Microdosimetric Spectrum Research Articles

Interpreting the biological effects of protons as a function of physical quantity: linear energy transfer or microdosimetric lineal energy spectrum?

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The primary advantage of using the “dose and LET” physical system is its relative simplicity, especially for presenting and recording results. Inclusion of additional information such as the energy spectrum of charged particles renders this approach adequate to describe the biological effects of large dose levels from homogeneous sources. The primary disadvantage of this system is that it does not provide a unique description of the stochastic nature of radiation interactions. We and others have used dose-averaged LET (LETd) as a correlative physical quantity to the relative biological effectiveness (RBE) of proton beams. This approach is based on established experimental findings that proton RBE increases with LETd. However, this approach might not be applicable to intensity-modulated proton therapy or other applications in which the proton energy spectrum is highly heterogeneous. In the current study, we irradiated cancer cells with scanning proton beams with identical LETd (3.4 keV/µm) but arising from two different proton energy/LET spectra (a narrow spectrum in group 1 and a widespread heterogeneous spectrum in group 2). Clonogenic survival after irradiation revealed significant differences in RBE at any cell surviving fraction: e.g., at a surviving fraction of 0.1, the RBE was 0.97 ± 0.03 in group 1 and 1.16 ± 0.04 in group 2 (p≤0.01), validating our hypothesis that LETd alone may not adequately indicate proton RBE. Further analysis showed that microdosimetric spectrum (the probability density function of the stochastic physical quantity lineal energy y) was helpful for interpreting observed differences in biological effects. However, more accurate use of microdosimetric spectrum to quantify RBE requires a cell line–specific mechanistic model.

Comparison of biological weighting functions to estimate the microdosimetric RBE in BNCT.

In the framework of the MUNES project, a prototype accelerator-based thermal neutron source was developed and installed at the Legnaro National Laboratories of INFN. The microdosimetric characterization of this radiation field was performed with a Tissue-Equivalent Proportional Counter with interchangeable cathode walls, either doped with 100ppm of 10B or without boron doping. A suitable subtraction procedure allowed to discriminate the gamma, neutron and BNC dose components (Selva etal., 2022, Appl. Radiat. Isot. 182, 110144). The measured microdosimetric spectra can be weighted with a biological weighting function to estimate the Relative Biological Effectiveness of the radiation field, for the purpose of intercomparison between different thermal neutron sources. This work compares, therefore, the biological doses resulting from four different weighting functions applied to the same initial microdosimetric spectrum, discussing strengths and limitations of each of them.

Prediction of fast neutron spectra with a spherical TEPC using a machine-learning algorithm

For many years, new unfolding methods based on machine learning have been studied and developed to improve the prediction capabilities of fluence spectra in neutron fields. These methods are mainly applied to traditional devices used for specific measurements like Bonner spheres, activation detectors or liquid scintillators. In this paper, we attempt to develop a new method based on the unfolding of the fluence spectrum from the micro-dosimetric spectrum measured by a tissue-equivalent proportional counter (TEPC). This type of counter is commonly used for neutron kerma measurements and quality factor assessments, but has never been employed as a neutron spectrometer. This work focuses on the fast neutron region, which is an extremely relevant subject in various fields of nuclear energy. We have tested different machine-learning models to define an unfolding algorithm that can be used to reconstruct the energy distribution of the fluence for spectra of various origins, ranging between 50 keV and 20 MeV.

Energy-Loss Straggling and Delta-Ray Escape in Solid-State Microdosimeters Used in Ion-Beam Therapy

Microdosimetry is increasingly adopted in the characterization of proton and carbon ion beams used in cancer therapy. Spectra and mean values of lineal energy calculated in frequency and dose are seen by many as the tools which, by complementing dosimetric measurements, allow for the most complete characterization of the therapeutic radiation fields. The urgency is now to consolidate the experience and converge to commonly accepted methodologies. In this context, the purpose of this work is to study the effects of the energy-loss straggling and the delta-ray escape, considering slab-sensitive volumes; these are, in fact, the typical shapes of solid-state microdosimeters, which are widely used in investigating light ion therapy beams. The method considers the energy distribution of delta rays resulting from the collision of the impinging ion and, taking into account the escape, convolutes it with itself as many times as the expected number of collisions in the sensitive volume thickness. The resulting distribution is compared to the experimental microdosimetric spectrum showing a substantially good agreement. The extension of the methodology to a wider range of ion energy and detector characteristics is instrumental for a detector-independent microdosimetric assessment of the radiation fields.

