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The effects of the charged ion species 4He, 12C and 20Ne on glioblastoma multiforme (GBM) T98G, U87 and LN18 cell lines were compared with the effects of 200 kVp X-rays (1.7 keV/μm). These cell lines have different genetic profiles. Individual GBM relative biological effectiveness (RBE) was estimated in two ways: the RBE10 at 10% survival fraction and the RBE2Gy after 2 Gy doses. The linear quadratic model radiosensitivity parameters α and β and the α/β ratio of each ion type were determined as a function of LET. Mono-energetic 4He, 12C and 20Ne ions were generated by the Heavy Ion Medical Accelerator at the National Institute of Radiological Sciences in Chiba, Japan. Colony-formation assays were used to evaluate the survival fractions. The LET of the various ions used ranged from 2.3 to 100 keV/μm (covering the depth-dose plateau region to clinically relevant LET at the Bragg peak). For U87 and LN18, the RBE10 increased with LET and peaked at 85 keV/μm, whereas T98G peaked at 100 keV/μm. All three GBM α parameters peaked at 100 keV/μm. There is a statistically significant difference between the three GBM RBE10 values, except at 100 keV/μm (P < 0.01), and a statistically significant difference between the α values of the GBM cell lines, except at 85 and 100 keV/μm. The biological response varied depending on the GBM cell lines and on the ions used., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Glioblastoma (GBM), a Grade IV brain tumour, is a well-known radioresistant cancer. To investigate one of the causes of radioresistance, we studied the capacity for potential lethal damage repair (PLDR) of three altered strains of GBM: T98G, U87 and LN18, irradiated with various ions and various levels of linear energy transfer (LET). The GBM cells were exposed to 12C and 28Si ion beams with LETs of 55, 100 and 200 keV/μm, and with X-ray beams of 1.7 keV/μm. Mono-energetic 12C ions and 28Si ions were generated by the Heavy Ion Medical Accelerator at the National Institute of Radiological Science, Chiba, Japan. Clonogenic assays were used to determine cell inactivation. The ability of the cells to repair potential lethal damage was demonstrated by allowing one identical set of irradiated cells to repair for 24 h before subplating. The results show there is definite PLDR with X-rays, some evidence of PLDR at 55 keV/μm, and minimal PLDR at 100 keV/μm. There is no observable PLDR at 200 keV/μm. This is the first study, to the authors' knowledge, demonstrating the capability of GBM cells to repair potential lethal damage following charged ion irradiations. It is concluded that a GBM's PLDR is dependent on LET, dose and GBM strain; and the more radioresistant the cell strain, the greater the PLDR.

Heavy particle irradiation produces complex DNA double strand breaks (DSBs) which can arise from primary ionisation events within the particle trajectory. Additionally, secondary electrons, termed delta-electrons, which have a range of distributions can create low linear energy transfer (LET) damage within but also distant from the track. DNA damage by delta-electrons distant from the track has not previously been carefully characterised. Using imaging with deconvolution, we show that at 8 hours after exposure to Fe (∼200 keV/µm) ions, γH2AX foci forming at DSBs within the particle track are large and encompass multiple smaller and closely localised foci, which we designate as clustered γH2AX foci. These foci are repaired with slow kinetics by DNA non-homologous end-joining (NHEJ) in G1 phase with the magnitude of complexity diminishing with time. These clustered foci (containing 10 or more individual foci) represent a signature of DSBs caused by high LET heavy particle radiation. We also identified simple γH2AX foci distant from the track, which resemble those arising after X-ray exposure, which we attribute to low LET delta-electron induced DSBs. They are rapidly repaired by NHEJ. Clustered γH2AX foci induced by heavy particle radiation cause prolonged checkpoint arrest compared to simple γH2AX foci following X-irradiation. However, mitotic entry was observed when ∼10 clustered foci remain. Thus, cells can progress into mitosis with multiple clusters of DSBs following the traversal of a heavy particle.

We investigated the earliest possible chromosome break and repair process in normal human fibroblasts irradiated with low and high LET (linear energy transfer) heavy ion radiation using the modified premature chromosome condensation (PCC) technique utilizing wortmannin (WM) during the fusion incubation period [M. Okada, S. Saito, R. Okayasu, Facilitated detection of chromosome break and repair at low levels of ionizing radiation by addition of wortmannin to G1-type PCC fusion incubation, Mutat. Res., 562 (2004) 11-17]. The initial numbers of breaks were approximately 10/cell/Gy in X-irradiated samples, followed by carbon (LET: 70 keV/microm), neon, and the number was around 5/cell/Gy in silicon (LET: 70 and 200 keV/microm) and iron (LET: 200 keV/microm) samples. If WM was not used, the initial numbers of breaks with silicon and iron were higher than those of X-rays. To quantify these data, we used initial repair ratio (IRR) defined as the number of G1 PCC breaks with WM divided by the number of breaks without WM. X-irradiation gave the maximum IRR ( approximately 2.0), while iron as well as silicon irradiation showed the minimum IRR ( approximately 1.0), suggesting almost no rejoining at the initial stage. Although there is a comparatively good correlation between the IRR value and the cell survival, the survival fraction with the repair data at 2 or 6h correlates better statistically. Our data indicate that high LET heavy ion irradiation induces a lower number of initial chromosome breaks with minimal repair when compared with low LET irradiation. These results at the chromosome level substantiate and extend the notion that high LET radiation produces complex-type DNA double strand breaks (DSBs).

