Yuki Kase

Microdosimetric Measurements and Estimation of Human Cell Survival for Heavy-Ion Beams

Abstract Kase, Y., Kanai, T., Matsumoto, Y., Furusawa, Y., Okamoto, H., Asaba, T., Sakama, M. and Shinoda, H. Microdosimetric Measurements and Estimation of Human Cell Survival for Heavy-Ion Beams. Radiat. Res. 166, 629–638 (2006). The microdosimetric spectra for high-energy beams of photons and proton, helium, carbon, neon, silicon and iron ions (LET = 0.5–880 keV/μm) were measured with a spherical-walled tissue-equivalent proportional counter at various depths in a plastic phantom. Survival curves for human tumor cells were also obtained under the same conditions. Then the survival curves were compared with those estimated by a microdosimetric model based on the spectra and the biological parameters for each cell line. The estimated α terms of the liner-quadratic model with a fixed β value reproduced the experimental results for cell irradiation for ion beams with LETs of less than 450 keV/μm, except in the region near the distal peak.

Biological characteristics of carbon-ion therapy

Purpose: Radiotherapy using charged and/or high-linear energy transfer (LET) particles has a long history, starting with proton beams up to now carbon-ions. Radiation quality of particle beams is different from conventional photons, and therefore the biological effects of high-LET irradiation have attracted scientific interests of many scientists in basic and clinical fields. A brief history of particle radiotherapy in the past half-century is followed by the reviewed biological effectiveness of high-LET charged particles. Results: The latter includes 54 papers presenting 506 RBE (relative biological effectiveness) values for carbon ions and a total of 290 RBE values for other ions identified from 48 papers. By setting a selection window of LET up to 100 keV/μm, we fitted a linear regression line to an LET-RBE relation. The resulting slope of the regression line had a dimension of μm/keV, and showed different steepness for different cells/tissues and endpoints as well. The steepest regression was found for chromosome aberration of human malignant melanoma while the shallowest was for apoptosis of rodent cells/tissue. Both tumour and normal tissue showed relatively shallower slopes than colony formation. Conclusions: In general, there is a large variation of slope values, but the majority (25 out of 29 values) of data was smaller than 0.05 μm/keV.

Treatment planning for a scanned carbon beam with a modified microdosimetric kinetic model

We describe a method to calculate the relative biological effectiveness in mixed radiation fields of therapeutic ion beams based on the modified microdosimetric kinetic model (modified MKM). In addition, we show the procedure for integrating the modified MKM into a treatment planning system for a scanned carbon beam. With this procedure, the model is fully integrated into our research version of the treatment planning system. To account for the change in radiosensitivity of a cell line, we measured one of the three MKM parameters from a single survival curve of the current cells and used the parameter in biological optimization. Irradiation of human salivary gland tumor cells was performed with a scanned carbon beam in the Heavy Ion Medical Accelerator in Chiba (HIMAC), and we then compared the measured depth-survival curve with the modified MKM predicted survival curve. Good agreement between the two curves proves that the proposed method is a candidate for calculating the biological effects in treatment planning for ion irradiation.

Biological Dose Estimation for Charged-Particle Therapy Using an Improved PHITS Code Coupled with a Microdosimetric Kinetic Model

Abstract Sato, T., Kase, Y., Watanabe, R., Niita, K. and Sihver, L. Biological Dose Estimation for Charged Particle Therapy Using an Improved PHITS Code Coupled with a Microdosimetric Kinetic Model. Radiat. Res. 171, 107–117 (2009). Microdosimetric quantities such as lineal energy, y, are better indexes for expressing the RBE of HZE particles in comparison to LET. However, the use of microdosimetric quantities in computational dosimetry is severely limited because of the difficulty in calculating their probability densities in macroscopic matter. We therefore improved the particle transport simulation code PHITS, providing it with the capability of estimating the microdosimetric probability densities in a macroscopic framework by incorporating a mathematical function that can instantaneously calculate the probability densities around the trajectory of HZE particles with a precision equivalent to that of a microscopic track-structure simulation. A new method for estimating biological dose, the product of physical dose and RBE, from charged-particle therapy was established using the improved PHITS coupled with a microdosimetric kinetic model. The accuracy of the biological dose estimated by this method was tested by comparing the calculated physical doses and RBE values with the corresponding data measured in a slab phantom irradiated with several kinds of HZE particles. The simulation technique established in this study will help to optimize the treatment planning of charged-particle therapy, thereby maximizing the therapeutic effect on tumors while minimizing unintended harmful effects on surrounding normal tissues.

Contributions of Direct and Indirect Actions in Cell Killing by High-LET Radiations

Abstract Hirayama, R., Ito, A., Tomita, M., Tsukada, T., Yatagai, F., Noguchi, M., Matsumoto, Y., Kase, Y., Ando, K., Okayasu, R., and Furusawa, F. Contributions of Direct and Indirect Actions in Cell Killing by High-LET Radiations. Radiat. Res. 171, 212–218 (2009). The biological effects of radiation originate principally in damages to DNA. DNA damages by X rays as well as heavy ions are induced by a combination of direct and indirect actions. The contribution of indirect action in cell killing can be estimated from the maximum degree of protection by dimethylsulfoxide (DMSO), which suppresses indirect action without affecting direct action. Exponentially growing Chinese hamster V79 cells were exposed to high-LET radiations of 20 to 2106 keV/μm in the presence or absence of DMSO and their survival was determined using a colony formation assay. The contribution of indirect action to cell killing decreased with increasing LET. However, the contribution did not reach zero even at very high LETs and was estimated to be 32% at an LET of 2106 keV/μm. Therefore, even though the radiochemically estimated G value of OH radicals was nearly zero at an LET of 1000 keV/μm, indirect action by OH radicals contributed to a substantial fraction of the biological effects of high-LET radiations. The RBE determined at a survival level of 10% increased with LET, reaching a maximum value of 2.88 at 200 keV/μm, and decreased thereafter. When the RBE was estimated separately for direct action (RBED) and indirect action (RBEI); both exhibited an LET dependence similar to that of the RBE, peaking at 200 keV/μm. However, the peak value was much higher for RBED (5.99) than RBEI (1.89). Thus direct action contributes more to the high RBE of high-LET radiations than indirect action does.

