PET imaging of DNA damage using (89)Zr-labelled anti-γH2AX-TAT immunoconjugates.

PURPOSE: The efficacy of most anticancer treatments, including radiotherapy, depends on an ability to cause DNA double-strand breaks (DSBs). Very early during the DNA damage signalling process, the histone isoform H2AX is phosphorylated to form γH2AX. With the aim of positron emission tomography (PET) imaging of DSBs, we synthesized a (89)Zr-labelled anti-γH2AX antibody, modified with the cell-penetrating peptide, TAT, which includes a nuclear localization sequence. METHODS: (89)Zr-anti-γH2AX-TAT was synthesized using EDC/NHS chemistry for TAT peptide linkage. Desferrioxamine conjugation allowed labelling with (89)Zr. Uptake and retention of (89)Zr-anti-γH2AX-TAT was evaluated in the breast adenocarcinoma cell line MDA-MB-468 in vitro or as xenografts in athymic mice. External beam irradiation was used to induce DSBs and expression of γH2AX. Since (89)Zr emits ionizing radiation, detailed radiobiological measurements were included to ensure (89)Zr-anti-γH2AX-TAT itself does not cause any additional DSBs. RESULTS: Uptake of (89)Zr-anti-γH2AX-TAT was similar to previous results using (111)In-anti-γH2AX-TAT. Retention of (89)Zr-anti-γH2AX-TAT was eightfold higher at 1 h post irradiation, in cells expressing γH2AX, compared to non-irradiated cells or to non-specific IgG control. PET imaging of mice showed higher uptake of (89)Zr-anti-γH2AX-TAT in irradiated xenografts, compared to non-irradiated or non-specific controls (12.1 ± 1.6 vs 5.2 ± 1.9 and 5.1 ± 0.8%ID/g, respectively; p < 0.0001). The mean absorbed dose to the nucleus of cells taking up (89)Zr-anti-γH2AX-TAT was twofold lower compared to (111)In-anti-γH2AX-TAT. Additional exposure of neither irradiated nor non-irradiated cells nor tissues to (89)Zr-anti-γH2AX-TAT resulted in any significant changes in the number of observable DNA DSBs, γH2AX foci or clonogenic survival. CONCLUSION: (89)Zr-anti-γH2AX-TAT allows PET imaging of DNA DSBs in a tumour xenograft mouse model.

A comprehensive Monte Carlo study of CT dose metrics proposed by the AAPM Reports 111 and 200.

PURPOSE: A Monte Carlo (MC) modeling of single axial and helical CT scan modes has been developed to compute single and accumulated dose distributions. The radiation emission characteristics of an MDCT scanner has been modeled and used to evaluate the dose deposition in infinitely long head and body PMMA phantoms. The simulated accumulated dose distributions determined the approach to equilibrium function, H(L). From these H ( L ) curves, dose-related information was calculated for different head and body clinical protocols. METHODS: The PENELOPE/penEasy package has been used to model the single axial and helical procedures and the radiation transport of photons and electrons in the phantoms. The bowtie filters, heel effect, focal-spot angle, and fan-beam geometry were incorporated. Head and body protocols with different pitch values were modeled for x-ray spectra corresponding to 80, 100, 120, and 140 kV. The analytical formulation for the single dose distributions and experimental measurements of single and accumulated dose distributions were employed to validate the MC results. The experimental dose distributions were measured with OSLDs and a thimble ion chamber inserted into PMMA phantoms. Also, the experimental values of the C T D I 100 along the center and peripheral axes of the CTDI phantom served to calibrate the simulated single and accumulated dose distributions. RESULTS: The match of the simulated dose distributions with the reference data supports the correct modeling of the heel effect and the radiation transport in the phantom material reflected in the tails of the dose distributions. The validation of the x-ray source model was done comparing the CTDI ratios between simulated, measured and CTDosimetry data. The average difference of these ratios for head and body protocols between the simulated and measured data was in the range of 13-17% and between simulated and CTDosimetry data varied 10-13%. The distributions of simulated doses and those measured with the thimble ion chamber are compatible within 3%. In this study, it was demonstrated that the efficiencies of the C T D I 100 measurements in head phantoms with nT = 20 mm and 120 kV are 80.6% and 87.8% at central and peripheral axes, respectively. In the body phantoms with n T = 40 mm and 120 kV, the efficiencies are 56.5% and 86.2% at central and peripheral axes, respectively. In general terms, the clinical parameters such as pitch, beam intensity, and voltage affect the Deq values with the increase of the pitch decreasing the Deq and the beam intensity and the voltage increasing its value. The H(L) function does not change with the pitch values, but depends on the phantom axis (central or peripheral). CONCLUSIONS: The computation of the pitch-equilibrium dose product, D ̂ eq , evidenced the limitations of the C T D I 100 method to determine the dose delivered by a CT scanner. Therefore, quantities derived from the C T D I 100 propagate this limitation. The developed MC model shows excellent compatibility with both measurements and literature quantities defined by AAPM Reports 111 and 200. These results demonstrate the robustness and versatility of the proposed modeling method.