Radiobiological Outcomes, Microdosimetric Evaluations and Monte Carlo Predictions in Eye Proton Therapy

CATANA (Centro di AdroTerapia ed Applicazioni Nucleari Avanzate) was the first Italian protontherapy facility dedicated to the treatment of ocular neoplastic pathologies. It is in operation at the LNS Laboratories of the Italian Institute for Nuclear Physics (INFN-LNS) and to date, 500 patients have been successfully treated. Even though proton therapy has demonstrated success in clinical settings, there is still a need for more accurate models because they are crucial for the estimation of clinically relevant RBE values. Since RBE can vary depending on several physical and biological parameters, there is a clear need for more experimental data to generate predictions. Establishing a database of cell survival experiments is therefore useful to accurately predict the effects of irradiations on both cancerous and normal tissue. The main aim of this work was to compare RBE values obtained from in-vitro experimental data with predictions made by the LEM II (Local Effect Model), Monte Carlo approaches, and semi-empirical models based on LET experimental measurements. For this purpose, the 92.1 uveal melanoma and ARPE-19 cells derived from normal retinal pigmented epithelium were selected and irradiated in the middle of clinical SOBP of the CATANA proton therapy facility. The remarkable results show the potentiality of using microdosimetric spectrum, Monte Carlo simulations and LEM model to predict not only the RBE but also the survival curves.

Microdosimetric quantities of an accelerator-based neutron source used for boron neutron capture therapy measured using a gas-filled proportional counter

Boron neutron capture therapy (BNCT) is an emerging radiation treatment modality, exhibiting the potential to selectively destroy cancer cells. Currently, BNCT is conducted using a nuclear reactor. However, the future trend is to move toward an accelerator-based system for use in hospital environments. A typical BNCT radiation field has several different types of radiation. The beam quality should be quantified to accurately determine the dose to be delivered to the target. This study utilized a tissue equivalent proportional counter (TEPC) to measure microdosimetric and macrodosimetric quantities of an accelerator-based neutron source. The micro- and macro-dosimetric quantities measured with the TEPC were compared with those obtained via the the particle and heavy ion transport code system (PHITS) Monte Carlo simulation. The absorbed dose from events >20 keV/μm measured free in air for a 1-h irradiation was calculated as 1.31 ± 0.02 Gy. The simulated result was 1.41 ± 0.07 Gy. The measured and calculated values exhibit good agreement. The relative biological effectiveness (RBE) that was evaluated from the measured microdosimetric spectrum was calculated as 3.7 ± 0.02, similar to the simulated value of 3.8 ± 0.1. These results showed the PHITS Monte Carlo simulation can simulate both micro- and macro-dosimetric quantities accurately. The RBE was calculated using a single-response function, and the results were compared with those of several other institutes that used a similar method. However, care must be taken when using such a single-response function for clinical application, as it is only valid for low doses. For clinical dose ranges (i.e., high doses), multievent distribution inside the target needs to be considered.

Tissue equivalence of diamond for heavy charged particles

A dedicated Geant4 study was developed to determine a correction factor (C) to convert the energy deposition response in diamond to water for heavy charged ions, with atomic number (Z) greater than 2 with energies typical of Galactic Cosmic Rays. The energy deposition response within an ideal diamond based microdosimeter was modelled and converted into a microdosimetric spectrum. The simulation was then repeated, substituting diamond with water. It was shown that by applying the correction factor, the energy deposition and microdosimetric response in diamond could be matched to that of water. The correction factor was determined to be C = 0.32 to 0.33. This study has shown a weak dependence of the correction factor C with respect to the Z of the projectile. The correction factor remains applicable for converting microdosimetric spectra in diamond to water for Galactic Cosmic Rays. This result is extremely encouraging and indicative of the applicability of diamond for use in radioprotection applications in space environments.

A FPGA-based software for microdosimetric data processing

The tissue equivalent proportional counter (TEPC) is the most accurate device for measuring microdosimetric properties of particle beams. Since microdosimetric quantities span over several decades, the electronic and acquisition chain should meet specific requirements. In order to cover the wide dynamic range of the signals generated by the TEPC, the output signal from the preamplifier is fed in parallel to three linear amplifiers which shape and amplify the signal with different gains. Very low-energy deposition events are filtered in the high-gain stage, and high-energy deposition events are processed in the low-gain stage. A new system with high acquisition performance and compact hardware was developed for this purpose. The analog-to-digital conversion is performed by a commercial acquisition system that includes a FPGA. Thanks to the FPGA a parallel high-speed acquisition on three channels can be performed. The software merges signals together from the three electronic chains and computes a real time microdosimetric spectrum giving a prompt information about the irradiation field. This acquisition system, which performs analog-to-digital conversion and signal processing at a sampling rate up to 15 MS/s, was tested by irradiating a TEPC with an Am-Be fast neutron field, an intense quasi-monoenergetic neutron beam and a 62 MeV/u helium ion beam.