Biophysical calculation of cell survival probabilities using amorphous track structure models for heavy-ion irradiation

Both the microdosimetric kinetic model (MKM) and the local effect model (LEM) can be used to calculate the surviving fraction of cells irradiated by high-energy ion beams. In this study, amorphous track structure models instead of the stochastic energy deposition are used for the MKM calculation, and it is found that the MKM calculation is useful for predicting the survival curves of the mammalian cells in vitro for (3)He-, (12)C- and (20)Ne-ion beams. The survival curves are also calculated by two different implementations of the LEM, which inherently used an amorphous track structure model. The results calculated in this manner show good agreement with the experimental results especially for the modified LEM. These results are compared to those calculated by the MKM. Comparison of the two models reveals that both models require three basic constituents: target geometry, photon survival curve and track structure, although the implementation of each model is significantly different. In the context of the amorphous track structure model, the difference between the MKM and LEM is primarily the result of different approaches calculating the biological effects of the extremely high local dose in the center of the ion track.

Let dependence of cell death, mutation induction and chromatin damage in human cells irradiated with accelerated carbon ions

We investigated the LET dependence of cell death, mutation induction and chromatin break induction in human embryo (HE) cells irradiated by accelerated carbon-ion beams. The results showed that cell death, mutation induction and induction of non-rejoining chromatin breaks detected by the premature chromosome condensation (PCC) technique had the same LET dependence. Carbon ions of 110 to 124keV/micrometer were the most effective at all endpoints. However, the number of initially induced chromatin breaks was independent of LET. About 10 to 15 chromatin breaks per Gy per cell were induced in the LET range of 22 to 230 keV/micrometer. The deletion pattern of exons in the HPRT locus, analyzed by the polymerase chain reaction (PCR), was LET-specific. Almost all of the mutants induced by 124 keV/micrometer beams showed deletion of the entire gene, while all mutants induced by 230keV/micrometer carbon-ion beams showed no deletion. These results suggest that the difference in the density distribution of carbon-ion track and secondary electron with various LET is responsible for the LET dependency of biological effects.

LET dependence of cell death and chromatin-break induction in normal human cells irradiated by neon-ion beams

We investigated the LET dependence of cell death and chromatin-break induction in normal human embryo cells irradiated by accelerated neon-ion beams. Neon-ion beams were generated by the Riken Ring Cyclotron (RRC) at the Institute of Physical and Chemical Research, Japan. Chromatin breaks were measured by counting the number of chromatin fragments detected by the premature chromosome condensation (PCC) technique. The results indicated that cell death and the induction of remaining chromatin breaks showed a qualitatively similar LET dependence. The LET RBE curves for both cell death and the induction of remaining chromatin breaks had a broad peak in the LET range of 120-300 keV/microm and steeply downward trend up to 340 keV/microm. These results suggest that there is a good correlation between cell death and the induction of remaining chromatin breaks by neon-ion beams with different LET values.

Biological dose calculation with Monte Carlo physics simulation for heavy-ion radiotherapy.

Treatment planning of heavy-ion radiotherapy involves predictive calculation of not only the physical dose but also the biological dose in a patient body. The biological dose is defined as the product of the physical dose and the relative biological effectiveness (RBE). In carbon-ion radiotherapy at National Institute of Radiological Sciences, the RBE value has been defined as the ratio of the 10% survival dose of 200 kVp x-rays to that of the radiation of interest for in vitro human salivary gland tumour cells. In this note, the physical and biological dose distributions of a typical therapeutic carbon-ion beam are calculated using the GEANT4 Monte Carlo simulation toolkit in comparison with those with the biological dose estimate system based on the one-dimensional beam model currently used in treatment planning. The results differed between the GEANT4 simulation and the one-dimensional beam model, indicating the physical limitations in the beam model. This study demonstrates that the Monte Carlo physics simulation technique can be applied to improve the accuracy of the biological dose distribution in treatment planning of heavy-ion radiotherapy.

Field size effect of radiation quality in carbon therapy using passive method

The authors have investigated the dependency of radiation quality and absorbed dose on radiation field size in therapeutic carbon beams. The field size of the broad beam, formed using the passive technique, was controlled from 20 to 100 mm per side with a multileaf collimator. The absorbed dose and radiation quality on the beam center were evaluated at several depths in a water phantom using microdosimetric technique in experiments and Monte Carlo simulations. With an increase in the field size, the radiation quality was reduced, although the absorbed dose grew at the center of the field. This indicates that the dose and radiation quality at the center of the broad beam are influenced by particles from the off-center region via large-angle scattering and that such particles have relatively low radiation quality and mainly consist of fragment particles. Because such a tendency appeared to be more remarkable in the deeper region of the water phantom, it is likely that fragment particles that are born in a water phantom have a marked role in determining the field size effect.