An analysis of the effects of chronic low dose-rate radiation exposure on cancer focusing on the differences among cancer types.

PURPOSE: The effect of chronic low dose-rate radiation exposure on cancers was investigated by analyzing the data of mice experiments conducted at the Institute for Environmental Sciences (IES). This analysis focuses on the differences between malignant lymphomas and solid cancers. MATERIALS AND METHODS: The analysis is conducted based on the mathematical model introduced in our previous work. The model is expanded to analyze malignant lymphomas and solid cancers separately. Using the expanded model, the effect of chronic low dose-rate radiation on malignant lymphomas and solid cancers are discussed based on their occurrences, progressions, and mortalities. RESULTS: Non-irradiated control group and 20 mGy/day × 400 days irradiated groups are analyzed. The analysis showed that radiation exposure shortened mean life expectancy for both malignant lymphomas and solid cancers (shorter by 89.6 days for malignant lymphomas and 149.3 days for solid cancers). For malignant lymphomas, both the occurrence and the progression are affected by radiation exposure. The mean age at which malignant lymphoma developed in mice was shortened by 32.7 days and the mean progression period was shortened by 57.3 days. The occurrence of solid cancer is also affected by radiation exposure, wherein the mean age at which solid cancer develops was shortened by 147.9 days. However, no significant change in progression period of solid cancers was seen in the analysis. CONCLUSIONS: The analysis showed that the occurrence and mean lifespan are affected in both malignant lymphomas and solid cancers. The shortening of the progression period is only seen in malignant lymphoma, no significant change was observed in solid cancers.

A mathematical model for radiation-induced life-shortening attributed to cancer.

PURPOSE: In this paper, we described our mathematical model for radiation-induced life shortening in detail and applied the model to the experimental data on mice to investigate the effect of radiation on cancer-related life-shortening. MATERIALS AND METHODS: Our mathematical model incorporates the following components: (i) occurrence of cancer, (ii) progression of cancer over time, and (iii) death from cancer. We evaluated the progression of cancer over time by analyzing the cancer incidence data and cumulative mortalities data obtained from mice experiments conducted at the Institute for Environmental Sciences (IES). RESULTS: We analyzed non-irradiated control and 20 mGy/day × 400 days irradiated groups. In the analysis, all malignant neoplasms were lumped together and referred to as 'cancer'. Our analysis showed that the reduction in lifespan (104 days in median) was the result of the early onset of cancer (68 days in median) and the shortening of the cancer progression period (48 days in median). CONCLUSIONS: We described in detail our mathematical model for radiation-induced life-shortening attributed to cancer. We analyzed the mice data obtained from the experiment conducted at the IES using our model. We decomposed radiation-induced life-shortening into the early onset of cancer and the shortening of the cancer progression period.

Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation in BNCT of Brain-Tumor-Model Rats-Ex Vivo Imaging of BPA Using MALDI Mass Spectrometry Imaging.

The blood-brain barrier (BBB) is likely to be intact during the early stages of brain metastatic melanoma development, and thereby inhibits sufficient drug delivery into the metastatic lesions. Our laboratory has been developing a system for boron drug delivery to brain cells via cerebrospinal fluid (CSF) as a viable pathway to circumvent the BBB in boron neutron capture therapy (BNCT). BNCT is a cell-selective cancer treatment based on the use of boron-containing drugs and neutron irradiation. Selective tumor targeting by boron with minimal normal tissue toxicity is required for effective BNCT. Boronophenylalanine (BPA) is widely used as a boron drug for BNCT. In our previous study, we demonstrated that application of the CSF administration method results in high BPA accumulation in the brain tumor even with a low dose of BPA. In this study, we evaluate BPA biodistribution in the brain following application of the CSF method in brain-tumor-model rats (melanoma) utilizing matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI). We observed increased BPA penetration to the tumor tissue, where the color contrast on mass images indicates the border of BPA accumulation between tumor and normal cells. Our approach could be useful as drug delivery to different types of brain tumor, including brain metastases of melanoma.

COMBINED ANALYSIS OF CANCER INCIDENCE AND LIFESPAN IN MICE EXPOSED TO CHRONIC LOW DOSE RATE RADIATION.

The authors performed a combined analysis using the data obtained from continuous low dose rate irradiation experiments on mice conducted at the Institute for Environmental Sciences, namely, cancer incidence data and lifespan data. They estimated the length of cancer progression period, which is difficult to assess experimentally. The combined analysis showed that the mean cancer progression period is 173 d in the control group and 103 d in the irradiated group.

Experimental verification of real-time gamma-ray energy spectrum and dose monitor.

