Adverse effects of cell-free and concentrated ascites reinfusion therapy for malignant ascites: a single-institute experience.

BACKGROUND: Cell-free and concentrated ascites reinfusion therapy (CART) is a strategy for improving various intractable symptoms due to refractory ascites, including hypoalbuminemia. CART has recently been applied in the treatment of cancer patients. This study was performed to assess the safety of CART in a single cancer institute. METHODS: We retrospectively reviewed 233 CART procedures that were performed for 132 cancer patients in our institute. RESULTS: The median weight of ascites before and after concentration was 4,720 g and 490 g (median concentration rate, 10.0-fold), The median amounts of total protein and albumin were 64.0 g and 32.6 g (median recovery rates, 44.9% and 49.0%), respectively. Thirty-three adverse events (AEs) were observed in 22 (9.4%) of 233 procedures; 30 of these events occurred after reinfusion. The most common reinfusion-related AEs were fever (13 events) and chills (10 events). Univariate analyses revealed no significant relationships between the frequency of AEs and age, sex, appearance of ascites, weight of harvested and concentrated ascites, the ascites processing rate (filtration and concentration), weight of saline used for membrane cleaning, amount of calculated total protein for infusion, or prophylaxis against AEs; the reinfusion rate of ≥ 125 mL/h or ≥ 10.9 g/h of total protein affected the frequency of AEs, regardless of the prophylactic use of steroids. CONCLUSIONS: The observed AEs were mainly mild reactions after reinfusion, which were related to a reinfusion rate of volume ≥ 125 mL/h, a simple indicator in practice, or total protein ≥ 10.9 g/h. Although our study was retrospective in nature and undertaken in a single institute, this information may be helpful for the management of cancer patients with refractory malignant ascites using CART.

Hyperpolarized 13 C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in†vivo Study.

The front cover artwork is provided by the group of Dr. Neil J. Stewart, Prof. Hiroshi Hirata, and Dr. Shingo Matsumoto (Hokkaido University, Japan) as well as Dr. Takuya Hashimoto (Chiba University, Japan). The image shows hyperpolarized 13 C fumarate metabolism to hyperpolarized 13 C malate, which is released into the extracellular space in regions of necrotic cell death, where the cell membrane is disrupted. Read the full text of the Article at 10.1002/cphc.202001038.

Hyperpolarized 13 C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in†vivo Study.

Hyperpolarized [1-13 C]fumarate is a promising magnetic resonance imaging (MRI) biomarker for cellular necrosis, which plays an important role in various disease and cancerous pathological processes. To demonstrate the feasibility of MRI of [1-13 C]fumarate metabolism using parahydrogen-induced polarization (PHIP), a low-cost alternative to dissolution dynamic nuclear polarization (dDNP), a cost-effective and high-yield synthetic pathway of hydrogenation precursor [1-13 C]acetylenedicarboxylate (ADC) was developed. The trans-selectivity of the hydrogenation reaction of ADC using a ruthenium-based catalyst was elucidated employing density functional theory (DFT) simulations. A simple PHIP set-up was used to generate hyperpolarized [1-13 C]fumarate at sufficient 13 C polarization for ex vivo detection of hyperpolarized 13 C malate metabolized from fumarate in murine liver tissue homogenates, and in vivo 13 C MR spectroscopy and imaging in a murine model of acetaminophen-induced hepatitis.

Usefulness of hematopoietic progenitor cell monitoring to predict autologous peripheral blood stem cell harvest timing: A single-center retrospective study.

