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.     

Transversal dose profile reconstruction for clinical proton beams: A detectors inter-comparison

PurposeThe main purpose of this work is the inter-comparison between different devices devoted to the transversal dose profile recostruction for daily QA tests in proton therapy.MethodsThe results obtained with the EBT3 radiochromic films, used as a reference, and other common quality control devices, have been compared with those obtained with a beam profiling system developed at the “Laboratori Nazionali del Sud” of Italian Institute for Nuclear Physics (INFN-LNS, Catania, Italy). It consists of a plastic scintillator screen (thickness 1 mm), mounted perpendicularly to the beam axis and coupled with a highly sensitive CCD detector in a light-tight box.Results and conclusionThe tests, carried out both at the INFN-LNS and Trento Proton Therapy Center facilities, show, in general, a good agreement between the different detectors. The beam profiling system, in particular, appears to be a promising quality control device for 2-D relative dosimetry, because of its linear response in a dose rate range useful for proton therapy treatments, its high spatial resolution and its short acquisition and processing time.     

A beam model for focused proton pencil beams

IntroductionWe present a beam model for Monte Carlo simulations of the IBA pencil beam scanning dedicated nozzle installed at the Skandion Clinic. Within the nozzle, apart from entrance and exit windows and the two ion chambers, the beam traverses vacuum, allowing for a beam that is convergent downstream of the nozzle exit.Materials and methodsWe model the angular, spatial and energy distributions of the beam phase space at the nozzle exit with single Gaussians, controlled by seven energy dependent parameters. The parameters were determined from measured profiles and depth dose distributions. Verification of the beam model was done by comparing measured and GATE acquired relative dose distributions, using plan specific log files from the machine to specify beam spot positions and energy.ResultsGATE-based simulations with the acquired beam model could accurately reproduce the measured data. The gamma index analysis comparing simulated and measured dose distributions resulted in >95% global gamma index pass rates (3%/2 mm) for all depths.ConclusionThe developed beam model was found to be sufficiently accurate for use with GATE e.g. for applications in quality assurance (QA) or patient motion studies with the IBA pencil beam scanning dedicated nozzles.     

Wax boluses and accuracy of EBT and RTQA radiochromic film detectors in radiotherapy with the JINR Phasotron proton beam

Aim

To present the results obtained using radiochromic films EBT and RTQA 1010P for the reconstruction the dose distributions for targets irradiated by proton beam and modified by wax boluses.

Background

In Medico-Technical Complex at the Joint Institute for Nuclear Research in Dubna implemented technology of wax boluses.

Materials and methods

Wax boluses are easier to make and they give better dose distributions than boluses made from modeling clay previously used at our center. We irradiated two imaginary targets, one shaped as a cylinder and the other one as two cuboids. The evaluated calibration curve was used for calculation of the dose distributions measured by the EBT and RTQA radiochromic film. In both cases, the measured dose distributions were compared to the dose distributions calculated by the treatment planning system (TPS). We also compared dose distributions using three different conformity indices at a 95% isodose.

Results

Better target coverage and better compliance of measurements (semiconductor detectors and radiochromic films) with calculated doses was obtained for cylindrical target than for cuboidal target. The 95% isodose covered well the tumor for both target shapes, while for cuboidal target larger volume around the target received therapeutic dose, due to the complicated target shape. The use wax boluses provided to be effective tool in modifying proton beam to achieve appropriate shape of isodose distribution.

Conclusion

EBT film yielded the best visual matching. Both EBT and RTQA films confirmed good conformity between calculated and measured doses, thus confirming that wax boluses used to modify the proton beam resulted in good dose distributions.     

Transversal dose distribution optimization for laser-accelerated proton beam medical applications by means of Geant4

The main purpose of this paper is to quantitatively study the possibility of delivering dose distributions of clinical relevance with laser-driven proton beams. A Monte Carlo application has been developed with the Geant4 toolkit, simulating the ELIMED (MEDical and multidisciplinary application at ELI-Beamlines) transport and dosimetry beam line which is being currently installed at the ELI-Beamlines in Prague (CZ). The beam line will be used to perform irradiations for multidisciplinary studies, with the purpose of demonstrating the possible use of optically accelerated ion beams for therapeutic purposes. The ELIMED Geant4-based application, already validated against reference transport codes, accurately simulates each single element of the beam line, necessary to collect the accelerated beams and to select them in energy. Transversal dose distributions at the irradiation point have been studied and optimized to try to quantitatively answer the question if such kind of beam lines, and specifically the systems developed for ELIMED in Prague, will be actually able to transport ion beams not only for multidisciplinary applications, such as pitcher-catcher nuclear reactions (e.g. neutrons), PIXE analysis for cultural heritage and space radiation, but also for delivering dose patterns of clinical relevance in a future perspective of possible medical applications.     