The aim of this work is to define a simplified semi-analytical beam transportation code that can calculate the spatial distribution of projectile fragments which are widely distributed in a patient's body during heavy-ion beam radiotherapy. In this code, we employed an elemental pencil beam model where the spatial distribution of radiation quality for an elemental beam is calculated and superposed according to the emittance ellipse of the narrow heavy-ion beam determined at the entrance of the target. The radiation quality for an elemental beam was calculated using Goldhaber's model of fragment distribution. The calculation results were compared with the experimental observations for a mono-energetic narrow (12)C beam measured at the secondary beam line in HIMAC. Despite its simplicity, the developed code could reproduce the experimental results well.

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.

The latest heavy ion therapy tends to require information about the spatial distribution of the quality of radiation in a patient's body in order to make the best use of any potential advantage of swift heavy ions for the therapeutic treatment of a tumour. The deflection of incident particles is described well by Molière's multiple-scattering theory of primary particles; however, the deflection of projectile fragments is not yet thoroughly understood. This paper reports on our investigation of the spatial distribution of fragments produced from a therapeutic carbon beam through nuclear reactions in thick water. A DeltaE-E counter telescope system, composed of a plastic scintillator, a gas-flow proportional counter and a BGO scintillator, was rotated around a water target in order to measure the spatial distribution of the radiation quality. The results revealed that the observed deflection of fragment particles exceeded the multiple scattering effect estimated by Molière's theory. However, the difference can be sufficiently accounted for by considering one term involved in the multiple-scattering formula; this term corresponds to a lateral 'kick' at the point of production of the fragment. This kick is successfully explained as a transfer of the intra-nucleus Fermi momentum of a projectile to the fragment; the extent of the kick obeys the expectation derived from the Goldhaber model.

To verify international uniformity in carbon beam dosimetry, an intercomparison programme was carried out at the heavy ion medical accelerator (HIMAC). Dose measurements with ionization chambers were performed for both unmodulated and 6 cm modulated 290 MeV/nucleon carbon beams. Although two different dosimetry procedures were employed, the evaluated values of absorbed dose were in good agreement. This comparison established a common framework for ionization chamber dosimetry between two different carbon beam therapy facilities.

For exact determination of absorbed dose in heavy-ion irradiation fields which are used in radiation therapy and biological experiments, ionization chambers have been characterized with defined heavy-ion beams and correction factors. The LET (linear energy transfer) dependence of columnar recombination in a parallel-plate ionization chamber has been examined. Using 135 MeV/u carbon and neon beams, the ion collection efficiency was measured for several gases (air, carbon dioxide, argon and tissue-equivalent gas). 95 MeV/u argon beams and 90 MeV/u iron beams were also used for measurements of columnar recombination in air. As expected by Jaffe theory, the inverse of the ratio of the ionization charge to the saturated ionization charge had a linear relationship with the inverse of the electric field strength in the region below 0.002 V(-1) cm. The gradient of the line increases as the LET of the heavy ions increases. A strong LET dependence of the gradient was observed in air and carbon dioxide. The LET dependence was not observed in tissue-equivalent gas, nitrogen or argon. The exact depth-dose distribution of the heavy-ion beam was obtained by this correction of the initial recombination effect for the collected ionization charge. The columnar recombination in air was analysed using Jaffe theory; the obtained parameter b (a track radius) should be in the range between 0.001 cm and 0.005 cm, whereas the value obtained by Jaffe is 0.00179 cm. The value of the parameter b should increase as the LET of the heavy-ion beam increases in order to reproduce the experimental values of the initial recombination.