INTRODUCTION: In autologous peripheral blood stem cell harvest (APBSCH), CD34-positive cells have been measured to assess the numbers of hematopoietic stem cells, but measurement requires specialized equipment. Recently, there was a report that peripheral blood hematopoietic progenitor cells (HPCs) are useful indicators of the presence of hematopoietic stem cells. We examined the usefulness of HPC monitoring to predict APBSCH timing. METHODS: We retrospectively analyzed the relationship between HPC and collected CD34-positive cells in 84 consecutive patients who underwent APBSCH. RESULTS: According to the receiver operating characteristics curve for the collection of ≥2 × 106 CD34-positive cells/kg, the HPC cut-off value on the day before collection was 21/µL, while that on the day of collection was 41/µL. No significant factors were found in the univariate analysis except for the HPC count on the day before collection (p < 0.001) and the day of collection (p < 0.001). According to the multivariate analysis, the HPC count on the day before collection (p < 0.001) and the day of collection (p < 0.001) were also factors that strongly influenced the quantity of CD34-positive cells collected. CONCLUSION: Our results suggest that the HPC count on not only the day of collection but also the day before collection is a good indicator for appropriate APBSCH timing.

Evaluation of SCCVII tumor cell survival in clamped and non-clamped solid tumors exposed to carbon-ion beams in comparison to X-rays.

The aim of this study was to measure the RBE (relative biological effectiveness) and OER (oxygen enhancement ratio) for survival of cells within implanted solid tumors following exposure to 290MeV/nucleon carbon-ion beams or X-rays. Squamous cell carcinoma cells (SCCVII) were transplanted into the right hind legs of syngeneic C3H male mice. Irradiation with either carbon-ion beams with a 6-cm spread-out Bragg peak (SOBP, at 46 and 80keV/µm) or X-rays was delivered to 5-mm or less diameter tumors. We defined three different oxygen statuses of the irradiated cells. Hypoxic and normoxic conditions in tumors were produced by clamping or not clamping the leg to avoid blood flow. Furthermore, single-cell suspensions were prepared from non-irradiated tumors and directly used to determine the radiation response of aerobic cells. Single-cell suspensions (aerobic condition) were fully air-saturated. Single-cell suspensions were prepared from excised and trypsinized tumors, and were used for in vivo-in vitro colony formation assays to obtain cell survival curves. The RBE values increased with increasing LET in SOBP beams. The maximum RBE values in three different oxygen conditions; hypoxic tumor, normoxic tumor and aerobic cells, were 2.16, 1.76 and 1.66 at an LET of 80keV/µm, respectively. After X-ray irradiation the OERh/n values (hypoxic tumor/normoxic tumor) were lower than the OERh/a (hypoxic tumor/aerobic cells), and were 1.87±0.13 and 2.52±0.11, respectively. The OER values of carbon-ion irradiated samples were small in comparison to those of X-ray irradiated samples. However, no significant changes of the OER at proximal and distal positions within the SOBP carbon-ion beams were observed. To conclude, we found that the RBE values for cell survival increased with increasing LET and that the OER values changed little with increasing LET within the SOBP carbon-ion beams.

Microdosimetric study on influence of low energy photons on relative biological effectiveness under therapeutic conditions using 6 MV linac.

PURPOSE: Microdosimetry has been developed for the evaluation of radiation quality, and single-event dose-mean lineal energy y(D) is well-used to represent the radiation quality. In this study, the changes of the relative biological effectiveness (RBE) values under the therapeutic conditions using a 6 MV linac were investigated with a microdosimetric method. METHODS: The y(D) values under the various irradiation conditions for x-rays from a 6 MV linac were measured with a tissue-equivalent proportional counter (TEPC) at an extremely low dose rate of a few tens of microGy/min by decreasing the gun grid voltage of the linac. According to the microdosimetric kinetic model (MK model), the RBE(MK) values for cell killing of the human salivary gland (HSG) tumor cells can be derived if the y(D) values are obtained from TEPC measurements. The Monte Carlo code GEANT4 was also used to calculate the photon energy distributions and to investigate the changes of the y(D) values under the various conditions. RESULTS: The changes of the y(D) values were less than approximately 10% when the field size and the depth in a phantom varied. However, in the measurements perpendicular to a central beam axis, large changes were observed between the y(D) values inside the field and those outside the field. The maximum increase of approximately 50% in the y(D) value outside the field was obtained compared with those inside the field. The GEANT4 calculations showed that there existed a large relative number of low energy photons outside of the field as compared with inside of the field. The percentages of the photon fluences below 200 keV outside the field were approximately 40% against approximately 8% inside the field. By using the MK model, the field size and the depth dependence of the RBEMK values were less than approximately 2% inside the field. However, the RBEMK values outside the field were 6.6% higher than those inside the field. CONCLUSIONS: The increase of the RBE(MK) values by 6.6% outside the field was observed. This increase is caused by the change of the photon energy distributions, especially the increase of the relative number of low energy photons outside the field.

