Metallic nanoparticle radiosensitisation of ion radiotherapy: A review

The use of gold nanoparticle (GNP) and other metal nanoparticle (MNP) radiosensitisers to enhance radiotherapy offers the potential of improved treatment outcomes. Originally intended for use with X-ray therapy, the possibility of enhanced hadron therapy is desirable due to the superior sparing of healthy tissue in hadron therapy compared to conventional X-ray therapy. While MNPs were not expected to be effective radiosensitisers for hadron therapy due to the limited Z dependence of interactions, recent experimental measurements have contradicted this expectation. Key experimental measurements and Monte Carlo simulations of MNP radiosensitisation for hadron irradiation are reviewed in the current work. Numerous experimental measurements have found a large radiosensitisation effect due to MNPs for proton and carbon ion irradiation. Experiments have also indicated that the radiosensitisation is due in large part to enhanced reactive oxygen species (ROS) production. Simulations have found a large radial dose and ROS enhancement on the nanoscale around a single MNP. However, the short range of the dose enhancement is insufficient for a large macroscale dose enhancement or enhanced biological effect in a cell model considering dose to the nucleus from GNPs in the cytoplasm (a distribution observed in most experiments).     

Influence of the Presence of Tissue Expanders on Energy Deposition for Post-Mastectomy Radiotherapy

An increasing number of studies have shown that post-mastectomy radiotherapy presents benefits associated with the patients survival and a significant fraction of the treated patients makes use of tissue expanders for breast reconstruction. Some models of tissue expanders have a magnetic disk on their surface that constitutes heterogeneity in the radiation field, which can affect the dose distribution during the radiotherapy treatment. In this study, the influence of a metallic heterogeneity positioned in a breast tissue expander was evaluated by means of Monte Carlo simulations using the MCNPX code and using Eclipse treatment planning system. Deposited energy values were calculated in structures which have clinical importance for the treatment. Additionally, the effect in the absorbed energy due to backscattering and attenuation of the incident beam caused by the heterogeneity, as well as due to the expansion of the prosthesis, was evaluated in target structures for a 6 MV photon beam by simulations. The dose distributions for a breast treatment were calculated using a convolution/superposition algorithm from the Eclipse treatment planning system. When compared with the smallest breast expander volume, underdosage of 7% was found for the largest volume of breast implant, in the case of frontal irradiation of the chest wall, by Monte Carlo simulations. No significant changes were found in dose distributions for the presence of the heterogeneity during the treatment planning of irradiation with an opposed pair of beams. Even considering the limitation of the treatment planning system, the results obtained with its use confirm those ones found by Monte Carlo simulations for a tangent beam irradiation. The presence of a heterogeneity didńt alters the dose distributions on treatment structures. The underdosage of 7% observed with Monte Carlo simulations were found for irradiation at 0°, not used frequently in a clinical routine.     

Monte Carlo simulation of gold nanoparticles for X-ray enhancement application

BackgroundGold nanoparticles (Au NPs) are regarded as potential agents that enhance the radiosensitivity of tumor cells for theranostic applications. To elucidate the biological mechanisms of radiation dose enhancement effects of Au NPs as well as DNA damage attributable to the inclusion of Au NPs, Monte Carlo (MC) simulations have been deployed in a number of studies.Scope of ReviewThis review paper concisely collates and reviews the information reported in the simulation research in terms of MC simulation of radiosensitization and dose enhancement effects caused by the inclusion of Au NPs in tumor cells, simulation mechanisms, benefits and limitations.Major conclusionsIn this review, we first explore the recent advances in MC simulation on Au NPs radiosensitization. The MC methods, physical dose enhancement and enhanced chemical and biological effects is discussed, followed by some results regarding the prediction of dose enhancement. We then review Multi-scale MC simulations of Au NP-induced DNA damages for X-ray irradiation. Moreover, we explain and look at Multi-scale MC simulations of Au NP-induced DNA damages for X-ray irradiation.General significanceUsing advanced chemical module-implemented MC simulations, there is a need to assess the radiation-induced chemical radicals that contribute to the dose-enhancing and biological effects of multiple Au NPs.     

