (3) refinement of DNA damage parameters for direct damage and indirect damage scoring. The simulation results are validated with experimental data in terms of Single Strand Break (SSB) yields for plasmid and Double Strand Break (DSB) yields for plasmid/human cell. In addition, the yields of indirect DSBs are compatible with the experimental scavengeable damage fraction. The simulation application also demonstrates agreement with experimental data of [Formula: see text]-H2AX yields for gamma ray irradiation. Using this application, it is now possible to predict biological response along time through track-structure MC simulations.

Evaluation of GATE-RTion (GATE/Geant4) Monte Carlo simulation settings for proton pencil beam scanning quality assurance.

PURPOSE: Geant4 is a multi-purpose Monte Carlo simulation tool for modeling particle transport in matter. It provides a wide range of settings, which the user may optimize for their specific application. This study investigates GATE/Geant4 parameter settings for proton pencil beam scanning therapy. METHODS: GATE8.1/Geant4.10.3.p03 (matching the versions used in GATE-RTion1.0) simulations were performed with a set of prebuilt Geant4 physics lists (QGSP_BIC, QGSP_BIC_EMY, QGSP_BIC_EMZ, QGSP_BIC_HP_EMZ), using 0.1mm-10mm as production cuts on secondary particles (electrons, photons, positrons) and varying the maximum step size of protons (0.1mm, 1mm, none). The results of the simulations were compared to measurement data taken during clinical patient specific quality assurance at The Christie NHS Foundation Trust pencil beam scanning proton therapy facility. Additionally, the influence of simulation settings was quantified in a realistic patient anatomy based on computer tomography (CT) scans. RESULTS: When comparing the different physics lists, only the results (ranges in water) obtained with QGSP_BIC (G4EMStandardPhysics_Option0) depend on the maximum step size. There is clinically negligible difference in the target region when using High Precision neutron models (HP) for dose calculations. The EMZ electromagnetic constructor provides a closer agreement (within 0.35 mm) to measured beam sizes in air, but yields up to 20% longer execution times compared to the EMY electromagnetic constructor (maximum beam size difference 0.79 mm). The impact of this on patient-specific quality assurance simulations is clinically negligible, with a 97% average 2%/2 mm gamma pass rate for both physics lists. However, when considering the CT-based patient model, dose deviations up to 2.4% are observed. Production cuts do not substantially influence dosimetric results in solid water, but lead to dose differences of up to 4.1% in the patient CT. Small (compared to voxel size) production cuts increase execution times by factors of 5 (solid water) and 2 (patient CT). CONCLUSIONS: Taking both efficiency and dose accuracy into account and considering voxel sizes with 2 mm linear size, the authors recommend the following Geant4 settings to simulate patient specific quality assurance measurements: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (in the phantom and range-shifter) and 10 mm (world); best agreement to measurement data was found for QGSP_BIC_EMZ reference physics list at the cost of 20% increased execution times compared to QGSP_BIC_EMY. For simulations considering the patient CT model, the following settings are recommended: No step limiter on proton tracks; production cuts of 1 mm for electrons, photons and positrons (phantom/range-shifter) and 10 mm (world) if the goal is to achieve sufficient dosimetric accuracy to ensure that a plan is clinically safe; or 0.1 mm (phantom/range-shifter) and 1 mm (world) if higher dosimetric accuracy is needed (increasing execution times by a factor of 2); most accurate results expected for QGSP_BIC_EMZ reference physics list, at the cost of 10-20% increased execution times compared to QGSP_BIC_EMY.

Advances in modelling gold nanoparticle radiosensitization using new Geant4-DNA physics models.

Gold nanoparticles have demonstrated significant radiosensitization of cancer treatment with x-ray radiotherapy. To understand the mechanisms at the basis of nanoparticle radiosensitization, Monte Carlo simulations are used to investigate the dose enhancement, given a certain nanoparticle concentration and distribution in the biological medium. Earlier studies have ordinarily used condensed history physics models to predict nanoscale dose enhancement with nanoparticles. This study uses Geant4-DNA complemented with novel track structure physics models to accurately describe electron interactions in gold and to calculate the dose surrounding gold nanoparticle structures at nanoscale level. The computed dose in silico due to a clinical kilovoltage beam and the presence of gold nanoparticles was related to in vitro brain cancer cell survival using the local effect model. The comparison of the simulation results with radiobiological experimental measurements shows that Geant4-DNA and local effect model can be used to predict cell survival in silico in the case of x-ray kilovoltage beams.

Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations.

The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (109) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (γ-H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de sûreté nucléaire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV.

Electron track structure simulations in a gold nanoparticle using Geant4-DNA.

