Computational approaches in the estimation of radiobiological damage for human-malignant cells irradiated with clinical proton and carbon beams.

PURPOSE: The use of Monte Carlo (MC) simulations capable of reproducing radiobiological effects of ionising radiation on human cell lines is of great importance, especially for cases involving protons and heavier ion beams. In the latter, huge uncertainties can arise mainly related to the effects of the secondary particles produced in the beam-tissue interaction. This paper reports on a detailed MC study performed using Geant4-based approach on three cancer cell lines, the HTB-177, CRL-5876 and MCF-7, that were previously irradiated with therapeutic proton and carbon ion beams. METHODS: A Geant4-based approach used jointly with analytical calculations has been developed to provide a more realistic estimation of the radiobiological damage produced by proton and carbon beams in tissues, reproducing available data obtained from in vitro cell irradiations. The MC "Hadrontherapy" Geant4 application and the Local Effect Model: LEM I, LEM II and LEM III coupled with the different numerical approaches: RapidRusso (RR) and RapidScholz (RS) were used in the study. RESULTS: Experimental survival curves are compared with those evaluated using the highlighted Geant4 MC-based approach via chi-square statistical analysis, for the combinations of radiobiological models and numerical approaches, as outlined above. CONCLUSION: This study has presented a comparison of the survival data from MC simulations to experimental survival data for three cancer cell lines. An overall best level of agreement was obtained for the HTB-177 cells.

Bragg Curve Detection of Low-Energy Protons by Radiophotoluminescence Imaging in Lithium Fluoride Thin Films.

Lithium fluoride (LiF) crystals and thin films are utilized as radiation detectors for energy diagnostics of proton beams. This is achieved by analyzing the Bragg curves in LiF obtained by imaging the radiophotoluminescence of color centers created by protons. In LiF crystals, the Bragg peak depth increases superlinearly with the particle energy. A previous study has shown that, when 35 MeV protons impinge at grazing incidence onto LiF films deposited on Si(100) substrates, the Bragg peak in the films is located at the depth where it would be found in Si rather than in LiF due to multiple Coulomb scattering. In this paper, Monte Carlo simulations of proton irradiations in the 1-8 MeV energy range are performed and compared to experimental Bragg curves in optically transparent LiF films on Si(100) substrates. Our study focuses on this energy range because, as energy increases, the Bragg peak gradually shifts from the depth in LiF to that in Si. The impact of grazing incidence angle, LiF packing density, and film thickness on shaping the Bragg curve in the film is examined. At energies higher than 8 MeV, all these quantities must be considered, although the effect of packing density plays a minor role.

Simultaneous imaging of luminescence and prompt x-rays during irradiation with spot-scanning proton beams at clinical dose level.

Prompt x-ray imaging is a promising method for observing the beam shape from outside a subject. However, its distribution is different from dose distribution, and thus a comparison with the dose is required. Meanwhile, luminescence imaging of water is a possible method for imaging the dose distribution. Consequently, we performed simultaneous imaging of luminescence and prompt x-rays during irradiation by proton beams to compare the distributions between these two different imaging methods. Optical imaging of water was conducted with spot-scanning proton beams at clinical dose level during irradiation to a fluorescein (FS) water phantom set in a black box. Prompt x-ray imaging was also conducted simultaneously from outside the black box using a developed x-ray camera during proton beam irradiation to the phantom. We measured images of the luminescence of FS water and prompt x-rays for various types of proton beams, including pencil beams, spread-out Bragg peak (SOBP) beams, and clinically used therapy beams. After the imaging, ranges were estimated from FS water and prompt x-rays and compared with those calculated with a treatment planning system (TPS). We could measure the prompt x-ray and FS water images simultaneously for all types of proton beams. The ranges estimated from the FS water and those calculated with the TPS closely matched, within a difference of several mm. Similar range difference was found between the results estimated from prompt x-ray images and those calculated with the TPS. We confirmed that the simultaneous imaging of luminescence and prompt x-rays were possible during irradiation with spot-scanning proton beams at a clinical dose level. This method can be applied to range estimation as well as comparison with the dose for prompt x-ray imaging or other imaging methods used in therapy with various types of proton beams at a clinical dose level.

General Purpose Transistor Characterized as Dosimetry Sensor of Proton Beams.