Dosimetric characterization of an 192Ir brachytherapy source with the Monte Carlo code PENELOPE

Monte Carlo calculations are highly spread and settled practice to calculate brachytherapy sources dosimetric parameters. In this study, recommendations of the AAPM TG-43U1 report have been followed to characterize the Varisource VS2000 ¹⁹²Ir high dose rate source, provided by Varian Oncology Systems.In order to obtain dosimetric parameters for this source, Monte Carlo calculations with PENELOPE code have been carried out. TG-43 formalism parameters have been presented, i.e., air kerma strength, dose rate constant, radial dose function and anisotropy function. Besides, a 2D Cartesian coordinates dose rate in water table has been calculated. These quantities are compared to this source reference data, finding results in good agreement with them.The data in the present study complement published data in the next aspects: (i) TG-43U1 recommendations are followed regarding to phantom ambient conditions and to uncertainty analysis, including statistical (type A) and systematic (type B) contributions; (ii) PENELOPE code is benchmarked for this source; (iii) Monte Carlo calculation methodology differs from that usually published in the way to estimate absorbed dose, leaving out the track-length estimator; (iv) the results of the present work comply with the most recent AAPM and ESTRO physics committee recommendations about Monte Carlo techniques, in regards to dose rate uncertainty values and established differences between our results and reference data.The results stated in this paper provide a complete parameter collection, which can be used for dosimetric calculations as well as a means of comparison with other datasets from this source.     

Understanding protein folding: small proteins in silico

Recent improvements in methodology and increased computer power now allow atomistic computer simulations of protein folding. We briefly review several advanced Monte Carlo algorithms that have contributed to this development. Details of folding simulations of three designed mini proteins are shown. Adding global translations and rotations has allowed us to handle multiple chains and to simulate the aggregation of six beta-amyloid fragments. In a different line of research we have developed several algorithms to predict local features from sequence. In an outlook we sketch how such biasing could extend the application spectrum of Monte Carlo simulations to structure prediction of larger proteins.     

Intercomparison of dose enhancement ratio and secondary electron spectra for gold nanoparticles irradiated by X-rays calculated using multiple Monte Carlo simulation codes

PurposeTargeted radiation therapy has seen an increased interest in the past decade. In vitro and in vivo experiments showed enhanced radiation doses due to gold nanoparticles (GNPs) to tumors in mice and demonstrated a high potential for clinical application. However, finding a functionalized molecular formulation for actively targeting GNPs in tumor cells is challenging. Furthermore, the enhanced energy deposition by secondary electrons around GNPs, particularly by short-ranged Auger electrons is difficult to measure. Computational models, such as Monte Carlo (MC) radiation transport codes, have been used to estimate the physical quantities and effects of GNPs. However, as these codes differ from one to another, the reliability of physical and dosimetric quantities needs to be established at cellular and molecular levels, so that the subsequent biological effects can be assessed quantitatively.MethodsIn this work, irradiation of single GNPs of 50 nm and 100 nm diameter by X-ray spectra generated by 50 and 100 peak kilovoltages was simulated for a defined geometry setup, by applying multiple MC codes in the EURADOS framework.ResultsThe mean dose enhancement ratio of the first 10 nm-thick water shell around a 100 nm GNP ranges from 400 for 100 kVp X-rays to 600 for 50 kVp X-rays with large uncertainty factors up to 2.3.ConclusionsIt is concluded that the absolute dose enhancement effects have large uncertainties and need an inter-code intercomparison for a high quality assurance; relative properties may be a better measure until more experimental data is available to constrain the models.     

Calculation of dose components in head phantom for boron neutron capture therapy.