Measurement of absorbed dose, quality factor, and dose equivalent in water phantom outside of the irradiation field in passive carbon-ion and proton radiotherapies.

PURPOSE: Successful results in carbon-ion and proton radiotherapies can extend patients' lives and thus present a treatment option for younger patients; however, the undesired exposure to normal tissues outside the treatment volume is a concern. Organ-specific information on the absorbed dose and the biological effectiveness in the patient is essential for assessing the risk, but experimental dose assessment has seldom been done. In this study, absorbed doses, quality factors, and dose equivalents in water phantom outside of the irradiation field were determined based on lineal energy distributions measured with a commercial tissue equivalent proportional counter (TEPC) at passive carbon-ion and proton radiotherapy facilities. METHODS: Measurements at eight positions in the water phantom were carried out at the Heavy-Ion Medical Accelerator in Chiba of the National Institute of Radiological Sciences for 400 and 290 MeV/u carbon beams and at the National Cancer Center Hospital East for a 235 MeV proton beam. RESULTS: The dose equivalent per treatment absorbed dose at the center of the range-modulated region H/Dt, decreased as the position became farther from the beam axis and farther from the phantom surface. The values of H/Dt ranged from 6.7 to 0.16 mSv/Gy for the 400 MeV/u carbon beam, from 1.3 to 0.055 mSv/Gy for the 290 MeV/u carbon beam, and from 4.7 to 0.24 mSv/GV for the 235 MeV proton beam. The values of the dose-averaged quality factor QD ranged from 2.4 to 4.6 for the 400 MeV/u beam, from 2.8 to 5.3 for the 290 MeV/u beam, and from 5.1 to 8.2 for the proton beam. The authors also observed differences in the distributions of H/Dt and QD between the carbon and proton beams. CONCLUSIONS: The authors experimentally obtained absorbed doses, dose-averaged quality factors, and dose equivalents in water phantom outside of the irradiation field in passive carbon-ion and proton radiotherapies with TEPC. These data are very useful for estimating the risk of secondary cancer after receiving passive radiotherapies and for verifying Monte Carlo calculations.

Development of a new microdosimetric biological weighting function for the RBE10 assessment in case of the V79 cell line exposed to ions from 1H to 238U.