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.     

Evaluations of a flat-panel based compact daily quality assurance device for proton pencil beam scanning (PBS) system

PurposeTo evaluate the flat-panel detector quenching effect and clinical usability of a flat-panel based compact QA device for PBS daily constancy measurements.Materials & MethodThe QA device, named Sphinx Compact, is composed of a 20x20 cm² flat-panel imager mounted on a portable frame with removable plastic modules for constancy checks of proton energy (100 MeV, 150 MeV, 200 MeV), Spread-Out-Bragg-Peak (SOBP) profile, and machine output. The potential quenching effect of the flat-panel detector was evaluated. Daily PBS QA tests of X-ray/proton isocenter coincidence, the constancy of proton spot position and sigma as well as the energy of pristine proton beam, and the flatness of SOBP proton beam through the 'transformed' profile were performed and analyzed. Furthermore, the sensitivity of detecting energy changes of pristine proton beam was also evaluated.ResultsThe quenching effect was observed at depths near the pristine peak regions. The flat-panel measured range of the distal 80% is within 0.9 mm to the defined ranges of the delivered proton beams. X-ray/proton isocenter coincidence tests demonstrated maximum mismatch of 0.3 mm between the two isocenters. The device can detect 0.1 mm change of spot position and 0.1 MeV energy changes of pristine proton beams. The measured transformed SOBP beam profile through the wedge module rendered as flat.ConclusionsEven though the flat-panel detector exhibited quenching effect at the Bragg peak region, the proton range can still be accurately measured. The device can fulfill the requirements of the daily QA tests recommended by the AAPM TG224 Report.     

A library of recombinant Babesia microti cell surface and secreted proteins for diagnostics discovery and reverse vaccinology

Human babesiosis is an emerging tick-borne parasitic disease and blood transfusion-transmitted infection primarily caused by the apicomplexan parasite, Babesia microti. There is no licensed vaccine for B. microti and the development of a reliable serological screening test would contribute to ensuring the safety of the donated blood supply. The recent sequencing of the B. microti genome has revealed many novel genes encoding proteins that can now be tested for their suitability as subunit vaccine candidates and diagnostic serological markers. Extracellular proteins are considered excellent vaccine candidates and serological markers because they are directly exposed to the host humoral immune system, but can be challenging to express as soluble recombinant proteins. We have recently developed an approach based on a mammalian expression system that can produce large panels of functional recombinant cell surface and secreted parasite proteins. Here, we use the B. microti genome sequence to identify 54 genes that are predicted to encode surface-displayed and secreted proteins expressed during the blood stages, and show that 41 (76%) are expressed using our method at detectable levels. We demonstrate that the proteins contain conformational, heat-labile, epitopes and use them to serologically profile the kinetics of the humoral immune responses to two strains of B. microti in a murine infection model. Using sera from validated human infections, we show a concordance in the host antibody responses to B. microti infections in mouse and human hosts. Finally, we show that BmSA1 expressed in mammalian cells can elicit high antibody titres in vaccinated mice using a human-compatible adjuvant but these antibodies did not affect the pathology of infection in vivo. Our library of recombinant B. microti cell surface and secreted antigens constitutes a valuable resource that could contribute to the development of a serological diagnostic test, vaccines, and elucidate the molecular basis of host-parasite interactions.     

Redox control of proton transfers in membrane b-type cytochromes: an absorption and resonance Raman study on bis(imidazole) and bis(imidazolate) model complexes of iron-protoporphyrin

