Study of dose component discrimination method using micelle gel dosimeters for quality assurance in boron neutron capture therapy.

Research and development of various accelerator-based irradiation systems for boron neutron capture therapy (BNCT) is underway throughout the world. Many of these systems are nearing or have started clinical trials. Before the start of treatment with BNCT, the relative biological effectiveness (RBE) for the fast neutrons (over 10 keV) incident to the irradiation field must be estimated. Measurements of RBE are typically performed by biological experiments with a phantom. Although the dose deposition due to secondary gamma rays is dominant, the relative contributions of thermal neutrons (below 0.5 eV) and fast neutrons are virtually equivalent under typical irradiation conditions in a water and/or acrylic phantom. Uniform contributions to the dose deposited from thermal and fast neutrons are based in part on relatively inaccurate dose information for fast neutrons. This study sought to improve the accuracy in the dose estimation for fast neutrons by using two phantoms made of different materials in which the dose components can be separated according to differences in the interaction cross sections. The development of a "dual phantom technique" for measuring the fast neutron component of dose is reported. One phantom was filled with pure water. The other phantom was filled with a water solution of lithium hydroxide (LiOH) capitalizing on the absorbing characteristics of lithium-6 (Li-6) for thermal neutrons. Monte Carlo simulations were used to determine the ideal mixing ratio of Li-6 in LiOH solution. Changes in the depth dose distributions for each respective dose component along the central beam axis were used to assess the LiOH concentration at the 0, 0.001, 0.01, 0.1, 1, and 10 wt. % levels. Simulations were also performed with the phantom filled with 10 wt. % 6LiOH solution for 95%-enriched Li-6. A phantom was constructed containing 10 wt. % 6LiOH solution based on the simulation results. Experimental characterization of the depth dose distributions of the neutron and gamma-ray components along the central axis was performed at Heavy Water Neutron Irradiation Facility installed at Kyoto University Reactor using activation foils and thermoluminescent dosimeters, respectively. Simulation results demonstrated that the absorbing effect for thermal neutrons occurred when the LiOH concentration was over 1%. The most effective Li-6 concentration was determined to be enriched 6LiOH with a solubility approaching its upper limit. Experiments confirmed that the thermal neutron flux and secondary gamma-ray dose rate decreased substantially; however, the fast neutron flux and primary gamma-ray dose rate were hardly affected in the 10%-6LiOH phantom. It was confirmed that the dose contribution of fast neutrons is improved from approximately 10% in the pure water phantom to approximately 50% in the 10%-6LiOH phantom. The dual phantom technique using the combination of a pure water phantom and a 10%-6LiOH phantom developed in this work provides an effective method for dose estimation of the fast neutron component in BNCT. Improvement in the accuracy achieved with the proposed technique results in improved RBE estimation for biological experiments and clinical practice.

As a method for three-dimensional quality assurance in boron neutron capture therapy (BNCT), micelle gel dosimeters are focused on. We are investigating dose-component discrimination method by using multiple gel dosimeters which have each different radiation quality specificity. In this study, the characteristics of each gel dosimeter for neutrons and gamma-rays were evaluated, and a dose-component discrimination method was suggested.

Preliminary study of a compact epithermal neutron absolute flux intensity measurement system for real-time in-vivo dose monitoring in boron neutron capture therapy