A commercial pMOS transistor (MOSFET), 3N163 from Vishay (USA), has been characterized as a low-energy proton beam dosimeter. The top of the samples' housing has been removed to guarantee that protons reached the sensitive area, that is, the silicon die. Irradiations took place at the National Accelerator Centre (Seville, Spain). During irradiations, the transistors were biased to improve the sensitivity, and the silicon temperature was monitored activating the parasitic diode of the MOSFET. Bias voltages of 0, 1, 5, and 10 V were applied to four sets of three transistors, obtaining an averaged sensitivity that was linearly dependent on this voltage. In addition, the short-fading effect was studied, and the uncertainty of this effect was obtained. The bias voltage that provided an acceptable sensitivity, (11.4 ± 0.9) mV/Gy, minimizing the uncertainty due to the fading effect (-0.09 ± 0.11) Gy was 1 V for a total absorbed dose of 40 Gy. Therefore, this off-the-shelf electronic device presents promising characteristics as a dosimeter sensor for proton beams.

In situcorrection of recombination effects in ultra-high dose rate irradiations with protons.

Background.At the Center for Proton Therapy at the Paul Scherrer Institute (PSI) the delivery of proton radiation is controlled via gas-based ionization chambers: the beam is turned off when a certain amount of preset charge has been collected. At low dose rates the charge collection efficiency in these detectors is unity, at ultra-high dose rates it is less due to induced charge recombination effects. If not corrected, the latter would lead to an overdosage.Purpose.In the scope of this work, we developed a novel approach to anin situcharge recombination correction for our dose defining detectors, when irradiated with a proton beam at ultra-high dose rates. This approach is based on the Two-Voltage-Method.Methods.We have translated this method to two separate devices operated simultaneously at different conditions. By doing so, the charge collection losses can be corrected directly and without the need for empirical correction values. This approach has been tested at ultra-high dose rates; proton beam was delivered by the COMET cyclotron to Gantry 1 at PSI.Results.We were able to correct the charge losses caused by recombination effects at local beam currents of approximately 700 nA (i.e. instantaneous dose rate of 3600 Gy s-1at isocenter). The corrected collected charges in our gaseous detectors were compared against recombination-free measurements with a Faraday cup. The ratio of both quantities shows no significant dose rate dependence within their respective combined uncertainties.Conclusions. Correcting recombination effects in our gas-based detectors with the novel method greatly eases the handling of Gantry 1 as 'FLASH test bench'. Not only is the application of a preset dose more accurate compared to using an empirical correction curve, also the re-determination of empirical correction curves in the case of a beam phase space change can be omitted.

Application of a simple DNA damage model developed for electrons to proton irradiation.

Proton beam therapy allows irradiating tumor volumes with reduced side effects on normal tissues with respect to conventional x-ray radiotherapy. Biological effects such as cell killing after proton beam irradiations depend on the proton kinetic energy, which is intrinsically related to early DNA damage induction. As such, DNA damage estimation based on Monte Carlo simulations is a research topic of worldwide interest. Such simulation is a mean of investigating the mechanisms of DNA strand break formations. However, past modellings considering chemical processes and DNA structures require long calculation times. Particle and heavy ion transport system (PHITS) is one of the general-purpose Monte Carlo codes that can simulate track structure of protons, meanwhile cannot handle radical dynamics simulation in liquid water. It also includes a simple model enabling the efficient estimation of DNA damage yields only from the spatial distribution of ionizations and excitations without DNA geometry, which was originally developed for electron track-structure simulations. In this study, we investigated the potential application of the model to protons without any modification. The yields of single-strand breaks, double-strand breaks (DSBs) and the complex DSBs were assessed as functions of the proton kinetic energy. The PHITS-based estimation showed that the DSB yields increased as the linear energy transfer (LET) increased, and reproduced the experimental and simulated yields of various DNA damage types induced by protons with LET up to about 30 keVµm-1. These results suggest that the current DNA damage model implemented in PHITS is sufficient for estimating DNA lesion yields induced after protons irradiation except at very low energies (below 1 MeV). This model contributes to evaluating early biological impacts in radiation therapy.

Investigating the lateral dose response functions of point detectors in proton beams.

