Monte Carlo GEANT4-based application for in vivo RBE study using small animals at LNS-INFN preclinical hadrontherapy facility

Preclinical studies represent an important step towards a deep understanding of the biological response to ionizing radiations. The effectiveness of proton therapy is higher than photons and, for clinical purposes, a fixed value of 1.1 is used for the relative biological effectiveness (RBE) of protons considered 1.1. Recent in vitro studies have reported that the RBE along the spread-out Bragg peak (SOBP) is not constant and, in particular, the RBE value increases on the distal part of SOBP. The present work has been carried-out in the perspective of a preclinical hadrontherapy facility at LNS-INFN and was focused on the experimental preparation of an in vivo study concerning the RBE variation along the SOBP. The main purpose of this work was to determine, using GEANT4-based Monte Carlo simulations, the best configuration for small animal treatments. The developed GEANT4 application simulates the proton-therapy beam line of LNS-INFN (CATANA facility) and allows to import the DICOM-CT images as targets. The RBE will be evaluated using a deterministic radiation damage like myelopathy as end-point. In fact, the dose at which the $50\%$ of animals will show the myelopathy is supposed to be LET-dependent. In this work, we studied different treatment configurations in order to choose the best two that maximize the LET difference reducing as much as possible the dose released to healthy tissue. The results will be useful to plan hadrontherapy treatments for preclinical in vivo studies and, in particular, for the future in vivo RBE studies.     

GEANT4 models for the secondary radiation flux in the collimation system of a 300 MeV proton microbeam

In Harbin, we are developing a 300 MeV proton microbeam for many applications in space science including upset studies in microelectronic devices, radiation hardness of materials for satellites and radiation effects in human tissues. There are also applications of this facility proposed for proton therapy. The microbeam system will employ a purpose-built proton synchrotron to provide the beam. However there are many challenges to be addressed in the design, construction and operation of this facility. Here we address two important design aspects for which we apply GEANT4 modeling. First, the high energy proton beam interacts strongly with beam line materials, especially the collimation slits, to produce showers of secondary particles which could introduce significant background signals and degrade the resolution of the proton microbeam. Second, the beam transport within the residual vacuum of the beam line may also introduce undesirable background radiation. In both cases mitigation strategies need to be incorporated during the design phase of the new system. We study the use of a dipole magnet following the aperture collimator to reduce the flux of secondary particles incident on the analysis chamber. Monte Carlo simulations are performed using GEANT4 and SRIM. By inserting the dipole magnet, we find as expected a significant reduction in the scattering of protons and other particles, such as neutrons and gamma rays, at the collimation system exit position. Secondary radiation from the residual gas pressure within the beam line vacuum system are also modelled and found to be negligible under the standard operating conditions.     

Quality assurance of carbon ion and proton beams: A feasibility study for using the 2D MatriXX detector

PurposeThe quality assurance (QA) procedures in particle therapy centers with active beam scanning make extensive use of films, which do not provide immediate results. The purpose of this work is to verify whether the 2D MatriXX detector by IBA Dosimetry has enough sensitivity to replace films in some of the measurements.MethodsMatriXX is a commercial detector composed of 32 × 32 parallel plate ionization chambers designed for pre-treatment dose verification in conventional radiation therapy. The detector and GAFCHROMIC® films were exposed simultaneously to a 131.44 MeV proton and a 221.45 MeV/u carbon-ion therapeutic beam at the CNAO therapy center of Pavia – Italy, and the results were analyzed and compared.ResultsThe sensitivity MatriXX on the beam position, beam width and field flatness was investigated. For the first two quantities, a method for correcting systematic uncertainties, dependent on the beam size, was developed allowing to achieve a position resolution equal to 230 μm for carbon ions and less than 100 μm for protons. The beam size and the field flatness measured using MatriXX were compared with the same quantities measured with the irradiated film, showing a good agreement.ConclusionsThe results indicate that a 2D detector such as MatriXX can be used to measure several parameters of a scanned ion beam quickly and precisely and suggest that the QA would benefit from a new protocol where the MatriXX detector is added to the existing systems.     