The neutron beam in a boron neutron capture therapy (BNCT) irradiation field comprises a range of energies with different relative biological effectiveness. The neutron energy spectrum can change over time due to variations in the neutron source. Current methods for measuring the neutron energy spectrum are impractical and have significant limitations, such as being time-consuming and posing radiation exposure risks; therefore, neutron energy spectrum measurement has not been incorporated into routine BNCT quality assurance (QA) procedures. To address these issues, we developed a cylindrical hemisphere accurate remote multilayer spectrometer (CHARMS) that integrates a liquid moderator supply and drainage system with real-time neutron detection for suitable use in the BNCT QA procedure. To validate CHARMS for QA procedures in BNCT irradiation field. We conducted experimental validations of CHARMS at the Heavy Water Neutron Irradiation Facility of Kyoto University Reactor under two irradiation conditions (with and without a collimator), performing three separate measurement sessions over 3 months. The total measurement time required by CHARMS to achieve a target neutron count uncertainty below 1% was less than 10min. Monitoring the neutron counts at ten uniformly spaced intervals during each measurement showed that most counts fell within a Poisson-derived standard deviation. The neutron energy spectrum under irradiation without collimator was successfully evaluated. However, because of the effects of the neutron beam intensity and angular distribution in BNCT, the neutron energy spectrum under irradiation with collimator could not be properly evaluated. The validity of the CHARMS for QA procedures in BNCT was confirmed. The rapid measurements and stable operation of the liquid moderator injection and drainage system show that CHARMS is well-suited for routine BNCT QA, eliminating the need for moderator replacement and thereby minimizing radiation exposure. Future work will address the challenges related to neutron beam intensity and angular distribution to enable the evaluation of neutron energy spectrum unfolding under collimated irradiation conditions, which is essential for clinical BNCT.

Simulation for improved collimation system of gamma-ray telescope system for boron neutron capture therapy at Kyoto University Reactor

Development and dosimetric evaluation of radiochromic PCDA vesicle gel dosimeters

The feasibility of neutron capture therapy (NCT) using an accelerator-based neutron source of the 7Li(p,n) reaction produced by 2.5 MeV protons was investigated by comparing the neutron beam tailored by both the Hiroshima University radiological research accelerator (HIRRAC) and the heavy water neutron irradiation facility in the Kyoto University reactor (KUR-HWNIF) from the viewpoint of the contamination dose ratios of the fast neutrons and the gamma rays. These contamination ratios to the boron dose were estimated in a water phantom of 20 cm diameter and 20 cm length to simulate a human head, with experiments by the same techniques for NCT in KUR-HWNIF and/or the simulation calculations by the Monte Carlo N-particle transport code system version 4B (MCNP-4B). It was found that the 7Li(p,n) neutrons produced by 2.5 MeV protons combined with 20, 25 or 30 cm thick D2O moderators of 20 cm diameter could make irradiation fields for NCT with depth–dose characteristics similar to those from the epithermal neutron beam at the KUR-HWNIF.

Preliminary study of 3D dose distribution evaluation in neutron capture therapy using a PVA-GTA-I radiochromic gel dosimeter.

Characteristics of the KUR Heavy Water Neutron Irradiation Facility as a neutron irradiation field with variable energy spectra

In recent years, various drug delivery systems circumventing the blood-brain barrier have emerged for treating brain tumors. This study aimed to improve the efficacy of brain tumor treatment in boron neutron capture therapy (BNCT) using cerebrospinal fluid (CSF) circulation to deliver boronophenylalanine (BPA) to targeted tumors. Previous experiments have demonstrated that boron accumulation in the brain cells of normal rats remains comparable to that after intravenous (IV) administration, despite BPA being administered via CSF at significantly lower doses (approximately 1/90 of IV doses). Based on these findings, BNCT was conducted on glioma model rats at the Kyoto University Research Reactor Institute (KUR), with BPA administered via CSF. This method involved implanting C6 cells into the brains of 8-week-old Wistar rats, followed by administering BPA and neutron irradiation after a 10-day period. In this study, the rats were divided into four groups: one receiving CSF administration, another receiving IV administration, and two control groups without BPA administration, with one subjected to neutron irradiation and the other not. In the CSF administration group, BPA was infused from the cisterna magna at 8 mg/kg/h for 2 h, while in the IV administration group, BPA was intravenously administered at 350 mg/kg via the tail vein over 1.5 h. Thermal neutron irradiation (5 MW) for 20 min, with an average fluence of 3.8 × 1012/cm2, was conducted at KUR's heavy water neutron irradiation facility. Subsequently, all of the rats were monitored under identical conditions for 7 days, with pre- and post-irradiation tumor size assessed through MRI and pathological examination. The results indicate a remarkable therapeutic efficacy in both BPA-administered groups (CSF and IV). Notably, the rats treated with CSF administration exhibited diminished BPA accumulation in normal tissue compared to those treated with IV administration, alongside maintaining excellent overall health. Thus, CSF-based BPA administration holds promise as a novel drug delivery mechanism in BNCT.