Electronic stopping power of diamond for electrons and positrons.

We assess a new data set of mass electronic stopping powers of diamond for electrons and positrons. To this end, an optical energy-loss function (OELF) for this material is generated from available experimental dielectric properties of the valence band and photoabsorption mass attenuation coefficients, supplemented with a Drude-type analytical expression to interpolate at intermediate energies. From this synthetic OELF, a mean excitation energy equal to (88.5 ± 2.0) eV is extracted and the density-effect correction is evaluated using Fano's simplified method. These quantities then allow calculating the mass electronic stopping power of diamond for electrons and positrons by means of the relativistic Bethe formula. The present results for 1 keV-1 GeV electrons in diamond are 0.9%-3.3% smaller than those corresponding to graphite as tabulated in ICRU Report 90.

Impact of photoelectric cross section data on systematic uncertainties for Monte Carlo breast dosimetry in mammography.

Monte Carlo (MC) simulations are employed extensively in breast dosimetry studies. In the energy interval of interest in mammography energy deposition is predominantly caused by the photoelectric effect, and the corresponding cross sections used by the MC codes to model this interaction process have a direct influence on the simulation results. The present work compares two photoelectric cross section databases in order to estimate the systematic uncertainty, related to breast dosimetry, introduced by the choice of cross sections for photoabsorption. The databases with and without the so-called normalization screening correction are denoted as 'renormalized' or 'un-normalized', respectively. The simulations were performed with the PENELOPE/penEasy code system, for a geometry resembling a mammography examination. The mean glandular dose (MGD), incident air kerma (Kair), normalized glandular dose (DgN) and glandular depth-dose (GDD(z)) were scored, for homogeneous breast phantoms, using both databases. The AAPM Report TG-195 case 3 was replicated, and the results were included. Moreover, cases with heterogeneous and anthropomorphic breast phantoms were also addressed. The results simulated with the un-normalized cross sections are in better overall agreement with the TG-195 data than those from the renormalized cross sections; for MGD the largest discrepancies are 0.13(6)% and 0.74(5)%, respectively. The MGD,Kairand DgN values simulated with the two databases show differences that diminish from approximately 10%/3%/6.8% at 8.25 keV down to 1.5%/1.7%/0.4% at 48.75 keV, respectively. For polyenergetic spectra, deviations up to 2.5% were observed. The disagreement between the GDDs simulated with the analyzed databases increases with depth, ranging from -1% near the breast entrance to 4% near the bottom. Thus, the choice of photoelectric cross section database affects the MC simulation results of breast dosimetry and adds a non-negligible systematic uncertainty to the dosimetric quantities used in mammography.

Impact of theI-value of diamond on the energy deposition in different beam qualities.

Diamond detectors are increasingly employed in dosimetry. Their response has been investigated by means of Monte Carlo (MC) methods, but there is no consensus on what mass densityρ, mean excitation energyIand number of conduction electrons per atomnceto use in the simulations. The ambiguity occurs due to its seeming similarity with graphite (both are carbon allotropes). Except for the difference inρbetween crystalline graphite (2.265 g cm-3) and diamond (3.515 g cm-3), their dielectric properties are assumed to be identical. This is incorrect, and the two materials should be distinguished: (ρ= 2.265 g cm-3,I= 81.0 eV,nce= 1) for graphite and (ρ= 3.515 g cm-3,I= 88.5 eV,nce= 0) for diamond. Simulations done with the MC codepenelopeshow that the energy imparted in diamond decreases by up to 1% with respect to 'pseudo-diamond' (ρ= 3.515 g cm-3,I= 81.0 eV,nce= 0) depending on the beam quality and cavity thickness. The energy imparted changed the most in cavities that are small compared with the range of electrons. The difference in the density-effect term relative to graphite was the smallest for diamond owing to an interplay effect thatρ,Iandncehave on this term, in contrast to pseudo-diamond media when eitherρorIalone were adjusted. The study also presents a parameterized density-effect correction function for diamond that may be used by MC codes like EGSnrc. Theestarprogram assumes thatnce= 2 for all carbon-based materials, hence it delivers an erroneous density-effect correction term for graphite and diamond. Despite the small changes of the energy imparted in diamond simulated with two differentIvalues and expected close-to-negligible deviation from the published small-field output correction data, it is important to pay attention to material properties and model the medium faithfully.