Report of a National Cancer Institute special panel: Characterization of the physical parameters of particle beams for biological research.

To define the physical parameters needed to characterize a particle beam in order to allow intercomparison of different experiments performed using different ions at the same facility and using the same ion at different facilities. At the request of the National Cancer Institute (NCI), a special panel was convened to review the current status of the field and to provide suggested metrics for reporting the physical parameters of particle beams to be used for biological research. A set of physical parameters and measurements that should be performed by facilities and understood and reported by researchers supported by NCI to perform pre-clinical radiobiology and medical physics of heavy ions were generated. Standard measures such as radiation delivery technique, beam modifiers used, nominal energy, field size, physical dose and dose rate should all be reported. However, more advanced physical measurements, including detailed characterization of beam quality by microdosimetric spectrum and fragmentation spectra, should also be established and reported. Details regarding how such data should be incorporated into Monte Carlo simulations and the proper reporting of simulation details are also discussed. In order to allow for a clear relation of physical parameters to biological effects, facilities and researchers should establish and report detailed physical characteristics of the irradiation beams utilized including both standard and advanced measures. Biological researchers are encouraged to actively engage facility staff and physicists in the design and conduct of experiments. Modeling individual experimental setups will allow for the reporting of the uncertainties in the measurement or calculation of physical parameters which should be routinely reported.

Feasibility study on the use of 3D silicon microdosimeter detectors for microdosimetric analysis in boron neutron capture therapy

This paper presents the feasibility study of a novel 3D mesa bridge microdosimeter and its use for BNCT dosimetry. The performance of the microdosimeter was studied using Monte Carlo simulation. The clinical BNCT field at Kyoto University Reactor (KUR) using both thermal and epithermal irradiation modes were used in this study. Results show that this microdosimeter can be utilised as an effective tool to measure microdosimetric spectrum in the BNCT field and experimental validation will follow once KUR is operational.

Indirect method to monitor the site size of sealed TEPCs

Tissue equivalent proportional counters (TEPCs) can be used as radiation monitors in different radiation environments, including on board of a spacecraft or aircraft. Usually, the gas density of the counter is set to simulate site sizes of 1 μm or 2 μm. However, especially for sealed counters which should be operative for long time without being refilled, the gas density inside the counter could change significantly. The immediate consequence of density variations is a gas gain shift. This in turn is not a serious problem, because the gas gain can be measured and corrected by increasing the bias voltage. A more critical consequence of an increase of the density is that the shape of the microdosimetric spectrum changes, affecting the response of the detector. Consequently, this limits the reliability of sealed TEPC over time, especially because the gas pressure is not directly monitored. Therefore, the aim of this study is to propose an experimental procedure to estimate the TEPC sensitive-site size by performing two independent measurements, one in a gamma radiation field and the other one in a neutron field. The results show that it is possible to assess the site size of sealed TEPCs with an accuracy of 5%.

Lineal energy calibration of a spherical TEPC.

Tissue-equivalent proportional counters (TEPCs) do not always allow built-in calibration alpha-particle sources, and the lineal energy calibration of these counters must be performed with an external radiation able to penetrate the detector walls. The irradiation field can be used for calibration if a particular marker point of known lineal energy is identified in the measured spectrum. This point is often identified with the proton edge, which corresponds to the maximum energy deposited by protons in the given volume. If the proton edge cannot be identified precisely in the measured spectrum, a gamma source can be used instead, identifying the maximum lineal energy due to electrons (e-edge). The technique was already described and applied for cylindrical TEPCs, allowing a calibration with an overall uncertainty smaller than 5 % (Conte et al. Lineal energy calibration of mini tissue equivalent gas-proportional counters (TEPC). AIP Conf. Proc. 1530, 171-178 (2013)). In the present work, this study was repeated for spherical detectors. First a marker point was identified in the microdosimetric spectrum of a (137)Cs gamma source, then a precise value of lineal energy was assigned to it. Gas pressures were varied to simulate diameters from 0.5 and 3 µm at density 1 g cm(-3). A simple power equation is given for allowing calibration of TEPCs filled with C3H8-TE gas at different pressures, using an external (137)Cs gamma source.