The element boron is not renowned among biologists, short of a few specialists who know that it is an essential nutrient for plants and an element in boromycin—an antibiotic compound produced by Streptomyces . Yet, on the whole, molecular biologists and, in particular, those in drug development seem to have little use for carbon's left‐hand neighbour in the periodic table. This is about to change. Currently, boron is largely produced in Turkey and the USA, and is used in a wide range of products, including glass, detergents, fire retardants, fibres to reinforce plane fuselages and body armour, and in superhard materials. Now, both researchers and the pharmaceutical industry are showing an increasing interest in boron as an alternative to carbon in drug design. > …both researchers and the pharmaceutical industry are showing an increasing interest in boron as an alternative to carbon in drug design A series of recent scientific and commercial developments indicate that boron‐based compounds are interesting drug candidates against all disease categories and might even speed up drug development. Pharmaceutical companies have already increased their boron research, particularly GlaxoSmithKline (GSK; Brentford, UK), which announced a US$2.5 billion investment in the US company Anacor (Palo Alto, CA, USA) in November 2008. Anacor was founded in 2002 to develop boron‐based antibacterial drugs, but has since expanded into antivirals and other targets with its boron‐based platform. Co‐founders Lucy Shapiro and Stephen Benkovic began collaborating in 2001 to look for novel inhibitors of several newly identified bacterial target sites that, they thought, could lead to more effective antibiotics. “They randomly inserted boron and got good activity,” said David Perry, CEO of Anacor. This serendipitous discovery led to the formation of Anacor a year later. “We were lucky,” Perry conceded. “At that stage we had no idea what the broader potential of boron …

The world's first clinical irradiation for boron neutron capture therapy (BNCT) was carried out using a neutron irradiation field for BNCT, installed at a research nuclear reactor in USA in 1951. After this year until 2012, BNCT has been performed only using reactor-based irradiation systems. In Kyoto University Research Reactor Institute (KURRI), BNCT clinical study using Heavy Water Facility installed in Kyoto University Reactor (KUR) came to be regularly performed from February 1990. At first, BNCT in this institute was performed just for malignant brain tumor and melanoma. The application was extended for head and neck tumors in 2001, and for body tumors such as liver tumor, lung tumor, malignant pleural mesothelioma, etc. in 2005. There were the several interruption periods, but 510 clinical irradiations were carried out using KUR Heavy Water Facility as of June 2016. Concurrently with the clinical study using KUR Heavy Water Facility, the development of accelerator-based system has been studied. In early 2009, the world's first accelerator-based system for BNCT clinical irradiation, Cyclotron-Based Epi-thermal Neutron Source (C-BENS) was completed. The clinical trial using C-BENS was started in 2012. BNCT using various accelerator-based irradiation systems including C-BENS may be carried out at plural facilities in the near future. Thus, it is the time when BNCT is shifting from a special particle therapy to a general therapy, now. The progress in BNCT at KURRI are reported focusing on the topics for physical engineering and medical physics.

Characteristic comparison between two different neutron spectrometers for boron neutron capture therapy irradiation field developed at Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor.

The remodeling construction of the KUR Heavy Water Neutron Irradiation Facility was completed at the end of March 1996, mainly for neutron capture therapy (NCT).1 The remodeled facility is available for the several “irradiation modes” whose neutron energy spectra are from almost pure thermal neutrons to epi-thermal neutrons, using the heavy water spectrum shifter and the thermal neutron filters of cadmium and boral. Clinical and experimental irradiations under the KUR continuous operation are possible using the radiation shield system and the equipment for the support of NCT clinical irradiations, such as a Remote Patient Carrier System with clinical collimators. We call the remodeled Heavy Water Facility and its accessory equipment, generally, “the KUR Advanced Clinical Irradiation System”.

Comparative efficacy of reactor vs. accelerator-based boron neutron capture therapy in U87MG glioblastoma models.