Objective. Point detector measurements in proton fields are perturbed by the volume effect originating from geometrical volume-averaging within the extended detector's sensitive volume and density perturbations by non-water equivalent detector components. Detector specific lateral dose response functionsK(x) can be used to characterize the volume effect within the framework of a mathematical convolution model, whereK(x) is the convolution kernel transforming the true dose profileD(x) into the measured signal profile of a detectorM(x). The aim of this work is to investigateK(x) for detectors in proton beams.Approach. TheK(x) for five detectors were determined by iterative deconvolution of measurements ofD(x) andM(x) profiles at 2 cm water equivalent depth of a narrow 150 MeV proton beam. Monte Carlo simulations were carried out for two selected detectors to investigate a potential energy dependence, and to study the contribution of volume-averaging and density perturbation to the volume effect.Main results. The Monte Carlo simulated and experimentally determinedK(x) agree within 2.1% of the maximum value. Further simulations demonstrate that the main contribution to the volume effect is volume-averaging. The results indicate that an energy or depth dependence ofK(x) is almost negligible in proton beams. While the signal reduction from a Semiflex 3D ionization chamber in the center of a gaussian shaped field with 2 mm sigma is 32% for photons, it is 15% for protons. When measuring the field with a microDiamond the trend is less pronounced and reversed with a signal reduction for protons of 3.9% and photons of 1.9%.Significance. The determinedK(x) can be applied to characterize the influence of the volume effect on detectors measured signal profiles at all clinical proton energies and measurement depths. The functions can be used to derive the actual dose distribution from point detector measurements.

Unexpected 13N concentrations in ISIS synchrotron room air.

The specific activity of air in the large open room housing the 800-MeV proton synchrotron of the ISIS Spallation Neutron and Muon Source has been measured. Air from several positions within the ISIS synchrotron room was sucked through a long flexible tube, and run past a shielded HPGe gamma-ray detector outside the synchrotron room. In spite of an expectation that 13N should be the largest component of the overall activity in the air, the results of the measurements are consistent with the presence in the air of 11C and 41Ar only, and suggest that the activity in the air is mostly created not in the synchrotron room itself but in the massive shielding monoliths around the neutron-producing targets, monoliths through which ventilation air is drawn into the synchrotron room. Typical specific activities of 11C and 41Ar in the air in the synchrotron room are ∼0.10 and ∼0.03 Bq cm-3 respectively, the upper limit for 13N being at most ∼0.01 Bq cm-3.

Experimental determination ofkQfactors for two types of ionization chambers in scanned proton beams.

Objective.Experimental determination of beam qualitykQfactors for two types of Farmer ionization chambers, NE2571 and IBA FC65-G, in a scanned proton beam for three nominal energies (140 MeV, 180 MeV and 220 MeV) based on water calorimetry.Approach.Beam quality correction factors were determined comparing the results obtained with water calorimetry and ionometry. Water calorimetry was performed to determine the absorbed dose at a depth of measurement in water of 5 g cm-2, limited by the extension of the calorimeter glass vessel used. For the ionometry, two chambers of each type were included in the study. The ionization chambers were calibrated in terms of absorbed dose to water in60Co at the Swedish Secondary Standard Dosimetry Laboratory, directly traceable to the BIPM, and were used according to the IAEA TRS-398 Code of Practice.Main results. ThekQvalues determined in the present work have been compared with the values tabulated in TRS-398 and its forthcoming update and also with those obtained in previous water calorimetric measurements and Monte Carlo calculations. All results were found to agree within the combined uncertainties of the different data.Significance. It is expected that the present work will serve as an experimental contribution tokQ-factors for the two chamber types and three scanned proton beam qualities used.

Mutagenic Effect of Proton Beams Characterized by Phenotypic Analysis and Whole Genome Sequencing in Arabidopsis.