Gold Nanoparticles (GNPs) have recently gained a lot of attention due to their potential benefit to improve the efficacy of X-ray radiotherapy. Owing to their high atomic number, GNPs are able to absorb higher quantities of incident radiation with respect to the surrounding tissue, producing, in particular, photoelectrons and low energy Auger electrons. These additional low energy electrons increase the local energy deposition in the region surrounding the GNP. Monte Carlo simulations play a key role in the investigation of GNP radio-enhancement and it is widely recognised that track structure physics models are the state-of-the-art for nano-scale studies. In 2016, we have developed track structure physics models for the Geant4-DNA toolkit allowing electron transport for microscopic bulk gold (Geant4_DNA_AU_2016) and we have recently improved them in the low energy domain (Geant4_DNA_AU_2018). In this paper, we report the benchmarking of these newly developed physics models when calculating the physical dose and the Dose Enhancement Factor (DEF) around a GNP. We demonstrate that Geant4_DNA_AU_2018 models give similar azimuthal distribution of two dimensional absorbed dose around a single GNP, but result in larger absorbed dose and DEF than Geant4_DNA_AU_2016 models. In parallel, we investigated the performance of a newly developed multiple scattering model in Geant4 based on the Goudsmit-Saunderson (GS) model, when used together with the electromagnetic physics models with the Geant4 Livermore condensed-history approach. Our results show that the GS model does not affect the results of the simulations when studying GNP radio-enhancement with a condensed-history approach.

Evaluation of early radiation DNA damage in a fractal cell nucleus model using Geant4-DNA.

The advancement of multidisciplinary research fields dealing with ionising radiation induced biological damage - radiobiology, radiation physics, radiation protection and, in particular, medical physics - requires a clear mechanistic understanding of how cellular damage is induced by ionising radiation. Monte Carlo (MC) simulations provide a promising approach for the mechanistic simulation of radiation transport and radiation chemistry, towards the in silico simulation of early biological damage. We have recently developed a fully integrated MC simulation that calculates early single strand breaks (SSBs) and double strand breaks (DSBs) in a fractal chromatin based human cell nucleus model. The results of this simulation are almost equivalent to past MC simulations when considering direct/indirect strand break fraction, DSB yields and fragment distribution. The simulation results agree with experimental data on DSB yields within 13.6% on average and fragment distributions agree within an average of 34.8%.

Geant4-DNA track-structure simulations for gold nanoparticles: The importance of electron discrete models in nanometer volumes.

PURPOSE: Gold nanoparticles (GNPs) are known to enhance the absorbed dose in their vicinity following photon-based irradiation. To investigate the therapeutic effectiveness of GNPs, previous Monte Carlo simulation studies have explored GNP dose enhancement using mostly condensed-history models. However, in general, such models are suitable for macroscopic volumes and for electron energies above a few hundred electron volts. We have recently developed, for the Geant4-DNA extension of the Geant4 Monte Carlo simulation toolkit, discrete physics models for electron transport in gold which include the description of the full atomic de-excitation cascade. These models allow event-by-event simulation of electron tracks in gold down to 10 eV. The present work describes how such specialized physics models impact simulation-based studies on GNP-radioenhancement in a context of x-ray radiotherapy. METHODS: The new discrete physics models are compared to the Geant4 Penelope and Livermore condensed-history models, which are being widely used for simulation-based NP radioenhancement studies. An ad hoc Geant4 simulation application has been developed to calculate the absorbed dose in liquid water around a GNP and its radioenhancement, caused by secondary particles emitted from the GNP itself, when irradiated with a monoenergetic electron beam. The effect of the new physics models is also quantified in the calculation of secondary particle spectra, when originating in the GNP and when exiting from it. RESULTS: The new physics models show similar backscattering coefficients with the existing Geant4 Livermore and Penelope models in large volumes for 100 keV incident electrons. However, in submicron sized volumes, only the discrete models describe the high backscattering that should still be present around GNPs at these length scales. Sizeable differences (mostly above a factor of 2) are also found in the radial distribution of absorbed dose and secondary particles between the new and the existing Geant4 models. The degree to which these differences are due to intrinsic limitations of the condensed-history models or to differences in the underling scattering cross sections requires further investigation. CONCLUSIONS: Improved physics models for gold are necessary to better model the impact of GNPs in radiotherapy via Monte Carlo simulations. We implemented discrete electron transport models for gold in Geant4 that is applicable down to 10 eV including the modeling of the full de-excitation cascade. It is demonstrated that the new model has a significant positive impact on particle transport simulations in gold volumes with submicron dimensions compared to the existing Livermore and Penelope condensed-history models of Geant4.

Local dose enhancement of proton therapy by ceramic oxide nanoparticles investigated with Geant4 simulations.