Monte Carlo determination of a nanoDot OSLD response using quality index for diagnostic kilovoltage X-ray beams

PurposeThis study aims to investigate the energy response of an optically stimulated luminescent dosimeter known as nanoDot for diagnostic kilovoltage X-ray beams via Monte Carlo calculations.MethodsThe nanoDot response is calculated as a function of X-ray beam quality in free air and on a water phantom surface using Monte Carlo simulations. The X-ray fluence spectra are classified using the quality index (QI), which is defined as the ratio of the effective energy to the maximum energy of the photons. The response is calculated for X-ray fluence spectra with QIs of 0.4, 0.5, and 0.6 with tube voltages of 50–137.6 kVp and monoenergetic photon beams. The surface dose estimated using the calculated response is verified by comparing it with that measured using an ionization chamber.ResultsThe nanoDot response in free air for monoenergetic photon beams (QI = 1.0) varies significantly at photon energies below 100 keV and reaches a factor of 3.6 at 25–30 keV. The response differs by up to approximately 6% between QIs of 0.4 and 0.6 for the same half-value layer (HVL). The response at the phantom surface decreases slightly owing to the backscatter effect, and it is almost independent of the field size. The agreement between the surface dose estimated using the nanoDot and that measured using the ionization chamber for assessing X-ray beam qualities is less than 2%.ConclusionsThe nanoDot response is indicated as a function of HVL for the specified QIs, and it enables the direct surface dose measurement.     

Characterization of a commercial scintillation detector for 2-D dosimetry in scanned proton and carbon ion beams

IntroductionPencil beam scanning technique used at CNAO requires beam characteristics to be carefully assessed and periodically checked to guarantee patient safety. This study aimed at characterizing the Lynx® detector (IBA Dosimetry) for commissioning and periodic quality assurance (QA) for proton and carbon ion beams, as compared to EBT3 films, currently used for QA checks.Methods and materialsThe Lynx® is a 2-D high-resolution dosimetry system consisting of a scintillating screen coupled with a CCD camera, in a compact light-tight box. The scintillator was preliminarily characterized in terms of short-term stability, linearity with number of particles, image quality and response dependence on iris setting and beam current; Lynx® was then systematically tested against EBT3 films. The detector response dependence on radiation LET was also assessed.ResultsPreliminary results have shown that Lynx is suitable to be used for commissioning and QA checks for proton and carbon ion scanning beams; the cross-check with EBT3 films showed a good agreement between the two detectors, for both single spot and scanned field measurements. The strong LET dependence of the scintillator due to quenching effect makes Lynx® suitable only for relative 2-D dosimetry measurements.ConclusionLynx® appears as a promising tool for commissioning and periodic QA checks for both protons and carbon ion beams. This detector can be used as an alternative of EBT3 films, allowing real-time measurements and analysis, with a significant time sparing.     

Configuration and validation of an analytical model predicting secondary neutron radiation in proton therapy using Monte Carlo simulations and experimental measurements

PurposeThis study focuses on the configuration and validation of an analytical model predicting leakage neutron doses in proton therapy.MethodsUsing Monte Carlo (MC) calculations, a facility-specific analytical model was built to reproduce out-of-field neutron doses while separately accounting for the contribution of intra-nuclear cascade, evaporation, epithermal and thermal neutrons. This model was first trained to reproduce in-water neutron absorbed doses and in-air neutron ambient dose equivalents, H*(10), calculated using MCNPX. Its capacity in predicting out-of-field doses at any position not involved in the training phase was also checked. The model was next expanded to enable a full 3D mapping of H*(10) inside the treatment room, tested in a clinically relevant configuration and finally consolidated with experimental measurements.ResultsFollowing the literature approach, the work first proved that it is possible to build a facility-specific analytical model that efficiently reproduces in-water neutron doses and in-air H*(10) values with a maximum difference less than 25%. In addition, the analytical model succeeded in predicting out-of-field neutron doses in the lateral and vertical direction. Testing the analytical model in clinical configurations proved the need to separate the contribution of internal and external neutrons. The impact of modulation width on stray neutrons was found to be easily adjustable while beam collimation remains a challenging issue. Finally, the model performance agreed with experimental measurements with satisfactory results considering measurement and simulation uncertainties.ConclusionAnalytical models represent a promising solution that substitutes for time-consuming MC calculations when assessing doses to healthy organs.     

Development and characterization of optical readout well-type glass gas electron multiplier for dose imaging in clinical carbon beams

The use of carbon ion beams in cancer therapy (also known as hadron therapy) is steadily growing worldwide; therefore, the demand for more efficient dosimetry systems is also increasing because daily quality assurance (QA) measurements of hadron radiotherapy is one of the most complex and time consuming tasks. The aim of this study is to develop a two-dimensional dosimetry system that offers high spatial resolution, a large field of view, quick data response, and a linear dose–response relationship.We demonstrate the dose imaging performance of a novel digital dose imager using carbon ion beams for hadron therapy. The dose imager is based on a newly-developed gaseous detector, a well-type glass gas electron multiplier. The imager is successfully operated in a hadron therapy facility with clinical intensity beams for radiotherapy. It features a high spatial resolution of less than 1 mm and an almost linear dose–response relationship with no saturation and very low linear-energy-transfer dependence. Experimental results show that the dose imager has the potential to improve dosimetry accuracy for daily QA.     