Application of neutrons to cancer treatment has been a subject of considerable clinical and research interest since the discovery of the neutron by Chadwick in 1932 (3). Boron neutron capture therapy (BNCT) is a technique of radiation oncology which is used in treating brain cancer (glioblastoma multiform) or melanoma and that consists of preferentially loading a compound containing 10B into the tumor location, followed by the irradiation of the patient with a beam of neutron. Dose distribution for BNCT is mainly based on Monte Carlo simulations. In this work, the absorbed dose spatial distribution resultant from an idealized neutron beam incident upon ahead phantom is investigated using the Monte Carlo N-particles code, MCNP 4B. The phantom model used is based on the geometry of a circular cylinder on which sits an elliptical cylinder capped by half an ellipsoid representing the neck and head, both filled with tissue-equivalent material. The neutron flux and the contribution of individual absorbed dose components, as a function of depths and of radial distance from the beam axis (dose profiles) in phantom model, is presented and discussed. For the studied beam the maximum thermal neutron flux is at a depth of 2 cm and the maximum gamma dose at a depth of 4 cm.     

Monte Carlo studies in Gold Nanoparticles enhanced radiotherapy: The impact of modelled parameters in dose enhancement

PurposeOver the last decades, Gold Nanoparticles (AuNPs) have been presented as an innovative approach in radiotherapy (RT) enhancement. Several studies have proven that the irradiation of tumors containing AuNPs could lead to more effective tumor control than irradiation alone. Studies with low kV photons and AuNPs conclude in encouraging results regarding the level of radioenhancement. However, experimental and theoretical studies with MV photons report controversial findings concerning the correlation between dose enhancement effect and tumor cell killing. The great variation in the experimental protocols and simulations complicates the comparison of their outcomes and depicts the need for limiting the variety of investigated parameters. Our purpose is to point out a possible direction for building realistic Monte Carlo (MC) models that could end up with promising results in MV photons RT enhancement.MethodsWe explored published in silico studies concerning AuNPs enhanced RT from 2010 to 2019. In this review, we discuss the different AuNPs and MV photon beams characteristics that have been reported and their effect in dose enhancement.ResultsAuNPs size, concentration, type of distribution along with photon beams energy and the presence of flattening filter in linear accelerators seem to be the major parameters that determine AuNPs radioenhancement in silico.ConclusionsPrior to AuNPs clinical translation in photon radiotherapy, in silico studies should emphasize on nanodosimetry and track structure codes than condensed history ones. Toxicity estimation and biological aspects should be implemented in MC simulations so as to achieve accurate and realistic modelling of AuNPs driven RT.     

Two-step validation of a Monte Carlo dosimetry framework for general radiology

The Monte Carlo technique is considered gold standard when it comes to patient-specific dosimetry. Any newly developed Monte Carlo simulation framework, however, has to be carefully calibrated and validated prior to its use. For many researchers this is a tedious work. We propose a two-step validation procedure for our newly built Monte Carlo framework and provide all input data to make it feasible for future related application by the wider community. The validation was at first performed by benchmarking against simulation data available in literature. The American Association of Physicists in Medicine (AAPM) report of task group 195 (case 2) was considered most appropriate for our application. Secondly, the framework was calibrated and validated against experimental measurements for trunk X-ray imaging protocols using a water phantom. The dose results obtained from all simulations and measurements were compared. Our Monte Carlo framework proved to agree with literature data, by showing a maximal difference below 4% to the AAPM report. The mean difference with the water phantom measurements was around 7%. The statistical uncertainty for clinical applications of the dosimetry model is expected to be within 10%. This makes it reliable for clinical dose calculations in general radiology. Input data and the described procedure allow for the validation of other Monte Carlo frameworks.     