Nanoparticles (NPs) have been shown to enhance X-ray radiotherapy and proton therapy of cancer. The effectiveness of radiation damage is enhanced in the presence of high atomic number (high-Z) NPs due to increased production of low energy, higher linear energy transfer (LET) secondary electrons when NPs are selectively internalized by tumour cells. This work quantifies the local dose enhancement produced by the high-Z ceramic oxide NPs Ta2O5 and CeO2, in the target tumour, for the first time in proton therapy, by means of Geant4 simulations. The dose enhancement produced by the ceramic oxides is compared against gold NPs. The energy deposition on a nanoscale around a single nanoparticle of 100nm diameter is investigated using the Geant4-DNA extension to model particle interactions in the water medium. Enhancement of energy deposition in nano-sized shells of water, local to the NP boundary, ranging between 14% and 27% was observed for proton energies of 5MeV and 50MeV, depending on the NP material. Enhancement of electron production and energy deposition can be correlated to the direct DNA damage mechanism if the NP is in close proximity to the nucleus.

Geant4 hadronic physics for space radiation environment.

PURPOSE: To test and to develop Geant4 (Geometry And Tracking version 4) Monte Carlo hadronic models with focus on applications in a space radiation environment. MATERIALS AND METHODS: The Monte Carlo simulations have been performed using the Geant4 toolkit. Binary (BIC), its extension for incident light ions (BIC-ion) and Bertini (BERT) cascades were used as main Monte Carlo generators. For comparisons purposes, some other models were tested too. The hadronic testing suite has been used as a primary tool for model development and validation against experimental data. RESULTS: The Geant4 pre-compound (PRECO) and de-excitation (DEE) models were revised and improved. Proton, neutron, pion, and ion nuclear interactions were simulated with the recent version of Geant4 9.4 and were compared with experimental data from thin and thick target experiments. CONCLUSIONS: The Geant4 toolkit offers a large set of models allowing effective simulation of interactions of particles with matter. We have tested different Monte Carlo generators with our hadronic testing suite and accordingly we can propose an optimal configuration of Geant4 models for the simulation of the space radiation environment.

The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial.

Malignant ascites is a common manifestation of advanced cancers, and treatment options are limited. The trifunctional antibody catumaxomab (anti-epithelial cell-adhesion molecule x anti-CD3) represents a targeted immunotherapy for the intraperitoneal (i.p.) treatment of malignant ascites secondary to epithelial cancers. In this phase II/III trial (EudraCT 2004-000723-15; NCT00836654), cancer patients (n = 258) with recurrent symptomatic malignant ascites resistant to conventional chemotherapy were randomized to paracentesis plus catumaxomab (catumaxomab) or paracentesis alone (control) and stratified by cancer type (129 ovarian and 129 nonovarian). Catumaxomab was administered as an i.p. infusion on Days 0, 3, 7 and 10 at doses of 10, 20, 50 and 150 mug, respectively. The primary efficacy endpoint was puncture-free survival. Secondary efficacy parameters included time to next paracentesis, ascites signs and symptoms and overall survival (OS). Puncture-free survival was significantly longer in the catumaxomab group (median 46 days) than the control group (median 11 days) (hazard ratio = 0.254: p < 0.0001) as was median time to next paracentesis (77 versus 13 days; p < 0.0001). In addition, catumaxomab patients had fewer signs and symptoms of ascites than control patients. OS showed a positive trend for the catumaxomab group and, in a prospectively planned analysis, was significantly prolonged in patients with gastric cancer (n = 66; 71 versus 44 days; p = 0.0313). Although adverse events associated with catumaxomab were frequent, they were manageable, generally reversible and mainly related to its immunologic mode of action. Catumaxomab showed a clear clinical benefit in patients with malignant ascites secondary to epithelial cancers, especially gastric cancer, with an acceptable safety profile.

Radiation transport calculations for 50 MV photon therapy beam using the Monte Carlo code GEANT4.

A new thin transmission target technique for fast dose delivery using narrow scanned photon beams has been developed. High-energy, 50-100 MeV, electron beams of low emittance incident on thin low-Z targets produce narrow and intense high-energy bremsstrahlung beams. However, electrons transmitted through the target are bent from the therapeutic beam by a purging magnet and have to be effectively absorbed in a dedicated electron collector. The electron-photon transport through a treatment head has been studied using the Monte Carlo simulation toolkit Geant4. The Geant4 electromagnetic physics processes have been compared with experimental data of radial dose profiles. The differences between calculated and measured radial dose distributions are approximately 2-10%. Preliminary investigations of the collector design have been carried out in order to minimise secondary electron and photon contamination of the therapeutic beam. The toolkit presented here is promising for further development of narrow photon beam therapy.