Optical absorption spectra and resonance Raman (RR) spectra, obtained with Soret excitation, are reported for bis(imidazole) and bis(imidazolate) complexes of iron(II)- and iron(III)-protoporphyrin IX, prepared in aqueous conditions. Perdeuteration experiments on the axial ligands permitted the assignment of the symmetric Fe-(ligand)₂ stretching mode of Fe[x]PP(L)₂ to RR bands at 203 (x = II; L = ImH), 212 (x = II; L = Im^–), 201 (x = III; L = ImH) and 226 cm^–1 (x = III; L = Im^–). These frequency differences indicate a strengthening of the axial bonds when the imidazole deprotonations occur. The larger difference observed for the ferric derivatives reflects the stronger -donor capability of the Im^– anion for iron(III) over iron(II). For the ferrous derivatives, the frequencies of several skeletal porphyrin modes (₄, ₁₀, ₁₁ and ₃₈) are downshifted by 2–10 cm^–1 upon deprotonation of the ligands. This effect corresponds to an increased back-bonding from the metal atom to the porphyrin ring when the axial ligand decreases its -acid strength. Bringing further support to this interpretation, an inverse linear relationship is established between the frequencies of (Fe(Il)-L₂) and ₁₁. This correlation is expected to monitor the overall H-bonding state of histidine ligands of reduced cytochromes b. On the other hand, absorption measurements have characterized large pK_a differences for the sequential imidazole ionizations of Fe[x]PP(ImH)₂ in aqueous cetyltrimethylammonium bromide (9.0 and 10.8 for x = 111; 13.0 and 14.1 for x = II). These titrations show that Fe(II)PP(Im^–)₂ and Fe(III)PP(ImH)₂ are good proton-acceptor and proton-donor, respectively, and suggest a model by which heme, located in a favorable environment inside a cytochrome, could couple a cycle of electron transfer with a proton transfer. Based on sequence data and structural models, it is further proposed that, in several membrane cytochromes b (b, b ₆, b ₅₅₉), a positively charged amino acid residue and an imidazolate ligand of the ferriheme could form an ion pair involved in a redox control of proton transfer.Abbreviations RR resonance Raman - EPR electron paramagnetic resonance - PP protoporphyrin IX - ImH imidazole - Im^– imidazolate - Im* imidazole or imidazolate - 1MeIm 1-methylimidazole - HisH histidine - His^– histidinate - CTABr cetyltrimethylammonium bromide - NaDS sodium dodecylsulphate - VLP very low potential - LP low potential - HP high potential     

Calibration of MTT assay in proton beams using radiochromic films

PurposeThis study provides methodology of calibrating as well as controlling the output for an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay irradiated in a low energy proton beam using EBT3-model GAFCHROMIC^TM film, without correcting for quenching effect.MethodsA calibrated Markus ionization chamber was used to measure the depth dose and beam output for 26.5 MeV protons produced by a CS30 cyclotron. A time-controlled aluminum cylinder was added in front of the horizontal beam-exit serving as a radiation shutter. Following the TRS-398 reference dosimetry protocol for proton beams, the output was calibrated in water at a reference depth of 3 mm. EBT3 film was calibrated for doses up to 8 Gy at the same depth. To verify the dose distribution for each 96-well MTT assay plate, EBT3 film was placed at the reference depth during irradiation and cell doses were scaled by measured percent depth dose (PDD) data.ResultsThe radiochromic film dosimetry system in this study provides dose measurements with an uncertainty better than 3.3% for doses higher than 1 Gy. From a single exposure and utilizing the Gaussian shape of the beam, multiple dose points can be obtained within different wells of the same plate ranging from 6.9 Gy (sigma ∼4%) in the central well, and 2 Gy (sigma ∼8%) for wells positioned closer to the periphery.ConclusionsWe described a methodology for radiochromic film-based dose monitoring system, using low-energy protons, which can be used for the MTT assay in any proton beam, except within Bragg peak region.     

Accurate proton treatment planning for pencil beam crossing titanium fixation implants

PurposeTo present a planning strategy for proton pencil-beam scanning when titanium implants need to be crossed by the beam.MethodsWe addressed three issues: the implementation of a CT calibration curve to assign to titanium the correct stopping power; the effect of artefacts on CT images and their reduction by a dedicated algorithm; the differences in dose computation depending on the dose engine, pencil-beam vs Monte-Carlo algorithms. We performed measurement tests on a simple cylinder phantom and on a real implant. These phantoms were irradiated with three geometries (single spots, uniform mono-energetic layer and uniform box), measuring the exit dose either by radio-chromic film or multi-layer ionization chamber. The procedure was then applied on two patients treated for chordoma.ResultsWe had to set in the calibration curve a mass density equal to 4.37 g/cm³ to saturated Hounsfield Units, in order to have the correct stopping power assigned to titanium in TPS. CT artefact reduction algorithm allowed a better reconstruction of the shape and size of the implant. Monte-Carlo resulted accurate in computing the dose distribution whereas the pencil-beam algorithm failed due to sharp density interfaces between titanium and the surrounding material. Finally, the treatment plans obtained on two patients showed the impact of the dose engine algorithm, with 10–20% differences between pencil-beam and Monte-Carlo in small regions distally to the titanium screws.ConclusionThe described combination of CT calibration, artefacts reduction and Monte-Carlo computation provides a reliable methodology to compute dose in patients with titanium implants.     