An improved biological weighting function (IBWF) is proposed to phenomenologically relate microdosimetric lineal energy probability density distributions with the relative biological effectiveness (RBE) for the in vitro clonogenic cell survival (surviving fraction = 10%) of the most commonly used mammalian cell line, i.e. the Chinese hamster lung fibroblasts (V79). The IBWF, intended as a simple and robust tool for a fast RBE assessment to compare different exposure conditions in particle therapy beams, was determined through an iterative global-fitting process aimed to minimize the average relative deviation between RBE calculations and literature in vitro data in case of exposure to various types of ions from 1H to 238U. By using a single particle- and energy- independent function, it was possible to establish an univocal correlation between lineal energy and clonogenic cell survival for particles spanning over an unrestricted linear energy transfer range of almost five orders of magnitude (0.2 keV µm-1 to 15 000 keV µm-1 in liquid water). The average deviation between IBWF-derived RBE values and the published in vitro data was ∼14%. The IBWF results were also compared with corresponding calculations (in vitro RBE10 for the V79 cell line) performed using the modified microdosimetric kinetic model (modified MKM). Furthermore, RBE values computed with the reference biological weighting function (BWF) for the in vivo early intestine tolerance in mice were included for comparison and to further explore potential correlations between the BWF results and the in vitro RBE as reported in previous studies. The results suggest that the modified MKM possess limitations in reproducing the experimental in vitro RBE10 for the V79 cell line in case of ions heavier than 20Ne. Furthermore, due to the different modelled endpoint, marked deviations were found between the RBE values assessed using the reference BWF and the IBWF for ions heavier than 2H. Finally, the IBWF was unchangingly applied to calculate RBE values by processing lineal energy density distributions experimentally measured with eight different microdosimeters in 19 1H and 12C beams at ten different facilities (eight clinical and two research ones). Despite the differences between the detectors, irradiation facilities, beam profiles (pristine or spread out Bragg peak), maximum beam energy, beam delivery (passive or active scanning), energy degradation system (water, PMMA, polyamide or low-density polyethylene), the obtained IBWF-based RBE trends were found to be in good agreement with the corresponding ones in case of computer-simulated microdosimetric spectra (average relative deviation equal to 0.8% and 5.7% for 1H and 12C ions respectively).

Biological dose estimation for charged-particle therapy using an improved PHITS code coupled with a microdosimetric kinetic model.

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.

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/mum 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/mum. Therefore, even though the radiochemically estimated G value of OH radicals was nearly zero at an LET of 1000 keV/mum, 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/mum, and decreased thereafter. When the RBE was estimated separately for direct action (RBE(D)) and indirect action (RBE(I)); both exhibited an LET dependence similar to that of the RBE, peaking at 200 keV/mum. However, the peak value was much higher for RBE(D) (5.99) than RBE(I) (1.89). Thus direct action contributes more to the high RBE of high-LET radiations than indirect action does.

Development of an irradiation method with lateral modulation of SOBP width using a cone-type filter for carbon ion beams.

Passive irradiation methods deliver an extra dose to normal tissues upstream of the target tumor, while in dynamic irradiation methods, interplay effects between dynamic beam delivery and target motion induced by breathing or respiration distort the dose distributions. To solve the problems of those two irradiation methods, the authors have developed a new method that laterally modulates the spread-out Bragg peak (SOBP) width. By reducing scanning in the depth direction, they expect to reduce the interplay effects. They have examined this new irradiation method experimentally. In this system, they used a cone-type filter that consisted of 400 cones in a grid of 20 cones by 20 cones. There were five kinds of cones with different SOBP widths arranged on the frame two dimensionally to realize lateral SOBP modulation. To reduce the number of steps of cones, they used a wheel-type filter to make minipeaks. The scanning intensity was modulated for each SOBP width with a pair of scanning magnets. In this experiment, a stepwise dose distribution and spherical dose distribution of 60 mm in diameter were formed. The nonflatness of the stepwise dose distribution was 5.7% and that of the spherical dose distribution was 3.8%. A 2 mm misalignment of the cone-type filter resulted in a nonflatness of more than 5%. Lateral SOBP modulation with a cone-type filter and a scanned carbon ion beam successfully formed conformal dose distribution with nonflatness of 3.8% for the spherical case. The cone-type filter had to be set to within 1 mm accuracy to maintain nonflatness within 5%. This method will be useful to treat targets moving during breathing and targets in proximity to important organs.

AAPM task group 224: Comprehensive proton therapy machine quality assurance.