Microdosimetric Approach to NIRS-defined Biological Dose Measurement for Carbon-ion Treatment Beam

The RBE-weighted absorbed dose, called "biological dose," has been routinely used for carbon-ion treatment planning in Japan to formulate dose prescriptions for treatment protocols. This paper presents a microdosimetric approach to measuring the biological dose, which was redefined to be derived from microdosimetric quantities measured by a tissue-equivalent proportional counter (TEPC). The TEPC was calibrated in (60)Co gamma rays to assure a traceability of the TEPC measurement to Japanese standards and to eliminate the discrepancies among matching counters. The absorbed doses measured by the TEPC were reasonably coincident with those measured by a reference ionization chamber. The RBE value was calculated from the microdosimetric spectrum on the basis of the microdosimetric kinetic model. The biological doses obtained by the TEPC were compared with those prescribed in the carbon-ion treatment planning system. We found that it was reasonable for the measured biological doses to decrease with depth around the rear SOBP region because of beam divergence, scattering effect, and fragmentation reaction. These results demonstrate that the TEPC can be an effective tool to assure the radiation quality in carbon-ion radiotherapy.

Microdosimetric investigation of the spectra from YAYOI by use of the Monte Carlo code PHITS

The purpose of this study was to obtain the neutron energy spectrum on the surface of the moderator of the Tokyo University reactor YAYOI and to investigate the origins of peaks observed in the neutron energy spectrum by use of the Monte Carlo Code PHITS for evaluating biological studies. The moderator system was modeled with the use of details from an article that reported a calculation result and a measurement result for a neutron spectrum on the surface of the moderator of the reactor. Our calculation results with PHITS were compared to those obtained with the discrete ordinate code ANISN described in the article. In addition, the changes in the neutron spectrum at the boundaries of materials in the moderator system were examined with PHITS. Also, microdosimetric energy distributions of secondary charged particles from neutron recoil or reaction were calculated by use of PHITS and compared with a microdosimetric experiment. Our calculations of the neutron energy spectrum with PHITS showed good agreement with the results of ANISN in terms of the energy and structure of the peaks. However, the microdosimetric dose distribution spectrum with PHITS showed a remarkable discrepancy with the experimental one. The experimental spectrum could not be explained by PHITS when we used neutron beams of two mono-energies.

Theoretical analysis of microdosimetric spectra and cluster formation for 103Pd and 125I photon emitters**Presented at the WC 2003, 03.05B: Second International Workshop on Mini and Micro Dosimetry and Its Applications.

In this work we have compared 125I or 103Pd from a microdosimetric point of view. The photon spectra at different positions around the seeds have first been calculated using EGSnrc Monte Carlo (MC) code. These photon spectra are used as input for the event-by-event MC code TRION to calculate the microdosimetric lineal energy (y) distribution for each isotope. The microdosimetric dose average lineal energy, yD, calculated in a sphere of 1 µm is 3.5 keV µm−1 for 125I and 4.0 keV µm−1 for 103Pd, agreeing well with values reported in the literature. yD in a 1 µm sphere diminishes slightly with the distance from the seed for 103Pd. This is due to the spectral hardening caused by the presence of a gamma-ray of 357.5 keV in the initial spectrum of 103Pd. In parallel with the calculation of the microdosimetric spectra, we have analysed the distribution of the size of the energy deposition clusters generated by these low energy photons in structures of 2 and 10 nm of radius. Due to Compton interactions, the fraction of very low energy electrons (<5 keV) generated by 125I photons is 51%, whereas it is only 27% for 103Pd. As these electrons deposit their energy very locally, the pattern of energy depositions contains more clusters of a few nm of radius for 125I than for 103Pd; the mean cluster orders are respectively 3.3 and 3.0 for 10 nm clusters. This is in opposition with the prediction based on the microdosimetric spectrum and the parameter yD and could be of importance for the damage to the cells.