Radioresistant tumours remain complex to manage with current radiotherapy (RT) techniques. Heavy ion beams were proposed for their treatment given their advantageous radiobiological properties. However, previous studies with patients resulted in serious adverse effects in the surrounding healthy tissues. Heavy ion RT could therefore benefit from the tissue-sparing effects of minibeam radiation therapy (MBRT). To investigate the potential of this combination, here we assessed the biochemical response to neon MBRT (NeMBRT) through synchrotron-based Fourier transform infrared microspectroscopy (SR-FTIRM). Healthy (BJ) and tumour (B16-F10) cell lines were subjected to seamless (broad beam) neon RT (NeBB) and NeMBRT at HIMAC. SR-FTIRM measurements were conducted at the MIRAS beamline of ALBA Synchrotron. Principal component analysis (PCA) permitted to assess the biochemical effects after the irradiations and 24 hours post-irradiation for the different RT modalities and doses. For the healthy cells, NeMBRT resulted in the most dissimilar spectral signatures from non-irradiated cells early after irradiations, mainly due to protein conformational modifications. Nevertheless, most of the damage appeared to recover one day post-RT; conversely, protein- and nucleic acid-related IR bands were strongly affected by NeBB 24 hours after treatment, suggesting superior oxidative damage and nucleic acid degradation. Tumour cells appeared to be less sensitive to NeBB than to NeMBRT shortly after RT. Still, after one day, both NeBB and the high-dose NeMBRT regions yielded important spectral modifications, suggestive of cell death processes, protein oxidation or oxidative stress. Lipid-associated spectral changes, especially due to the NeBB and NeMBRT peak groups for the tumour cell line, were consistent with reactive oxygen species attacks. [ABSTRACT FROM AUTHOR]

Microdosimetry is a particularly powerful method to estimate the relative biological effectiveness (RBE) of any mixed radiation field. This is particularly convenient for therapeutic heavy ion therapy (HIT) beams, referring to ions larger than protons, where the RBE of the beam can vary significantly along the Bragg curve. Additionally, due to the sharp dose gradients at the end of the Bragg peak (BP), or spread out BP, to make accurate measurements and estimations of the biological properties of a beam a high spatial resolution is required, less than a millimetre. This requirement makes silicon microdosimetry particularly attractive due to the thicknesses of the sensitive volumes commonly being ∼10 m or less. Monte Carlo (MC) codes are widely used to study the complex mixed HIT radiation field as well as to model the response of novel microdosimeter detectors when irradiated with HIT beams. Therefore it is essential to validate MC codes against experimental measurements. This work compares measurements performed with a silicon microdosimeter in mono-energetic , and ion beams of therapeutic energies, against simulation results calculated with the Geant4 toolkit. Experimental and simulation results were compared in terms of microdosimetric spectra (dose lineal energy,), the dose mean lineal energy, y D and the RBE10, as estimated by the microdosimetric kinetic model (MKM). Overall Geant4 showed reasonable agreement with experimental measurements. Before the distal edge of the BP, simulation and experiment agreed within ∼10% for y D and ∼2% for RBE10. Downstream of the BP less agreement was observed between simulation and experiment, particularly for the and beams. Simulation results downstream of the BP had lower values of y D and RBE10 compared to the experiment due to a higher contribution from lighter fragments compared to heavier fragments. [ABSTRACT FROM AUTHOR]

This article presents a study of the response of the silicon on insulator (SOI) microdosimeter with 3-D sensitive volumes (SVs) to 400 MeV/u 16O and 500 MeV/u 56Fe ions mimicking galactic cosmic rays outside and inside the International Space Station (ISS). An average quality factor (Q) and the dose equivalent (H) of the radiation field were obtained experimentally, and the results were compared with GEANT4 simulations. [ABSTRACT FROM AUTHOR]

An image-intensified, camera-based track imaging system has been developed to measure the tracks of ions in a scintillator block. To study the performance of the detector unit in the system, two types of scintillators, a dosimetrically tissue-equivalent plastic scintillator EJ-240 and a CsI(Tl) scintillator, were separately irradiated with carbon ion ( 12 C) beams of therapeutic energy from HIMAC at NIRS. The images of individual ion tracks in the scintillators were acquired by the newly developed track imaging system. The ranges reconstructed from the images are reported here. The range resolution of the measurements is 1.8 mm for 290 MeV/u carbon ions, which is considered a significant improvement on the energy resolution of the conventional Δ E / E method. The detector is compact and easy to handle, and it can fit inside treatment rooms for in-situ studies, as well as satisfy clinical quality assurance purposes. [ABSTRACT FROM AUTHOR]

Clinical trials for tumor treatment using highly energetic heavy ions are now in progress at the HIMAC. In order to achieve the radiotherapy more precisely, it is important to know the distribution of the electron density in a human body. For this purpose, we have developed a broad beam heavy ion CT system. The performance, especially the electron density resolution, of this system is estimated in this work. Some kinds of the solution targets with the known electron densities were used as samples. The projection data were obtained using 12C of 290 MeV/u, 20Ne of 400 MeV/u and 4He of 150 MeV/u. The experimental values were in good agreement with the calculated values. [Copyright &y& Elsevier]