PURPOSE:  Task Group (TG) 224 was established by the American Association of Physicists in Medicine's Science Council under the Radiation Therapy Committee and Work Group on Particle Beams. The group was charged with developing comprehensive quality assurance (QA) guidelines and recommendations for the three commonly employed proton therapy techniques for beam delivery: scattering, uniform scanning, and pencil beam scanning. This report supplements established QA guidelines for therapy machine performance for other widely used modalities, such as photons and electrons (TG 142, TG 40, TG 24, TG 22, TG 179, and Medical Physics Practice Guideline 2a) and shares their aims of ensuring the safe, accurate, and consistent delivery of radiation therapy dose distributions to patients. METHODS:  To provide a basis from which machine-specific QA procedures can be developed, the report first describes the different delivery techniques and highlights the salient components of the related machine hardware. Depending on the particular machine hardware, certain procedures may be more or less important, and each institution should investigate its own situation. RESULTS:  In lieu of such investigations, this report identifies common beam parameters that are typically checked, along with the typical frequencies of those checks (daily, weekly, monthly, or annually). The rationale for choosing these checks and their frequencies is briefly described. Short descriptions of suggested tools and procedures for completing some of the periodic QA checks are also presented. CONCLUSION:  Recommended tolerance limits for each of the recommended QA checks are tabulated, and are based on the literature and on consensus data from the clinical proton experience of the task group members. We hope that this and other reports will serve as a reference for clinical physicists wishing either to establish a proton therapy QA program or to evaluate an existing one.

Liver phantom design and dosimetric verification in participating institutions for a proton beam therapy in patients with resectable hepatocellular carcinoma: Japan Clinical Oncology Group trial (JCOG1315C).

BACKGROUND AND PURPOSE: In Japan, the first domestic clinical trial of proton beam therapy for the liver was initiated as the Japan Clinical Oncology Group trial (JCOG1315C: Non-randomized controlled study comparing proton beam therapy and hepatectomy for resectable hepatocellular carcinoma). Purposes of this study were to develop a new dosimetric verification system and to carry out a credentialing for the JCOG1315C clinical trial. MATERIALS AND METHODS: Accuracy and differences in doses in proton treatment planning among participating institutions were surveyed and investigated. We designed and developed a suitable water tank-type liver phantom for a dosimetric verification of proton beam therapy for liver. In a visiting survey of five institutions participating in the clinical trial, we performed the dosimetric verification using the liver phantom and an air-filled ionization chamber. RESULTS: The shape of the dose distributions calculated in proton treatment planning was characteristic and dependent on the manufacturers of the proton beam therapy system, the proton treatment planning system and the setup at the participating institutions. Widths of the lateral penumbra were 5.8-12.7 mm among participating institutions. The accuracy between the calculated and the measured doses in the proton irradiation was within 3% at five measurement points including both points on the isocenter and off the isocenter. CONCLUSIONS: These findings confirmed the accuracy of the delivery doses in the institutions participating in the clinical trial, and the clinical trial with integration of all institutions (five institutions) could be initiated.

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.

Dose contributions from large-angle scattered particles in therapeutic carbon beams.

In carbon therapy, doses at center of spread-out Bragg peaks depend on field size. For a small field of 5 x 5 cm2, the central dose reduces to 96% of the central dose for the open field in case of 400 MeV/n carbon beam. Assuming the broad beam injected to the water phantom is made up of many pencil beams, the transverse dose distribution can be reconstructed by summing the dose distribution of the pencil beams. We estimated dose profiles of this pencil beam through measurements of dose distributions of broad uniform beams blocked half of the irradiation fields. The dose at a distance of a few cm from the edge of the irradiation field reaches up to a few percent of the central dose. From radiation quality measurements of this penumbra, the large-angle scattered particles were found to be secondary fragments which have lower LET than primary carbon beams. Carbon ions break up in beam modifying devices or in water phantom through nuclear interaction with target nuclei. The angular distributions of these fragmented nuclei are much broader than those of primary carbon particles. The transverse dose distribution of the pencil beam can be approximated by a function of the three-Gaussian form. For a simplest case of mono-energetic beam, contributions of the Gaussian components which have large mean deviations become larger as the depth in the water phantom increases.