On the relativistic impulse approximation for the calculation of Compton scattering cross sections and photon interaction coefficients used in kV dosimetry.

We calculate differential and integrated cross sections for the Compton interaction as well as mass attenuation ([Formula: see text]), mass energy-transfer ([Formula: see text]), and mass energy-absorption ([Formula: see text]) coefficients, within the relativistic impulse approximation (RIA) using Compton profiles (CPs) obtained from unrestricted Hartree-Fock electron densities. We investigate the impact of using molecular as opposed to atomic CPs on dosimetric photon interaction coefficients for air, water and graphite, and compare our cross sections to the simpler Waller-Hartree (WH) and Klein-Nishina (KN) formalisms. We find that differences in [Formula: see text] and [Formula: see text] resulting from the choice of CPs within the RIA are small relative to the differences between the RIA, WH, and KN calculations. Surprisingly, although the WH binding corrections seem accurate when considering [Formula: see text], there are significant discrepancies between the WH and RIA results when we look at [Formula: see text]. The WH theory can differ substantially from the predictions of KN and the RIA in the tens of keV range (e.g. 6%-10% at 20 keV), when Compton scattering becomes the dominant interaction mechanism. For lower energies, the disagreement further grows to about one order of magnitude at 1 keV. However, since the photoelectric effect transfers more energy than the Compton interaction in the tens of keV range and below, the differences in the total [Formula: see text] values resulting from the choice of Compton models (KN, WH, or RIA) are not larger than 0.4%, and the differences between WH and the other two theories are no longer prominent.

Monte Carlo simulation and analysis of proton energy-deposition patterns in the Bragg peak.

The spatial pattern of energy depositions is crucial for understanding the mechanisms that modify the relative biological effectiveness of different radiation qualities. In this paper, we present data on energy-deposition properties of mono-energetic protons (1-20 MeV) and their secondary electrons in liquid water. Proton-impact ionization was described by means of the Hansen-Kocbach-Stolterfoht doubly differential cross section (DDCS), thus modelling both the initial energy and angle of the emitted electron. Excitation by proton impact was included to account for the contribution of this interaction channel to the electronic stopping power of the projectile. Proton transport was implemented assuming track-segment conditions, whereas electrons were followed down to 50 eV by the Monte Carlo code PENELOPE. Electron intra-track energy-deposition properties, such as slowing-down and energy-imparted spectra of electrons, were calculated. Furthermore, the use of DDCSs enabled the scoring of electron inter-track properties. We present novel results for 1, 5 and 20 MeV single-proton-track frequencies of distances between the nearest inter- (e(-)-e(-), e(-)-H+) and intra-track (e(-)-e(-), e(-)-H+, H+-H+) energy-deposition events. By setting a threshold energy of 17.5 eV, commonly employed as a surrogate to discriminate for elementary damage in the DNA, the variation in these frequencies was studied as well. The energy deposited directly by the proton represents a large amount of the total energy deposited along the track, but when an energy threshold is adopted the relative contribution of the secondary electrons becomes larger for increasing energy of the projectile. We found that the frequencies of closest energy-deposition events per nanometre decrease with proton energy, i.e. for lower proton energies a denser ionization occurs, following the trend of the characteristic LET curves. In conclusion, considering the energy depositions due to the delta electrons and at the core of the track, 1 MeV protons have an intrinsic capability of generating about five times more dual depositions within the characteristic 2 nm of the DNA-chain structure than 20 MeV protons.

Monte Carlo based water/medium stopping-power ratios for various ICRP and ICRU tissues.