Radiation protection from external exposure to radionuclides: A Monte Carlo data handbook

The availability of a resource collecting dose factors for the evaluation of the absorbed doses from external exposure during the manipulation of radioactive substances is fundamental for radiological protection purposes. Monte Carlo simulations are useful for the accurate calculation of dose distributions in complex geometries, particularly in presence of extended spectra of multi-radiation sources. We considered, as possible irradiation scenarios, a point source, a uniform planar source resembling a contaminated surface, several source volumes contained in plastic or glass receptacles, and the direct skin contamination case, implementing the corresponding Monte Carlo simulations in GAMOS (GEANT4-based Architecture for Medicine-Oriented Simulations). A set of 50 radionuclides was studied, focusing the attention on those ones mainly used in nuclear medicine, both for diagnostic and therapeutic purposes, in nuclear physics laboratories and for instrument calibration. Skin dose equivalents at 70 μm of depth and deep dose equivalents at 10 mm of depth are reported for different configurations and organized in easy-to-read tables.     

Lower confidence bounds for prediction accuracy in high dimensions via AROHIL Monte Carlo

MOTIVATION: Implementation and development of statistical methods for high-dimensional data often require high-dimensional Monte Carlo simulations. Simulations are used to assess performance, evaluate robustness, and in some cases for implementation of algorithms. But simulation in high dimensions is often very complex, cumbersome and slow. As a result, performance evaluations are often limited, robustness minimally investigated and dissemination impeded by implementation challenges. This article presents a method for converting complex, slow high-dimensional Monte Carlo simulations into simpler, faster lower dimensional simulations. RESULTS: We implement the method by converting a previous Monte Carlo algorithm into this novel Monte Carlo, which we call AROHIL Monte Carlo. AROHIL Monte Carlo is shown to exactly or closely match pure Monte Carlo results in a number of examples. It is shown that computing time can be reduced by several orders of magnitude. The confidence bound method implemented using AROHIL outperforms the pure Monte Carlo method. Finally, the utility of the method is shown by application to a number of real microarray datasets.     

Sensitivity of alanine dosimeters with gadolinium exposed to 6 MV photons at clinical doses

In this study we analyzed the ESR signal of alanine dosimeters with gadolinium exposed to 6 MV linear accelerator photons. We observed that the addition of gadolinium brings about an improvement in the sensitivity to photons because of its high atomic number. The experimental data indicated that the addition of gadolinium increases the sensitivity of the alanine to 6 MV photons. This enhancement was better observed at high gadolinium concentrations for which the tissue equivalence is heavily reduced. However, information about the irradiation setup and of the radiation beam features allows one to correct for this difference. Monte Carlo simulations were carried out to obtain information on the expected effect of the addition of gadolinium on the dose absorbed by the alanine molecules inside the pellets. These results are compared with the experimental values, and the agreement is discussed.     

Comparison of neutron organ and effective dose coefficients for PIMAL stylized phantom in bent postures in standard irradiation geometries

Neutron dose coefficients for standard irradiation geometries have been reported in International Commission on Radiological Protection (ICRP) Publication 116 for the ICRP Publication 110 adult reference phantoms. In the present work, organ and effective dose coefficients have been calculated for a receptor in both upright and articulated (bent) postures representing more realistic working postures exposed to a mono-energetic neutron radiation field. This work builds upon prior work by Dewji and co-workers comparing upright and bent postures for exposure to mono-energetic photon fields. Simulations were conducted using the Oak Ridge National Laboratory’s articulated stylized adult phantom, “Phantom wIth Moving Arms and Legs” (PIMAL) software package, and the Monte Carlo N-Particle (MCNP) version 6.1.1 radiation transport code. Organ doses were compared for the upright and bent (45° and 90°) phantom postures for neutron energies ranging from 1 × 10^??9 to 20 MeV for the ICRP Publication 116 external exposure geometries—antero-posterior (AP), postero-anterior (PA), and left and right lateral (LLAT, RLAT). Using both male and female phantoms, effective dose coefficients were computed using ICRP Publication 103 methodology. The resulting coefficients for articulated phantoms were compared to those of the upright phantom. Computed organ and effective dose coefficients are discussed as a function of neutron energy, phantom posture, and source irradiation geometry. For example, it is shown here that for the AP and PA irradiation geometries, the differences in the organ coefficients between the upright and bent posture become more pronounced with increasing bending angle. In the AP geometry, the brain dose coefficients are expectedly higher in the bent postures than in the upright posture, while all other organs have lower dose coefficients, with the thyroid showing the greatest difference. Overall, the effective dose estimated for the upright phantom is more conservative than that for the articulated phantom, which may have ramifications in the estimation or reconstruction of radiation doses.     