Protons may have contributed to the evolution of plants as a major component of cosmic-rays and also have been used for mutagenesis in plants. Although the mutagenic effect of protons has been well-characterized in animals, no comprehensive phenotypic and genomic analyses has been reported in plants. Here, we investigated the phenotypes and whole genome sequences of Arabidopsis M2 lines derived by irradiation with proton beams and gamma-rays, to determine unique characteristics of proton beams in mutagenesis. We found that mutation frequency was dependent on the irradiation doses of both proton beams and gamma-rays. On the basis of the relationship between survival and mutation rates, we hypothesized that there may be a mutation rate threshold for survived individuals after irradiation. There were no significant differences between the total mutation rates in groups derived using proton beam or gamma-ray irradiation at doses that had similar impacts on survival rate. However, proton beam irradiation resulted in a broader mutant phenotype spectrum than gamma-ray irradiation, and proton beams generated more DNA structural variations (SVs) than gamma-rays. The most frequent SV was inversion. Most of the inversion junctions contained sequences with microhomology and were associated with the deletion of only a few nucleotides, which implies that preferential use of microhomology in non-homologous end joining was likely to be responsible for the SVs. These results show that protons, as particles with low linear energy transfer (LET), have unique characteristics in mutagenesis that partially overlap with those of low-LET gamma-rays and high-LET heavy ions in different respects.

High-Energy Proton-Beam-Induced Polymerization/Oxygenation of Hydroxynaphthalenes on Meteorites and Nitrogen Transfer from Urea: Modeling Insoluble Organic Matter?

Formation and structural modification of oxygenated polycyclic aromatic hydrocarbons (oxyPAHs) by UV irradiation on minerals have recently been proposed as a possible channel of PAH transformation in astrochemical and prebiotic scenarios of possible relevance for the origin of life. Herein, it is demonstrated that high-energy proton-beam irradiation in the presence of various meteorites, including stony iron, achondrite, and chondrite types, promotes the conversion of two representative oxyPAH compounds, 1-naphthol and 1,8-dihydroxynaphthalene, to complex mixtures of oxygenated and oligomeric derivatives. The main identified products include polyhydroxy derivatives, isomeric dimers encompassing benzofuran and benzopyran scaffolds, and, notably, a range of quinones and perylene derivatives. Addition of urea, a prebiotically relevant chemical precursor, expanded the range of identified species to include, among others, quinone diimines. Proton-beam irradiation of oxyPAH modulated by nitrogen-containing compounds such as urea is proposed as a possible contributory mechanism for the formation and processing of insoluble organic matter in meteorites and in prebiotic processes.

Preparation of a radiobiology beam line at the 18 MeV proton cyclotron facility at CNA.

Proton therapy has gained interest in recent years due to its excellent clinical outcomes. However, the lack of accurate biological data, especially in the Bragg peak region of clinical beams, makes it difficult to implement biophysically optimized treatment plans in clinical practice. In this context, low energy proton accelerator facilities provide the perfect environment to collect good radiobiological data, as they can produce high LET beams with narrow energy distributions. This study presents the radiobiology beam line that has been designed at the 18 MeV proton cyclotron facility at the National Centre of Accelerators (CNA, Seville, Spain), to perform irradiations of mono-layer cell cultures. To ensure that all the cells receive the same dose with a suitable dose rate, low beam intensities and broad and homogeneous beam profiles are necessary. To do so, at the CNA an unfocused beam has been used, broadened with a 500 µm thick aluminium scattering foil. Homogeneous dose profiles, with deviations lower than 10% have been obtained over a circular surface of 35 mm diameter for an incident average energy of 12.8 MeV. Further, a Monte Carlo simulation of the beam line has been developed with Geant4, and benchmarked towards experimental measurements, with differences generally below 1%. Once validated, the code has been used, together with an ionization chamber, for dosimetry studies, to characterize the beam and monitor the dose. Finally, cultures of Human Bone Osteosarcoma cells (U2OS) have been successfully irradiated at the radiobiology beam line, investigating the effects of radiation in terms of DNA damage induction.

An in silico planning study comparing doses and estimated risk of toxicity in 3D-CRT, IMRT and proton beam therapy of patients with thymic tumours.