The potential application of β-delayed particle decay beam 9C in cancer therapy

A radioactive ion beam like 9C serves as a double radiation source and may be useful in cancer treatment, where the essential irradiation comes from the external beam itself and the extra one is due to the low-energy particles emitted internally during the decay of 9C. Based on the microdosimetric specific energy spectrum in cell nuclei, a model to evaluate the biological effect induced by the internally emitted particles from a β-delayed particle decay beam has been developed. In this paper, using this model the additional contributions to the cell-killing effect due to the emitted particles from stopping 9C ions were incorporated in the design of spread-out Bragg peaks (SOBP) for radioactive 9C beams. For this purpose, a simulated annealing algorithm was employed to optimize the superposing weighting fractions of all monoenergetic beams so that a uniform cell survival level could be realized across the SOBP within an acceptable deviation of 5%. SOBPs with different widths and at different cell survival levels were designed for both therapeutic 9C and 12C beams for comparison. The potential use of the 9C beam in radiotherapy compared to the 12C beam, which is commonly adopted in the practices of current heavy-ion therapy, is shown systematically in terms of the distributions of biological effective dose and cell survival along the beam penetration.

Simulation of Proton Neutralization Effect for Neutron Dosimetry

Neutron dose is transferred to biological materials through the recoil protons produced by elastic scattering. When a low-velocity proton collides with the atoms or molecules of a target, it changes to a hydrogen atom by electron capture; this hydrogen atom then changes to a proton by losing the electron. Because the hydrogen atom has a different ionization cross section from that of a proton, the charge exchange processes need to be considered to calculate stopping power for low energy protons. The proton neutralization effect has been simulated by using a proton track structure code developed by taking into account charge exchange processes. The microdosimetric spectrum for 1 MeV neutrons was calculated by assuming a continuous slowing down approximation (csda) and the results of the proton track code. It was found that hydrogen atoms after proton neutralized by electron capture contribute about 24% to neutron dose.

Characterization of miniature tissue-equivalent proportional counters for neutron radiotherapy applications

A miniature tissue-equivalent proportional counter (TEPC) system has been developed to facilitate microdosimetric measurements in high-flux mixed fields. Counters with collecting volumes of 12.3 and 2.65 mm3 have been constructed using various tissue-equivalent wall materials, including those loaded with 10B for evaluation of the effects of the boron neutron capture reaction. These counters provide a measure of both the absorbed dose and associated radiation quality, allowing an assessment of the utility and relative effectiveness of various neutron radiotherapy techniques such as boron neutron capture therapy (BNCT), boron neutron capture enhanced fast neutron therapy (BNCEFNT) and intensity modulated neutron radiotherapy (IMNRT). An evaluation of the physical parameters affecting the measured microdosimetric spectrum, the gas multiplication characteristics and the measurement of absorbed dose is presented. In addition, important aspects of the calibration and low energy extrapolation techniques for the microdosimetric spectrum are provided.

LET distributions measured at the CERF facility with the RRMD-III.

The LET distributions in front of the 80 cm-thick concrete side shield at the CERF facility were measured with a Si detector telescope (RRMD-III) covered with and without a 1 cm-thick acrylic plate. In these measurements, a slight difference between the LET distributions was seen as a result of recoil protons and/or carbon particles by neutrons. Also, the LET distributions are compared with the micro-dosimetric spectrum (i.e., lineal energy distribution) measured with a cylindrical TEPC under the same conditions.

Photoneutrons from high energy medical linear accelerators: Measurement of the spectrum and dose using a miniature proportional counter

A new method of measuring photoneutron dose to the patient during treatment with high energy photon or electron beams is presented. This method has the advantage of providing not only the dose, but the microdosimetric spectrum at the same time. A miniature cylindrical gas proportional counter (0.5 mm diameter by 0.5 mm height) has been used to measure scatter radiation from a 20 MV teletherapy photon beam. At atmospheric pressure, filled with propane base tissue equivalent gas, this counter simulates a unit density tissue region of approximately 0.9 microns. We present here single event microdosimetric spectra measured outside the primary beam 1.4 m from the target. This technique allows a single measurement to determine the scattered dose due to gammas and photoneutron contamination, as well as the quality factor of the photoneutrons. Spectral components from scattered photons and the photoneutrons are easily separated, and dose contributions can be estimated. The ratio of photoneutron dose measured by the proportional counter to photon dose at isocenter is 0.75 x 10(-4). Neutron dose was also measured using a bubble neutrometer. The proportional counter and neutrometer agree within experimental errors. This type of instrument is shown to be a viable technique for determination of exposure of patient and also personnel to photoneutrons, providing not only a dose determination, but also a spectrum that can be used to estimate quality factors for equivalent dose. Its main drawback is that it requires a lengthy (several hours) measurement because of low count rate of the neutrons.