The purpose of this study is to develop a portable monitor that can measure the energy spectrum and dose of gamma-rays simultaneously in real time for the benefit of medical staff who must work in clinical radiation environments. For this purpose, we have developed a prototype monitor using a CsI (Tl) scintillator combined with a multi-pixel photon counter (MPPC). For real-time measurement, we employed an improved sequential Bayesian estimation (k-α method) to convert the measured pulse height spectrum into an energy spectrum. Then we confirmed that reconstruction of the energy spectrum and dose estimation could simultaneously be carried out in real time by the k-α method in a radiation field composed of mixed standard gamma-ray sources. In this study, we carried out measurements in a background gamma-ray field to confirm applicability of the prototype monitor to the weakest type of radiation field. In addition, we conducted measurements in front of a nuclear fuel storage room (∼2 µSv/h) in the authors' laboratory to evaluate practicality of the monitor for measuring fields with a complex energy spectrum. As a result, it was found that the dose could be estimated in about 20 s after start of measurements even in the background field. For the energy spectrum, it was instantly reconstructed within 60 s in front of the fuel storage room. On the other hand, it could successfully be estimated within 10 min in the background gamma-ray field. Currently, the convergence of the energy spectrum is determined visually from time dependent change of the spectrum and dose. As a next step, we will attempt to develop a more quantitative procedure for determining the convergence.

Cerebrospinal fluid-based boron delivery system may help increase the uptake boron for boron neutron capture therapy in veterinary medicine: A preliminary study with normal rat brain cells.

Boron neutron capture therapy (BNCT) is a non-invasive type of radiation therapy developed for humans and translated to veterinary medicine. However, clinical trials on BNCT for patients with brain tumors are on-going. To improve the therapeutic efficacy of BNCT for brain tumors, we developed a boron delivery system that involves the cerebrospinal fluid (CSF), in contrast to the conventional method that involves intravenous (IV) administration. This study aimed to investigate the time-concentration profile of boron in the CSF as well as the uptake rate of boron by the brain cells after administering L-p­boronophenylalanine (BPA) into the lateral ventricle of normal rats. Brain cell uptake rates were compared between the CSF-based and IV administration methods. The CSF-based and IV administration methods achieved comparable brain cell uptake levels; however, the former method involved lower BPA doses than the latter method. These findings suggest that the CSF method may reduce the economic and physical burdens associated with this treatment in brain tumor patients. Future studies should validate these findings in rat models of brain tumors.

Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation for BNCT in a Rat Melanoma Model.

Recently, exploitation of cerebrospinal fluid (CSF) circulation has become increasingly recognized as a feasible strategy to solve the challenges involved in drug delivery for treating brain tumors. Boron neutron capture therapy (BNCT) also faces challenges associated with the development of an efficient delivery system for boron, especially to brain tumors. Our laboratory has been developing a system for boron delivery to brain cells using CSF, which we call the "boron CSF administration method". In our previous study, we found that boron was efficiently delivered to the brain cells of normal rats in the form of small amounts of L-p-boronophenylalanine (BPA) using the CSF administration method. In the study described here, we carried out experiments with brain tumor model rats to demonstrate the usefulness of the CSF administration method for BNCT. We first investigated the boron concentration of the brain cells every 60 min after BPA administration into the lateral ventricle of normal rats. Second, we measured and compared the boron concentration in the melanoma model rats after administering boron via either the CSF administration method or the intravenous (IV) administration method, with estimation of the T/N ratio. Our results revealed that boron injected by the CSF administration method was excreted quickly from normal cells, resulting in a high T/N ratio compared to that of IV administration. In addition, the CSF administration method resulted in high boron accumulation in tumor cells. In conclusion, we found that using our developed CSF administration method results in more selective delivery of boron to the brain tumor compared with the IV administration method.

Design of SPECT for BNCT to measure local boron dose with GAGG scintillator.

Boron Neutron Capture Therapy (BNCT) is a promising cancer therapy, which has recently been in practical use in Japan especially using an accelerator. In BNCT real-time measurement of local boron dose is required. In the present study, a novel design of a SPECT system for BNCT (BNCT-SPECT) has been carried out to realize estimation of the local boron dose, i.e., treatment effect of BNCT. Necessary performance which BNCT community requires includes accuracy of 5% and spatial resolution of 5 mm, which are regarded to be difficult to realize. A possible design was investigated to meet the requirements. The design results we achieved are as follows: As for the elemental detection device, GAGG (3.5 × 3.5 × 30 mm3) was selected, and for the collimator, the collimator hole diameter was 3.5 mm, the collimator hole pitch was 4 mm and the collimator length was 26 cm. For the obtained performance with the design, the accuracy was 4.4% and the spatial resolution was 5.1 mm. Currently prior to production of the real system, a prototype of BNCT-SPECT is being developed to acquire real projection data to confirm the performance and examine our own image reconstruction method with the obtained projection data.