PURPOSE: To compare the dose distributions produced in patients (pts) treated for thymic tumours with spot-scanning proton beam therapy (PBT) implemented with single-field uniform dose (SFUD), intensity-modulated radiation therapy (IMRT) and three-dimensional conformal photon-beam based radiotherapy (3D-CRT). METHODS: Twelve pts, treated with 3D-CRT, were included. Alternative IMRT and SFUD plans were constructed. The IMRT plans were created using a setup with beams incident from 5 to 6 different angles. For the SFUD plans, a field-specific planning target volume (PTV) was created for each patient and a clinical target volume (CTV)-based robust optimization was performed. A robustness evaluation was performed for the CTV for all SFUD plans. A dosimetric evaluation was conducted for the doses to the CTV and organs at risk (OARs) for all plans. The normal tissue complication probability (NTCP), for different endpoints, was calculated using the Lyman-Kutcher-Burman (LKB)-model and compared between plans. RESULTS: SFUD was associated with significantly lower mean doses to the oesophagus, the heart, the left anterior descending coronary artery (LAD), lungs and breasts compared to 3D-CRT and IMRT. The maximum dose given to the spinal cord was significantly lower with SFUD. The risks for pneumonitis, esophagitis and myelopathy were significantly reduced in the SFUD plans. CONCLUSIONS: The present study showed dosimetric advantages of using scanned-beam PBT for the treatment of thymic tumours, as compared to 3D-CRT and IMRT, especially in regard to lower doses to the oesophagus and lungs. The risk of toxicity was reduced with SFUD.

Comparison of gastric-cancer radiotherapy performed with volumetric modulated arc therapy or single-field uniform-dose proton therapy.

BACKGROUND: Proton-beam therapy of large abdominal cancers has been questioned due to the large variations in tissue density in the abdomen. The aim of this study was to evaluate the importance of these variations for the dose distributions produced in adjuvant radiotherapy of gastric cancer (GC), implemented with photon-based volumetric modulated arc therapy (VMAT) or with proton-beam single-field uniform-dose (SFUD) method. MATERIAL AND METHODS: Eight GC patients were included in this study. For each patient, a VMAT- and an SFUD-plan were created. The prescription dose was 45 Gy (IsoE) given in 25 fractions. The plans were prepared on the original CT studies and the doses were thereafter recalculated on two modified CT studies (one with extra water filling and the other with expanded abdominal air-cavity volumes). RESULTS: Compared to the original VMAT plans, the SFUD plans resulted in reduced median values for the V18 of the left kidney (26%), the liver mean dose (14.8 Gy (IsoE)) and the maximum dose given to the spinal cord (26.6 Gy (IsoE)). However, the PTV coverage decreased when the SFUD plans were recalculated on CT sets with extra air- (86%) and water-filling (87%). The added water filling only led to minor dosimetric changes for the OARs, but the extra air caused significant increases of the median values of V18 for the right and left kidneys (10% and 12%, respectively) and of V10 for the liver (12%). The density changes influenced the dose distributions in the VMAT plans to a minor extent. CONCLUSIONS: SFUD was found to be superior to VMAT for the plans prepared on the original CT sets. However, SFUD was inferior to VMAT for the modified CT sets.

Localized radiation necrosis model in mouse brain using proton ion beams.

Brain radiation necrosis is the most serious late adverse event that occurs after 6 months following radiation therapy. Effective treatment for this irreversible brain necrosis has not been established yet. This study tries to establish brain radiation necrosis mouse model using proton or helium beam. The right cerebral hemispheres of C57BL/6J mouse brains were irradiated at doses of 40, 50, 60 Gy with charged particles. In 60 Gy group, brain necrosis that recapitulates human disease was detected after 8 months.

Function of chromatin structure and dynamics in DNA damage, repair and misrepair: γ-rays and protons in action.

According to their physical characteristics, protons and ion beams promise a revolution in cancer radiotherapy. Curing protocols however reflect rather the empirical knowledge than experimental data on DNA repair. This especially holds for the spatio-temporal organization of repair processes in the context of higher-order chromatin structure-the problematics addressed in this work. The consequences for the mechanism of chromosomal translocations are compared for gamma rays and proton beams.

Ionization and electron capture in ion-molecule collisions: classical (CTMC) and semiclassical calculations.

Total cross-sections for electron capture and electron production in proton collisions with N2, CO and H2O, are evaluated using a classical trajectory Monte Carlo treatment for collision energies between 30 and 3000 keV. A semiclassical close-coupling treatment has been also employed for proton collisions with H2O, to discuss the accuracy of the CTMC treatment. Singly differential cross-sections for electron production have been also evaluated. Total and differential cross are compared with experimental data.

Feasibility of Using Distal Endpoints for In-room PET Range Verification of Proton Therapy.

