Application of TEPC microdosimetry to boron neutron capture therapy

Boron neutron capture therapy (BNCT) is a bimodal radiation therapy used primarily for highly malignant gliomas. Tissue-equivalent proportional counter (TEPC) microdosimetry has proven an ideal dosimetry technique for BNCT, facilitating accurate separation of the photon and neutron absorbed dose components, assessment of radiation quality and measurement of the BNC dose. A miniature dual-TEPC system has been constructed to facilitate microdosimetry measurements with excellent spatial resolution in high-flux clinical neutron capture therapy beams. A 10B-loaded TEPC allows direct measurement of the secondary charged particle spectrum resulting from the BNC reaction. A matching TEPC fabricated from brain-tissue-equivalent plastic allows evaluation of secondary charged particle spectra from photon and neutron interactions in normal brain tissue. Microdosimetric measurements performed in clinical BNCT beams using these novel miniature TEPCs are presented, and the advantages of this technique for such applications are discussed.     

Fricke gel dosimetry in boron neutron capture therapy

Gel dosimetry allows three-dimensional (3D) measurement of absorbed dose in tissue-equivalent dosemeter phantoms. Gel phantoms are imaged using optical techniques. In neutron capture therapy (NCT), properly designed gel dosemeters can give 3D dose distributions, due to the various components of the secondary radiation, in phantoms exposed in the thermal or epithermal column of a nuclear reactor. In addition to the therapeutic dose arising from the reaction 10B(n,alpha)7Li, the other dose components are also obtainable, i.e. the gamma dose (due to reactor background and to the reaction 1H(n,gamma)2H of thermal neutrons with hydrogen, the dose due to protons emitted in the reaction 14N(n,p)14C of thermal neutrons with nitrogen and the dose due to recoil protons resulting from elastic scattering of epithermal neutrons.     

Dose measuring system for boron neutron capture therapy

Dose measuring systems for boron neutron capture therapy (BNCT) of brain tumors are presented. The systems are a real-time monitoring system, an integral measuring system and a ¹⁰B concentration measuring system. The real-time monitoring with a small PN junction silicon detector made it possible to simultaneously measure the thermal neutron flux and the gamma dose rate in a patient during neutron therapy. Another monitoring of dose equivalents of thermal neutrons and gamma rays was performed with a BGO scintillation detector connected to an optical fiber. The accurate neutron fluence and gamma dose were determined with the integral measurements of the foil activation method and thermoluminescent dosimeters (TLDs) after irradiation. Kerma doses of thermal neutrons and gamma-rays were also measured with the TLD at the same time. Preliminary measurements of ¹⁰B concentration in tissue and blood of a patient were carried out by prompt gamma-ray spectroscopy.     

Microdosimetric spectra of the THOR neutron beam for boron neutron capture therapy

A primary objective of the BNCT project in Taiwan, involving THOR (Tsing Hua Open Pool Reactor), was to examine the potential treatment of hepatoma. To characterise the epithermal neutron beam in THOR, the microdosimetry distributions in lineal energy were determined using paired tissue-equivalent proportional counters with and without boron microfoils. Microdosimetry results were obtained in free-air and at various depths in a PMMA phantom near the exit of the beam port. A biological weighting function, dependent on lineal energy, was used to estimate the relative biological effectiveness of the beam. An effective RBE of 2.7 was found at several depths in the phantom.     

Microdosimetry of neutron field for boron neutron capture therapy at Kyoto university reactor

Microdosimetric single event spectrum in a human body simulated by an acrylic phantom has been measured for the clinical BNCT field at the Kyoto University Reactor (KUR). The recoil particles resulting from the initial reaction and subsequent interactions, namely protons, electrons, alpha particles and carbon nuclei are identified in the microdosimetric spectrum. The relative contributions to the neutron dose from proton, alpha particles and carbon are estimated to be about 0.9, 0.07 and 0.3, respectively, four depths between 5 and 41 mm. We estimate that the dose averaged lineal energy, yD decreased with depth from 64 to 46 keV microm(-1). Relative biological effectiveness (RBE) of this neutron field using a response function for the microdosimetric spectrum was estimated to decrease from 3.6 to 2.9 with increasing depth.     