Commissioning of the 4-D treatment delivery system for organ motion management in synchrotron-based scanning ion beams

PurposeThe aim of this work was the commissioning of delivery procedures for the treatment of moving targets in scanning pencil beam hadrontherapy.MethodsEBT3 films fixed to the Anzai Respiratory Phantom were exposed to carbon ion scanned homogeneous fields (E = 332 MeV/u). To evaluate the interplay effect, field size and flatness for 3 different scenarios were compared to static condition: gated irradiation or repainting alone and combination of both. Respiratory signal was provided by Anzai pressure sensor or optical tracking system (OTS). End-exhale phase and 1 s gating window were chosen (2.5 mm residual motion). Dose measurements were performed using a PinPoint ionization chamber inserted into the Brainlab ET Gating Phantom. A sub-set of tests was also performed using proton beams.ResultsThe combination of gating technique and repainting (N = 5) showed excellent results (6.1% vs 4.3% flatness, identical field size and dose deviation within 1.3%). Treatment delivery time was acceptable. Dose homogeneity for gated irradiation alone was poor. Both Anzai sensor and OTS appeared suitable for providing respiratory signal. Comparisons between protons and carbon ions showed that larger beam spot sizes represent more favorable condition for minimizing motion effect.ConclusionResults of measurements performed on different phantoms showed that the combination of gating and layered repainting is suitable to treat moving targets using scanning ion beams. Abdominal compression using thermoplastic masks, together with multi-field planning approach and multi-fractionation, have also been assessed as additional strategies to mitigate the effect of patient respiration in the clinical practice.     

Effect of brassinosteroids on growth and proton extrusion in the alga Chlorella vulgaris Beijerinck (Chlorophyceae)

Brassinolide, as a plant hormone, promotes growth of a number of plant species. Similar effects are induced by its epimer 24-epibrassinolide. In this paper we discuss the effects of brassinosteroids on the growth and proton extrusion in the green alga Chlorella vulgaris (Chlorophyceae). At concentrations between 10^–15 and 10^–8 m, brassinolide and 24-epibrassinolide induce a significant stimulation of growth and H⁺ extrusion. The growth was associated with an increase in the capability of algal cells to acidify the medium, where brassinolide is biologically more active than 24-epibrassinolide.Abbreviations BL brassinolide - BR(s) brassinosteroid(s) - epiBL 24-epibrassinolide - DW dry weight - IAA indole-3-acetic acid     

Phenomenological and molecular models of biological proton transfers

In this paper, the main models describing the transfer of a proton in a molecular system are presented. Models valid when the intersite coupling is weak (non-adiabatic and electronically adiabatic regimes) and strong (adiabatic regime) are described. We distinguish molecular models in which the rate constant is obtained by considering explicitly various degrees of freedom of the system and simpler, phenomenological models built to account for the kinetic isotope effect. The relations between the various models are discussed. Their application to specific systems is illustrated by several studies reported in the literature, with a special emphasis on biological systems.     

The effective molarity (EM) puzzle in proton transfer reactions

The DFT and HF calculation results for the proton transfer reactions of three different systems reveal that the reaction mechanism (transfer of a proton to a nucleophile) is largely determined by the distance between the two reactive centers (r).Systems with relatively large r values tend to abstract a proton from a molecule of water, whereas, these with a relatively small r values prefer to be engaged intramolecularly and their interaction with water is only via hydrogen bonding. Further, the results indicate that the effective molarity (log EM) for an intramolecular process is strongly correlated with the distance between the two reacting centers (r) in accordance with Menger’s “spatiotemporal hypothesis”.     

A machine learning-based framework for delivery error prediction in proton pencil beam scanning using irradiation log-files

PurposeThis study aims to investigate the use of machine learning models for delivery error prediction in proton pencil beam scanning (PBS) delivery.MethodsA dataset of planned and delivered PBS spot parameters was generated from a set of 20 prostate patient treatments. Planned spot parameters (spot position, MU and energy) were extracted from the treatment planning system (TPS) for each beam. Delivered spot parameters were extracted from irradiation log-files for each beam delivery following treatment. The dataset was used as a training dataset for three machine learning models which were trained to predict delivered spot parameters based on planned parameters. K-fold cross validation was employed for hyper-parameter tuning and model selection where the mean absolute error (MAE) was used as the model evaluation metric. The model with lowest MAE was then selected to generate a predicted dose distribution for a test prostate patient within a commercial TPS.ResultsAnalysis of the spot position delivery error between planned and delivered values resulted in standard deviations of 0.39 mm and 0.44 mm for x and y spot positions respectively. Prediction error standard deviation values of spot positions using the selected model were 0.22 mm and 0.11 mm for x and y spot positions respectively. Finally, a three-way comparison of dose distributions and DVH values for select OARs indicates that the random-forest-predicted dose distribution within the test prostate patient was in closer agreement to the delivered dose distribution than the planned distribution.ConclusionsPBS delivery error can be accurately predicted using machine learning techniques.