Characterization of prompt gamma-ray emission with respect to the Bragg peak for proton beam range verification: A Monte Carlo study

In this paper we report a Geant4 simulation study to investigate the characteristic prompt gamma (PG) emission in a water phantom for real-time monitoring of the Bragg peak (BP) during proton beam irradiation. The PG production, emission spatial correlation with the BP, and position preference for detection with respect to the BP have been quantified in different PG energy windows as a function of proton pencil-beam energy from 100 to 200 MeV. The PG response to small BP shifts was evaluated using a 2 cm-thick slab with different human body materials embedded in a water phantom. Our results show that the prominent characteristic PG emissions of 4.44, 5.21 and 6.13 MeV exhibit distinctive correlation with the dose deposition curve. The accuracy in BP position identification using these characteristic PG rays is highly consistent as the beam energy increases from 100 to 200 MeV. There exists a position preference for PG detection with respect to the BP position, which has a strong dependence on the proton beam energy and PG energies. It was also observed that a submillimeter shift of the BP position can be realized by using PG signals. These results indicate that the characteristic PG signal is sensitive and reliable for BP tracking. Although the maximization of the PG measurement associated with the BP is difficult, it can be optimized with energy and detection position preferences.     

The FLUKA Monte Carlo code coupled with an OER model for biologically weighted dose calculations in proton therapy of hypoxic tumors

IntroductionThe increased radioresistance of hypoxic cells compared to well-oxygenated cells is quantified by the oxygen enhancement ratio (OER). In this study we created a FLUKA Monte Carlo based tool for inclusion of both OER and relative biological effectiveness (RBE) in biologically weighted dose (ROWD) calculations in proton therapy and applied this to explore the impact of hypoxia.MethodsThe RBE-weighted dose was adapted for hypoxia by making RBE model parameters dependent on the OER, in addition to the linear energy transfer (LET). The OER depends on the partial oxygen pressure (pO₂) and LET. To demonstrate model performance, calculations were done with spread-out Bragg peaks (SOBP) in water phantoms with pO₂ ranging from strongly hypoxic to normoxic (0.01–30 mmHg) and with a head and neck cancer proton plan optimized with an RBE of 1.1 and pO₂ estimated voxel-by-voxel using [¹⁸F]-EF5 PET. An RBE of 1.1 and the Rørvik RBE model were used for the ROWD calculations.ResultsThe SOBP in water had decreasing ROWD with decreasing pO₂. In the plans accounting for oxygenation, the median target doses were approximately a factor 1.1 lower than the corresponding plans which did not consider the OER. Hypoxia adapted target ROWDs were considerably more heterogeneous than the RBE_1.1-weighted doses.ConclusionWe realized a Monte Carlo based tool for calculating the ROWD. Read-in of patient pO₂ and estimation of ROWD with flexibility in choice of RBE model was achieved, giving a tool that may be useful in future clinical applications of hypoxia-guided particle therapy.     

Optimization of in vitro expansion of macaque CD4 T cells using anti-CD3 and co-stimulation for autotransfusion therapy

BACKGROUND: Our laboratory has previously shown that adoptive transfer of in vitro-expanded autologous purified polyclonal CD4(+) T cells using anti-CD3/CD28-coated beads induced antiviral responses capable of controlling SIV replication in vivo. METHODS: As CD4(+) T cells comprise several phenotypic and functional lineages, studies were carried out to optimize the in vitro culture conditions for maximal CD4(+) T-cell expansion, survival and delineate the phenotype of these expanded CD4(+) T cells to be linked to maximal clinical benefit. RESULTS AND CONCLUSIONS: The results showed that whereas anti-monkey CD3gamma/epsilon was able to induce T-cell proliferation and expansion in combination with antibodies against multiple co-stimulatory molecules, monkey CD3epsilon cross reacting antibodies failed to induce proliferation of macaque CD4(+) T cells. Among co-stimulatory signals, anti-CD28 stimulation was consistently superior to anti-4-1BB, CD27 or ICOS while the use of anti-CD154 failed to deliver a detectable proliferation signal. Increasing the relative anti-CD28 co-stimulatory signal relative to anti-CD3 provided a modest enhancement of expansion. Additional strategies for optimization included attempts to neutralize free radicals, enhancement of glucose uptake by T cells or addition of T-cell stimulatory cytokines. However, none of these strategies provided any detectable proliferative advantage. Addition of 10 autologous irradiated feeder cells/expanding T cell provided some enhancement of expansion; however, given the high numbers of T cell needed, this approach was deemed impractical and costly, and lower ratios of feeder to expanding T cells failed to provide such benefit. The most critical parameter for efficient expansion of purified CD4(+) T cells from multiple monkeys was the optimization of space and culture conditions at culture inception. Finally, anti-CD3/28-expanded CD4(+) T cells uniformly exhibited a central memory phenotype, absence of CCR5 expression, marked CXCR4 expression in vitro, low levels of caspase 3 but also of Bcl-2 expression.     