Simplified estimation method for dose distributions around field junctions in proton craniospinal irradiation.

In radiotherapy involving craniospinal irradiation (CSI), field junctions of therapeutic beams are necessary, because a CSI target is generally several times larger than the maximum field size of the beams. The purpose of this study was to develop a simplified method for estimating dose uniformity around the field junctions in proton CSI. We estimated the dose profiles around the field junctions of proton beams using a simplified field-junction model, in which partial lateral dose distributions around the field edge were assumed to be approximated using the error function. We measured the lateral dose distributions of the proton beams planned for the CSI treatment using a two-dimensional (2D) ionization chamber array. Although dose hot spots and cold spots tend to be underestimated by a chamber array because of the partial volume effect of the sensitive volume and discrete chamber positions, the model estimation results were fairly consistent with the measurements obtained using a 2D chamber array subjected to CSI-simulated serial irradiation. The simplified junction model enabled us to estimate the dose distributions and dependence of the setup position gap on the dose uniformity around the field junctions on the basis of the field-by-field dose profiles measured using the 2D chamber array.

Microdosimetric measurements and estimation of human cell survival for heavy-ion beams.

The microdosimetric spectra for high-energy beams of photons and proton, helium, carbon, neon, silicon and iron ions (LET = 0.5-880 keV/microm) 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 alpha terms of the liner-quadratic model with a fixed beta value reproduced the experimental results for cell irradiation for ion beams with LETs of less than 450 keV/microm, except in the region near the distal peak.

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.

Responses of a diamond detector to high-LET charged particles.

The responses of a commercial diamond detector (type 60003, PTW-Freiburg) to several heavy ions were examined. The responses to heavy-ion beams reached stable levels with relatively small pre-irradiation doses compared to photon-beam irradiations. The responses also reached stable levels with a smaller pre-irradiation dose when the dose rate of the He beams was increased. A total accumulated dose of about 5 Gy was required for the pre-irradiation dose of heavy-ion beams. No angular dependence of the detector responses was observed within a deviation of 5%. The dose-rate dependence of the detector responses to heavy-ion beams was far smaller than that to gamma rays. The decrease in the response was within 0.9%, with a variation from 0.88 to 18.2 Gy min(-1) in the carbon beam. We examined the LET dependence of the diamond detector responses using various kinds of heavy-ion beams. The responses had particle dependence in addition to LET dependence. The responses decreased more with higher LET particles and decreased less with large-Z particles. We proposed a gradual-saturation model based on the track structure under several simple assumptions to explain the LET and particle dependences of the response.

Designing a ridge filter based on a mouse foot skin reaction to spread out Bragg-peaks for carbon-ion radiotherapy.

BACKGROUND AND PURPOSE: Carbon-ion radiotherapy uses spread-out Bragg peaks (SOBP) to produce uniform biological effects within a target volume. The relative biological effectiveness is determined by the in vitro cell kill after a single dose is employed to design the SOBP. A question remains as to whether biological effects for in vivo tissues after fractionated doses are also uniform within the SOBP. MATERIAL AND METHODS: Mouse foot skin was irradiated with fractionated doses of carbon ions at various linear energy transfer (LET) values. A new ridge filter was designed based on alpha and beta values for each LET to cause moderate skin reaction, and was studied concerning its uniformity. RESULTS: The reciprocal total doses of intermediate-LET carbon ions and of reference gamma rays linearly increased with an increase of a dose per fraction in Fe-plots. As the single total dose of higher LET run off linearity, data obtained from 2 to 6 fractions were used to design a new ridge filter. The physical dose distribution of the new ridge filter was almost identical to, and indistinguishable from, the ridge filter designed based on the in vitro cell kill. CONCLUSIONS: The LET dependence of alpha is a principle of the biological factor to be used for designing spread-out Bragg peaks of carbon-ion radiotherapy.