Doses for experiments with microbeams and microcrystals: Monte Carlo simulations in RADDOSE‐3D

Increasingly, microbeams and microcrystals are being used for macromolecular crystallography (MX) experiments at synchrotrons. However, radiation damage remains a major concern since it is a fundamental limiting factor affecting the success of macromolecular structure determination. The rate of radiation damage at cryotemperatures is known to be proportional to the absorbed dose, so to optimize experimental outcomes, accurate dose calculations are required which take into account the physics of the interactions of the crystal constituents. The program RADDOSE‐3D estimates the dose absorbed by samples during MX data collection at synchrotron sources, allowing direct comparison of radiation damage between experiments carried out with different samples and beam parameters. This has aided the study of MX radiation damage and enabled prediction of approximately when it will manifest in diffraction patterns so it can potentially be avoided. However, the probability of photoelectron escape from the sample and entry from the surrounding material has not previously been included in RADDOSE‐3D, leading to potentially inaccurate does estimates for experiments using microbeams or microcrystals. We present an extension to RADDOSE‐3D which performs Monte Carlo simulations of a rotating crystal during MX data collection, taking into account the redistribution of photoelectrons produced both in the sample and the material surrounding the crystal. As well as providing more accurate dose estimates, the Monte Carlo simulations highlight the importance of the size and composition of the surrounding material on the dose and thus the rate of radiation damage to the sample. Minimizing irradiation of the surrounding material or removing it almost completely will be key to extending the lifetime of microcrystals and enhancing the potential benefits of using higher incident X‐ray energies.     

Reservoir boundaries in Brownian dynamics simulations of ion channels

Brownian dynamics (BD) simulations provide a practical method for the calculation of ion channel conductance from a given structure. There has been much debate about the implementation of reservoir boundaries in BD simulations in recent years, with claims that the use of improper boundaries could have large effects on the calculated conductance values. Here we compare the simple stochastic boundary that we have been using in our BD simulations with the recently proposed grand canonical Monte Carlo method. We also compare different methods of creating transmembrane potentials. Our results confirm that the treatment of the reservoir boundaries is mostly irrelevant to the conductance properties of an ion channel as long as the reservoirs are large enough.     

Multiple-source models for electron beams of a medical linear accelerator using BEAMDP computer code

AimThe aim of this work was to develop multiple-source models for electron beams of the NEPTUN 10PC medical linear accelerator using the BEAMDP computer code.BackgroundOne of the most accurate techniques of radiotherapy dose calculation is the Monte Carlo (MC) simulation of radiation transport, which requires detailed information of the beam in the form of a phase-space file. The computing time required to simulate the beam data and obtain phase-space files from a clinical accelerator is significant. Calculation of dose distributions using multiple-source models is an alternative method to phase-space data as direct input to the dose calculation system.Materials and methodsMonte Carlo simulation of accelerator head was done in which a record was kept of the particle phase-space regarding the details of the particle history. Multiple-source models were built from the phase-space files of Monte Carlo simulations. These simplified beam models were used to generate Monte Carlo dose calculations and to compare those calculations with phase-space data for electron beams.ResultsComparison of the measured and calculated dose distributions using the phase-space files and multiple-source models for three electron beam energies showed that the measured and calculated values match well each other throughout the curves.ConclusionIt was found that dose distributions calculated using both the multiple-source models and the phase-space data agree within 1.3%, demonstrating that the models can be used for dosimetry research purposes and dose calculations in radiotherapy.     