Development of epi-thermal neutron beam intensity detector with 71Ga(n,γ)72Ga reaction for boron neutron capture therapy.

Based on the activation method using 71Ga(n,γ)72Ga reaction, a cubic neutron flux intensity detector for epi-thermal neutrons was designed for boron neutron capture therapy (BNCT), and experimentally tested with a prototype detector in a neutron field produced at OKTAVIAN facility of Osaka University, Japan. The experimental test results and related analysis indicated that the performance of the detector was confirmed to be acceptable in the neutron field of BNCT. Practically, the neutron flux intensity mainly covering from 0.5 eV to 10 keV can be measured within 3% by the present detector.

DESIGN IMPROVEMENT OF A LIQUID-MODERATOR-BASED NEUTRON SPECTROMETER FOR BNCT.

Boron neutron capture therapy is known to be an effective radiation cancer therapy that requires neutron irradiation. A neutron field generated by an accelerator-based neutron source has various energy spectra, and it is necessary to evaluate the neutron spectrum in the treatment field. However, the method used to measure the neutron spectrum in the treatment field is not well established. Many researchers are making efforts to improve the spectrometers. To solve this problem, we are developing a liquid-moderator-based neutron spectrometer that is based on the same theory as that of the Bonner sphere spectrometer. The spectrometer uses a liquid moderator and absorber. In the present study, we performed a design study to improve the previously developed liquid-moderator-based neutron spectrometer. By carrying out a numerical simulation of the designed new spectrometer, we finally assessed and confirmed the validity of this spectrometer numerically.

DEVELOPMENT OF ISOTOPICALLY ENRICHED BORON-DOPED ALUMINA DOSIMETER FOR THERMAL NEUTRONS.

A novel optically stimulated luminescence (OSL) detector containing isotopically enriched boron was developed for thermal neutron dosimetry. Alumina containing isotopically enriched boron (Al2O3:B) was synthesised by the sol-gel method. The Al2O3:B was annealed up to ~1800 K. For X-ray diffractometer (XRD) analysis, the diffraction pattern of the Al2O3:B had reflex peaks corresponding to α-Al2O3. The sensitivity of Al2O3:B to photons was slightly 2% of that of a commercial Al2O3:C. The Al2O3:B detector had satisfactory linearity in X-ray dose measurement. A thermal neutron field was constructed using a 241Am-Be neutron source and graphite blocks. A pair of Al2O3:10B and Al2O3:11B detectors were set in the thermal neutron field. The response of Al2O3:10B was larger than that of Al2O3:11B owing to the 10B(n,α)7Li reactions. The sensitivity of Al2O3:10B to thermal neutrons was estimated to be two orders less than the photon sensitivity. Therefore, the pair of Al2O3:10B and Al2O3:11B detectors were useful for thermal neutron dosimetry.

Performance testing of the neutron flux monitors from 10keV to 1MeV developed for BNCT: A preliminary study.

The neutron flux monitors from 10keV to 1MeV designed for boron neutron capture therapy (BNCT) were experimentally tested with prototype monitors in an appropriate neutron field produced at the intense deuterium-tritium neutron source facility OKTAVIAN of Osaka University, Japan. The experimental test results and related analysis indicated that the performance of the monitors was good and the neutron fluxes from 10keV to 1MeV of practical BNCT neutron sources can be measured within 10% by the monitors.

Experimental study on the performance of an epithermal neutron flux monitor for BNCT.

The performance of an epithermal neutron (0.5eV

First operation and effect of a new tandem-type ion source based on electron cyclotron resonance.

A new tandem type source has been constructed on the basis of electron cyclotron resonance plasma for producing synthesized ion beams in Osaka University. Magnetic field in the first stage consists of all permanent magnets, i.e., cylindrically comb shaped one, and that of the second stage consists of a pair of mirror coil, a supplemental coil and the octupole magnets. Both stage plasmas can be individually operated, and produced ions in which is energy controlled by large bore extractor also can be transported from the first to the second stage. We investigate the basic operation and effects of the tandem type electron cyclotron resonance ion source (ECRIS). Analysis of ion beams and investigation of plasma parameters are conducted on produced plasmas in dual plasmas operation as well as each single operation. We describe construction and initial experimental results of the new tandem type ion source based on ECRIS with wide operation window for aiming at producing synthesized ion beams as this new source can be a universal source in future.

Accessibility condition of wave propagation and multicharged ion production in electron cyclotron resonance ion source plasma.