First experiments on neutron detection on the accelerator-based source for boron neutron capture therapy

A pilot accelerator-based source of epithermal neutrons, which is intended for wide application in clinics for boron neutron capture therapy, has been constructed at the Budker Institute of Nuclear Physics (Novosibirsk). A stationary proton beam has been obtained and near-threshold neutron generation regime has been realized. Results of the first experiments on neutron generation using the proposed source are described.     

Filter, collimator and moderating material to achieve boron neutron capture enhanced fast neutron therapy

The combination of fast neutron therapy and boron neutron capture therapy is currently being studied as a possible treatment for some radio-resistant brain tumours. In an attempt to design a boron-enhanced fast neutron therapy beam for the Fermilab Fast Neutron Therapy Facility, the use of moderating material surrounding the patient's head has been investigated. Graphite, polyethylene, water and heavy water were studied as moderating materials, using MCNP. The use of tungsten, iron, lead and bismuth as materials for a small filter and collimator near the patient's head was investigated. Calculations showed that a filter and collimator made of tungsten with a graphite moderator was capable of producing a dose enhancement of 17.3 +/- 0.6% for a 100 microg g(-1) loading of 10B for a 5.6 cm diameter beam while delivering 1.5 Gy in 7 min.     

Microdosimetric study for interpretation of outcomes from boron neutron capture therapy clinical trials

Boron neutron capture therapy is a brachyradiotherapy utilizing the (10)B(n,alpha)(7)Li reaction that has been used to treat glioblastoma multiforme (GBM), melanoma and colon carcinoma liver metastases. GBM clinical trials resulted in modestly improved life expectancies compared with conventional therapies. Early results trials focused on malignant melanoma and colon carcinoma provide dramatically better results. Macrodosimetry cannot explain these apparent differences. The dichotomy can only be understood using microdosimetry techniques. A computer program has been created to provide an improved tissue model. This model permits the dose in each cell's cytoplasm, nucleus, and the interstitium to be calculated for ellipsoidal cells placed in either random or ordered locations. The nuclei can be centered or eccentric. The new model provides insight into the micro level for differences in the trials. The differences arise from the tissue's cellular geometry and the effects of neighboring cells. These results help to explain the observed clinical outcomes.     

From radiation-induced chromosome damage to cell death: modelling basic mechanisms and applications to boron neutron capture therapy

Cell death is a crucial endpoint in radiation-induced biological damage: on one side, cell death is a reference endpoint to characterise the action of radiation in biological targets; on the other side, any cancer therapy aims to kill tumour cells. Starting from Lea's target theory, many models have been proposed to interpret radiation-induced cell killing; after briefly discussing some of these models, in this paper, a mechanistic approach based on an experimentally observed link between chromosome aberrations and cell death was presented. More specifically, a model and a Monte Carlo code originally developed for chromosome aberrations were extended to simulate radiation-induced cell death applying an experimentally observed one-to-one relationship between the average number of 'lethal aberrations' (dicentrics, rings and deletions) per cell and -ln S, S being the fraction of surviving cells. Although such observation was related to X rays, in the present work, the approach was also applied to protons and alpha particles. A good agreement between simulation outcomes and literature data provided a model validation for different radiation types. The same approach was then successfully applied to simulate the survival of cells enriched with boron and irradiated with thermal neutrons at the Triga Mark II reactor in Pavia, to mimic a typical treatment for boron neutron capture therapy.     

Improved methods for the generation of 24.5 keV neutron beams with possible application to boron neutron capture therapy

The production of epithermal neutron beams, filtered to provide a spectrum in which a small energy range predominates, is of importance for radiobiological research and in the development and calibration of instruments for monitoring intermediate energy neutrons. The penetration characteristics of intermediate energy neutrons in tissue lead to the possibility of application in the field of neutron capture therapy if beams of sufficient intensity and adequate spectral properties can be generated. In this paper methods of utilising the 24.5 keV antiresonance in the iron neutron cross section are described, and the DENIS (depth enhanced neutron intense source) principle by which beam intensities may be optimised is explained. Calculations and experimental measurements in an in-core facility in the DIDO reactor at Harwell have indicated that a DENIS scatterer can achieve a 6-fold improvement in 24.5 keV beam intensity compared with a conventional titanium disc scatterer.     