Water/medium stopping-power ratios, s(w,m), have been calculated for several ICRP and ICRU tissues, namely adipose tissue, brain, cortical bone, liver, lung (deflated and inflated) and spongiosa. The considered clinical beams were 6 and 18 MV x-rays and the field size was 10 x 10 cm(2). Fluence distributions were scored at a depth of 10 cm using the Monte Carlo code PENELOPE. The collision stopping powers for the studied tissues were evaluated employing the formalism of ICRU Report 37 (1984 Stopping Powers for Electrons and Positrons (Bethesda, MD: ICRU)). The Bragg-Gray values of s(w,m) calculated with these ingredients range from about 0.98 (adipose tissue) to nearly 1.14 (cortical bone), displaying a rather small variation with beam quality. Excellent agreement, to within 0.1%, is found with stopping-power ratios reported by Siebers et al (2000a Phys. Med. Biol. 45 983-95) for cortical bone, inflated lung and spongiosa. In the case of cortical bone, s(w,m) changes approximately 2% when either ICRP or ICRU compositions are adopted, whereas the stopping-power ratios of lung, brain and adipose tissue are less sensitive to the selected composition. The mass density of lung also influences the calculated values of s(w,m), reducing them by around 1% (6 MV) and 2% (18 MV) when going from deflated to inflated lung.

Absorbed dose evaluation of Auger electron-emitting radionuclides: impact of input decay spectra on dose point kernels and S-values.

The aim of this study was to investigate the impact of decay data provided by the newly developed stochastic atomic relaxation model BrIccEmis on dose point kernels (DPKs - radial dose distribution around a unit point source) and S-values (absorbed dose per unit cumulated activity) of 14 Auger electron (AE) emitting radionuclides, namely 67Ga, 80mBr, 89Zr, 90Nb, 99mTc, 111In, 117mSn, 119Sb, 123I, 124I, 125I, 135La, 195mPt and 201Tl. Radiation spectra were based on the nuclear decay data from the medical internal radiation dose (MIRD) RADTABS program and the BrIccEmis code, assuming both an isolated-atom and condensed-phase approach. DPKs were simulated with the PENELOPE Monte Carlo (MC) code using event-by-event electron and photon transport. S-values for concentric spherical cells of various sizes were derived from these DPKs using appropriate geometric reduction factors. The number of Auger and Coster-Kronig (CK) electrons and x-ray photons released per nuclear decay (yield) from MIRD-RADTABS were consistently higher than those calculated using BrIccEmis. DPKs for the electron spectra from BrIccEmis were considerably different from MIRD-RADTABS in the first few hundred nanometres from a point source where most of the Auger electrons are stopped. S-values were, however, not significantly impacted as the differences in DPKs in the sub-micrometre dimension were quickly diminished in larger dimensions. Overestimation in the total AE energy output by MIRD-RADTABS leads to higher predicted energy deposition by AE emitting radionuclides, especially in the immediate vicinity of the decaying radionuclides. This should be taken into account when MIRD-RADTABS data are used to simulate biological damage at nanoscale dimensions.

Determination of LaBr3(Ce) internal background using a HPGe detector and Monte Carlo simulations.

The presence of (138)La and (227)Ac impurities in LaBr3(Ce) scintillator crystals is a drawback for their use in environmental radiation monitoring. A method is presented to evaluate the internal (138)La activity. Firstly, an experimental set-up is prepared with the LaBr3(Ce) crystal acting as the radiation source and an HPGe detector that acquires the photon spectrum. Then, the internal background spectrum is simulated with a modified version of the PENELOPE/penEasy Monte Carlo code. The simulated spectra agree with measurements conducted at ultra-low-background facilities.

Monte Carlo Evaluation of Auger Electron-Emitting Theranostic Radionuclides.