A new tandem type source of electron cyclotron resonance (ECR) plasmas has been constructing for producing synthesized ion beams in Osaka University. Magnetic mirror field configuration with octupole magnets can be controlled to various shape of ECR zones, namely, in the 2nd stage plasma to be available by a pair mirror and a supplemental coil. Noteworthy correlations between these magnetic configurations and production of multicharged ions are investigated in detail, as well as their optimum conditions. We have been considering accessibility condition of electromagnetic and electrostatic waves propagating in ECR ion source plasma, and then investigated their correspondence relationships with production of multicharged ions. It has been clarified that there exits efficient configuration of ECR zones for producing multicharged ion beams experimentally, and then has been suggested from detail accessibility conditions on the ECR plasma that new resonance, i.e., upper hybrid resonance, must have occurred.

Experimental results of superimposing 9.9 GHz extraordinary mode microwaves on 2.45 GHz ECRIS plasma.

Efficient production of multicharged ions has been investigated on the tandem-type ECRIS in Osaka University. According to the consideration of the accessibility conditions of microwaves to resonance and cutoff regions, it was suggested that the upper hybrid resonance (UHR) heating contributed to enhancement of ion beam intensity. In order to enhance multicharged ion beams efficiently, injecting higher frequency microwave with extraordinary (X-mode) toward UHR region has been tried. In this study, 2.45 GHz frequency microwaves are used for conventional ECR discharge, and 9.9 GHz frequency microwaves with X-mode are superimposed for UHR heating. The effects of additive microwave injection are investigated experimentally in terms of plasma parameters and electron energy distribution function (EEDF) measured by Langmuir probe and ion beam current. As the results show, it is confirmed that the electrons in the high energy region are affected by 9.9 GHz X-mode microwave injection from the detailed analysis of EEDF.

Production of multicharged metal ion beams on the first stage of tandem-type ECRIS.

Multicharged metal ion beams are required to be applied in a wide range of fields. We aim at synthesizing iron-endohedral fullerene by transporting iron ion beams from the first stage into the fullerene plasma in the second stage of the tandem-type electron cyclotron resonance ion source (ECRIS). We developed new evaporators by using a direct ohmic heating method and a radiation heating method from solid state pure metal materials. We investigate their properties in the test chamber and produce iron ions on the first stage of the tandem-type ECRIS. As a result, we were successful in extracting Fe(+) ion beams from the first stage and introducing Fe(+) ion beams to the second stage. We will try synthesizing iron-endohedral fullerene on the tandem-type ECRIS by using these evaporators.

Producing multicharged fullerene ion beam extracted from the second stage of tandem-type ECRIS.

We have been constructing the tandem-type electron cyclotron resonance ion source (ECRIS). Two ion sources of the tandem-type ECRIS are possible to generate plasma individually, and they also confined individual ion species by each different plasma parameter. Hence, it is considered to be suitable for new materials production. As the first step, we try to produce and extract multicharged C60 ions by supplying pure C60 vapor in the second stage plasma because our main target is producing the endohedral fullerenes. We developed a new evaporator to supply fullerene vapor, and we succeeded in observation about multicharged C60 ion beam in tandem-type ECRIS for the first time.

Basic detection property of an array-type CdTe detector for BNCT-SPECT - Measurement and analysis of anti-coincidence events.

Our research group is now investigating a BNCT-SPECT system with cadmium tellurite (CdTe) detectors, which can obtain a three-dimensional image of the BNCT treatment effect by measuring the 478keV gamma-rays emitted from an excited state of the 7Li nucleus generated by the 10B(n,α) reaction. The BNCT-SPECT system is composed of a collimator and an array-type CdTe detector. In this study, we produced an array detector with two CdTe elements to test the basic detection property for anti-coincidence events. Our investigation confirmed that the detector offers an improved S/N ratio by the anti-coincidence detection. We also proposed an estimation method using the MCNP5 to analyze coincidence events in the detector.

Neutron intensity monitor with activation foil for p-Li neutron source for BNCT--Feasibility test of the concept.

Proton-lithium (p-Li) reaction is being examined worldwide as a candidate nuclear production reaction for accelerator based neutron source (ABNS) for BNCT. In this reaction, the emitted neutron energy is not so high, below 1 MeV, and especially in backward angles the energy is as low as about 100 keV. The intensity measurement was thus known to be difficult so far. In the present study, a simple method was investigated to monitor the absolute neutron intensity of the p-Li neutron source by employing the foil activation method based on isomer production reactions in order to cover around several hundreds keV. As a result of numerical examination, it was found that (107)Ag, (115)In and (189)Os would be feasible. Their features found out are summarized as follows: (107)Ag: The most convenient foil, since the half life is short. (115)In: The accuracy is the best at 0°, though it cannot be used for backward angles. And (189)Os: Suitable nuclide which can be used in backward angles, though the gamma-ray energy is a little too low. These would be used for p-Li source monitoring depending on measuring purposes in real BNCT scenes.