Evaluating the usefulness of the direct density reconstruction algorithm for intensity modulated and passively scattered proton therapy: Validation using an anthropomorphic phantom

PurposeAccurate calculation of the proton beam range inside a patient is an important topic in proton therapy. In recent times, a computed tomography (CT) image reconstruction algorithm was developed for treatment planning to reduce the impact of the variation of the CT number with changes in imaging conditions. In this study, we investigated the usefulness of this new reconstruction algorithm (DirectDensity™: DD) in proton therapy based on its comparison with filtered back projection (FBP).MethodsWe evaluated the effects of variations in the X-ray tube potential and target size on the FBP- and DD-image values and investigated the usefulness of the DD algorithm based on the range variations and dosimetric quantity variations.ResultsFor X-ray tube potential variations, the range variation in the case of FBP was up to 12.5 mm (20.8%), whereas that of DD was up to 3.3 mm (5.6%). Meanwhile, for target size variations, the range variation in the case of FBP was up to 2.2 mm (2.5%), whereas that of DD was up to 0.9 mm (1.4%). Moreover, the variations observed in the case of DD were smaller than those of FBP for all dosimetric quantities.ConclusionThe dose distributions obtained using DD were more robust against variations in the CT imaging conditions (X-ray tube potential and target size) than those obtained using FBP, and the range variations were often less than the dose calculation grid (2 mm). Therefore, the DD algorithm is effective in a robust workflow and reduces uncertainty in range calculations.     

Optimization of carbon and nitrogen sources and growth factors for the production of an aquaculture probiotic (Pseudomonas MCCB 103) using response surface methodology

AIM: To develop a new medium for enhanced production of biomass of an aquaculture probiotic Pseudomonas MCCB 103 and its antagonistic phenazine compound, pyocyanin. METHODS AND RESULTS: Carbon and nitrogen sources and growth factors, such as amino acids and vitamins, were screened initially in a mineral medium for the biomass and antagonistic compound of Pseudomonas MCCB 103. The selected ingredients were further optimized using a full-factorial central composite design of the response surface methodology. The medium optimized as per the model for biomass contained mannitol (20 g l(-1)), glycerol (20 g l(-1)), sodium chloride (5 g l(-1)), urea (3.3 g l(-1)) and mineral salts solution (20 ml l(-1)), and the one optimized for the antagonistic compound contained mannitol (2 g l(-1)), glycerol (20 g l(-1)), sodium chloride (5.1 g l(-1)), urea (3.6 g l(-1)) and mineral salts solution (20 ml l(-1)). Subsequently, the model was validated experimentally with a biomass increase by 19% and fivefold increase of the antagonistic compound. CONCLUSION: Significant increase in the biomass and antagonistic compound production could be obtained in the new media. SIGNIFICANCE AND IMPACT OF THE STUDY: Media formulation and optimization are the primary steps involved in bioprocess technology, an attempt not made so far in the production of aquaculture probiotics.     

A gas chromatography-mass spectrometry method for the measurement of fatty acid omega and omega(-1) hydroxylation kinetics by CYP4A1 using an artificial membrane system

A gas chromatography-mass spectrometry assay method for the analysis of lauric, myristic, and palmitic acids and their omega and omega(-1) hydroxylated metabolites from in vitro incubations of cytochrome P450 CYP4A1, involving solid-phase extraction and trimethysilyl derivatization, was developed. The assay was linear, precise, and accurate over the range 0.5 to 50microM for all the analytes. It has the advantages of a more rapid analysis time, an improved sensitivity, and a wider range of analytes compared with other methods. An artificial membrane system was optimized for application to purified CYP4A1 enzyme by investigating the molar ratios of cytochrome b(5) and cytochrome P450 reductase present in the incubation mixture. Using this method, the kinetics of omega and omega(-1) oxidation of lauric, myristic, and palmitic acids by CYP4A enzymes were measured and compared in rat liver microsomes and an artificial membrane system.