UNLABELLED: Several radionuclides used in medical imaging emit Auger electrons, which, depending on the targeting strategy, either may be exploited for therapeutic purposes or may contribute to an unintentional mean absorbed dose burden. In this study, the virtues of 12 Auger electron-emitting radionuclides were evaluated in terms of cellular S values in concentric and eccentric cell-nucleus arrangements and by comparing their dose-point kernels. METHODS: The Monte Carlo code PENELOPE was used to transport the full particulate spectrum of (67)Ga, (80m)Br, (89)Zr, (90)Nb, (99m)Tc, (111)In, (117m)Sn, (119)Sb, (123)I, (125)I, (195m)Pt, and (201)Tl by means of event-by-event simulations. Cellular S values were calculated for varying cell and nucleus radii, and the effects of cell eccentricity on S values were evaluated. Dose-point kernels were determined up to 30 µm. Energy deposition at DNA scales was also compared with an α emitter, (223)Ra. RESULTS: PENELOPE-determined S values were generally within 10% of MIRD values when the source and target regions strongly overlapped, that is, S(nucleus←nucleus) configurations, but greater differences were noted for S(nucleus←cytoplasm) and S(nucleus←cell surface) configurations. Cell eccentricity had the greatest effect when the nucleus was small, compared with the cell size, and when the radiation sources were on the cell surface. Dose-point kernels taken together with the energy spectra of the radionuclides can account for some of the differences in energy deposition patterns between the radionuclides. The energy deposition of most Auger electron emitters at DNA scales of 2 nm or less exceeded that of a monoenergetic 5.77-MeV α particle, but not for (223)Ra. CONCLUSION: A single-cell dosimetric approach is required to evaluate the efficacy of individual radionuclides for theranostic purposes, taking cell geometry into account, with internalizing and noninternalizing targeting strategies.

Limitations (and merits) of PENELOPE as a track-structure code.

PURPOSE: To outline the limitations of PENELOPE (acronym of PENetration and Energy LOss of Positrons and Electrons) as a track-structure code, and to comment on modifications that enable its fruitful use in certain microdosimetry and nanodosimetry applications. METHODS: Attention is paid to the way in which inelastic collisions of electrons are modelled and to the ensuing implications for microdosimetry analysis. RESULTS: Inelastic mean free paths and collision stopping powers calculated with PENELOPE and two well-known optical-data models are compared. An ad hoc modification of PENELOPE is summarized where ionization and excitation of liquid water by electron impact is simulated using tables of realistic differential and total cross sections. CONCLUSIONS: PENELOPE can be employed advantageously in some track-structure applications provided that the default model for inelastic interactions of electrons is replaced by suitable tables of differential and total cross sections.

A Monte Carlo program for the analysis of low-energy electron tracks in liquid water.

A Monte Carlo code for the event-by-event simulation of electron transport in liquid water is presented. The code, written in C++, can accommodate different interaction models. Currently it implements cross sections for ionizing collisions calculated with the model developed by Dingfelder et al (1998 Radiat. Phys. Chem. 53 1-18, 2008 Radiat. Res. 169 584-94) and cross sections for elastic scattering computed within the static-exchange approximation (Salvat et al 2005 Comput. Phys. Commun. 165 157-90). The latter cross sections coincide with those recommended in ICRU Report 77 (2007). Other included interaction mechanisms are excitation by electron impact and dissociative attachment. The main characteristics of the code are summarized. Various track penetration parameters, including the detour factor, are defined as useful tools to quantify the geometrical extent of electron tracks in liquid water. Results obtained with the present microdosimetry code are given in the form of probability density functions for initial electron kinetic energies ranging from 0.1 to 10 keV. The sensitivity of the simulated distributions to the choice of alternative physics models has been briefly explored. The discrepancies with equivalent simulations reported by Wilson et al (2004 Radiat. Res. 161 591-6) stem from the adopted cross sections for elastic scattering, which determine largely the spatial evolution of low-energy electron tracks.

Monte Carlo simulation of correction factors for IAEA TLD holders.

The IAEA standard thermoluminescent dosimeter (TLD) holder has been developed for the IAEA/WHO TLD postal dose program for audits of high-energy photon beams, and it is also employed by the ESTRO-QUALity assurance network (EQUAL) and several national TLD audit networks. Factors correcting for the influence of the holder on the TL signal under reference conditions have been calculated in the present work from Monte Carlo simulations with the PENELOPE code for (60)Co gamma-rays and 4, 6, 10, 15, 18 and 25 MV photon beams. The simulation results are around 0.2% smaller than measured factors reported in the literature, but well within the combined standard uncertainties. The present study supports the use of the experimentally obtained holder correction factors in the determination of the absorbed dose to water from the TL readings; the factors calculated by means of Monte Carlo simulations may be adopted for the cases where there are no measured data.