In an effort to verify the dose delivery in proton therapy, Positron Emission Tomography (PET) scans have been employed to measure the distribution of ß+ radioactivity produced from nuclear reactions of the protons with native nuclei. Because the dose and PET distributions are difficult to compare directly, the range verification is currently carried out by comparing measured and Monte Carlo (MC) simulation predicted PET distributions. In order to reduce the reliance on MC, simulated PET (simPET) and dose distal endpoints were compared to explore the feasibility of using distal endpoints for in-room PET range verification. MC simulations were generated for six head and neck patients with corrections for radiological decay, biological washout, and PET resolution. One-dimensional profiles of the dose and simPET were examined along the direction of the beam and covering the cross section of the beam. The chosen endpoints of the simPET (x-intercept of the linear fit to the distal falloff) and planned dose (20-50% of maximum dose) correspond to where most of the protons are below the threshold energy for the nuclear reactions. The difference in endpoint range between the distal surfaces of the dose and MC-PET were compared and the spread of range differences were assessed. Among the six patients, the mean difference between MC-PET and dose depth was found to be -1.6 mm to +0.5 mm between patients, with a standard deviation of 1.1 to 4.0 mm across the individual beams. In clinical practice, regions with deviations beyond the safety margin need to be examined more closely and can potentially lead to adjustments to the treatment plan.

The qweak experiment: A search for new physics at the tev scale by measurement of the proton's weak charge / El experimento qweak: una búsqueda de nueva física en la escala de tev mediante la medición de la carga débil del protón

El acoplamiento observado del protón al bosón-Z, es decir, la «carga débil¼ del protón, varía con la escala de distancia. Experimentos de alta energía han medido con gran precisión el acoplamiento a cortas distancias. Qweakrealizará la medición a una transferencia de momentum de sólo 0,3 (GeV/c)2. El «corrimiento¼ del acoplamiento de altas a bajas energías se puede calcular corrigiendo por efectos de nubes de partículas virtuales en el vacío. Debido a que las correcciones dependen de todas las partículas que existen en la naturaleza, y no únicamente de las descubiertas hasta la fecha, cualquier diferencia entre la carga débil medida a bajas energías y la calculada, podría indicar la existencia de nueva física. Una medición de Qweak al 4% sería sensible a nueva física en la escala de unos cuantos TeV. El experimento Qweak aprovechará el hecho de que el poder analizador longitudinal (que viola la paridad), Az, es proporcional a la carga débil del protón. El experimento intentará medir Az (cuyo valor predicho es -0,3 ppm) con una incertidumbre combinada, estadística y sistemática, del 2,2% correspondiente a una incertidumbre total del 4% en Qweak. Esto requiere de una precisión estadística de 5 x , que se puede alcanzar en 2, 200 horas con un haz de electrones de 180 µA, polarizado al 85%, incidente sobre un blanco de hidrógeno líquido de 0,35 m. Un sistema sincronizado de adquisición de datos integrará las señales de corriente del detector sobre cada estado de espín y extraerá la componente que viola paridad, correlacionada con la helicidad.

The observed coupling of the proton to the Z-boson, i.e. the «weak charge¼ of the proton, varies with distance scale. The coupling has already been accurately measured at short distances by high energy experiments. Qweak will make the measurement at a momentum transfer of only 0.3 (GeV/c)2. The «running¼ of the coupling from high to low energy can be calculated by correcting for the effect of clouds of virtual particles in the vacuum. Because the corrections depend on all of nature’s particles, not only those which have been discovered, a difference between the calculated and measured low energy weak charge could signal new physics. A measurement of Qweak to 4% will be sensitive to new physics at the few TeVscale. The Qweak experiment will use the fact that the parity-violating longitudinal analyzing power, Az, is proportional to the proton’s weak charge. The experiment plans to measure the predicted Az of -0.3 ppm with a combined statistical and systematic uncertainty of 2.2%, corresponding to a total uncertainty of 4% in Qweak. This requires a statistical precision of 5 x , which can be achieved in 2200 hours with an 85% polarized, 180 µA electron beam incident on a 0.35 m liquid hydrogen target. A synchronous data acquisition system will integrate the detector current signals over each spin state and extract the helicity correlated, parity violating component.