Synthesis and conformational and NMR studies of alpha-D-mannopyranosyl and alpha-D-mannopyranosyl-(1----2)-alpha-D-mannopyranosyl linked to L-serine and L-threonine.

alpha-D-Mannopyranosyl and alpha-D-mannopyranosyl-(1----2)-alpha-D- mannopyranosyl linked to L-serine and L-threonine have been synthesised as model substances for the linkage region in certain O-linked glycoproteins. Metropolis Monte Carlo simulations were performed with a modified version of the GESA program, to yield theoretical NOEs and interatomic distances as ensemble-average values, and these were compared with results from steady-state NOE experiments. The NOEs were determined as ensemble-average and as global minimum values. NMR chemical shift differences, obtained for signals of the glycopeptides relative to those of the respective monomers, were interpreted in terms of short inter-residue atomic distances as found within the global minima, and on the basis of averaged distances derived from Monte Carlo simulations.     

Assessment of the neutron dose field around a biomedical cyclotron: FLUKA simulation and experimental measurements

In the planning of a new cyclotron facility, an accurate knowledge of the radiation field around the accelerator is fundamental for the design of shielding, the protection of workers, the general public and the environment.Monte Carlo simulations can be very useful in this process, and their use is constantly increasing. However, few data have been published so far as regards the proper validation of Monte Carlo simulation against experimental measurements, particularly in the energy range of biomedical cyclotrons.In this work a detailed model of an existing installation of a GE PETtrace 16.5 MeV cyclotron was developed using FLUKA. An extensive measurement campaign of the neutron ambient dose equivalent H¹(10) in marked positions around the cyclotron was conducted using a neutron rem-counter probe and CR39 neutron detectors. Data from a previous measurement campaign performed by our group using TLDs were also re-evaluated.The FLUKA model was then validated by comparing the results of high-statistics simulations with experimental data. In 10 out of 12 measurement locations, FLUKA simulations were in agreement within uncertainties with all the three different sets of experimental data; in the remaining 2 positions, the agreement was with 2/3 of the measurements.Our work allows to quantitatively validate our FLUKA simulation setup and confirms that Monte Carlo technique can produce accurate results in the energy range of biomedical cyclotrons.     

Monte Carlo modeling of the Siemens Optifocus multileaf collimator

We have developed a new component module for the BEAMnrc software package, called SMLC, which models the tongue-and-groove structure of the Siemens Optifocus multileaf collimator. The ultimate goal is to perform accurate Monte Carlo simulations of the IMRT treatments carried out with Optifocus. SMLC has been validated by direct geometry checks and by comparing quantitatively the results of simulations performed with it and with the component module VARMLC. Measurements and Monte Carlo simulations of absorbed dose distributions of radiation fields sensitive to the tongue-and-groove effect have been performed to tune the free parameters of SMLC. The measurements cannot be accurately reproduced with VARMLC. Finally, simulations of a typical IMRT field showed that SMLC improves the agreement with experimental measurements with respect to VARMLC in clinically relevant cases.PACS number87.55. K-     

Calculation of the diffusion coefficient of thiophene oligomers using molecular dynamics

Electropolymerisation is a very useful methodology for conducting polymers synthesis. A total comprehension of this process will help on the designing of new materials with improved optical and electrical properties. In this sense, computational simulations can deliver important information at atomic scale. Within a kinetic Monte Carlo scheme, diffusion rates are crucial to obtain accurate predictions; however, experimental values of this dynamic property for different oligomers are very scarce among literature. In this study, the diffusion coefficient (D) of thiophene oligomers (1Th–6Th) has been calculated using molecular dynamics simulations coupled with the Einstein expression. Results are in the order of experimental values, demonstrating that this methodology is a fast and reliable alternative to calculate diffusion coefficients with low computational costs.