Brain tumour and infiltrations dosimetry of boron neutron capture therapy combined with 252Cf brachytherapy

This article presents a dosimetric investigation of boron neutron capture therapy (BNCT) combined with (252)Cf brachytherapy for brain tumour control. The study was conducted through computational simulation in MCNP5 code, using a precise and discrete voxel model of a human head, in which a hypothetical brain tumour was incorporated. A boron concentration ratio of 1:5 for healthy-tissue: tumour was considered. Absorbed and biologically weighted dose rates and neutron fluency in the voxel model were evaluated. The absorbed dose rate results were exported to SISCODES software, which generates the isodose surfaces on the brain. Analyses were performed to clarify the relevance of boron concentrations in occult infiltrations far from the target tumour, with boron concentration ratios of 1:1 up to 1:50 for healthy-tissue:infiltrations and healthy-tissue:tumour. The average biologically weighted dose rates at tumour area exceed up to 40 times the surrounding healthy tissue dose rates. In addition, the biologically weighted dose rates from boron have the main contribution at the infiltrations, especially far from primary tumour. In conclusion, BNCT combined with (252)Cf brachytherapy is an alternative technique for brain tumour treatment because it intensifies dose deposition at the tumour and at infiltrations, sparing healthy brain tissue.     

On the development of computational tools for the design of beam assemblies for boron neutron capture therapy

This article is the first in a series devoted to the development of efficient and accurate computational tools for the design of beam assemblies for boron neutron capture therapy within the framework of discrete ordinates spectral nodal methods of neutron transport theory. We begin our study with a multi-layer representation of an assembly, and we derive a discrete ordinates matrix operator that replaces without spatial truncation error the entire multi-layer domain in neutron transmission computations. With the matrix operator derived here, we compute without further ado the angular distribution of neutrons leaving the multi-layer assembly, avoiding thus the use of general-purpose discrete ordinates codes founded in the discretization and numerical solution of the neutron transport equation over a number of spatial cells and angular directions throughout the domain. We perform numerical experiments with a four-layer model assembly, and we conclude this article with a discussion and directions for further developments.     

Determination of boron-containing compounds in urine and blood plasma from boron neutron capture therapy patients. The importance of using coupled techniques

The necessity of using coupled techniques to analyze samples from boron neutron capture therapy (BNCT) patients prior to element-specific detection has been demonstrated. BNCT patients were infused with p-boronophenylalanine (BPA)-fructose complex before the therapy started. Urine and blood plasma samples were collected at different times after the start of the BPA administration and were run on a porous graphitic carbon column coupled on-line to an inductively coupled plasma-atomic emission spectrometer (ICP-AES) and an ICP time-of-flight mass spectrometer (TOF-MS). In addition to BPA, a possible metabolite to BPA and some minor boron-containing compounds, eluting close to the front, were also found in the urine and plasma samples. Because only the total concentration of boron has been measured so far in earlier studies, the suspected metabolite could not be detected, and this is the first report indicating its presence in urine and plasma of BNCT patients. The abundance of 10B in urine was about the same for BPA and its possible metabolite (98-99%). The ratio between the possible metabolite and BPA was found to differ in the urine from different patients. Most of the patients had a metabolite concentration of approximately 10 mol % of the BPA content in their urine 5-11 h after the start of the BPA administration. This ratio increased to between 30 and 80% when 24 h had passed. The ratio of metabolite to BPA was found to be lower in the plasma than in the urine samples at comparable time after the start of BPA infusion. Preliminary results from micro-LC-electrospray ionization (ESI)-MS/MS measurements on four urine samples indicate that the metabolite has a higher mass than BPA.     

Dynamic secondary ion mass spectrometry analysis of boron from boron neutron capture therapy drugs in co-cultures: single-cell imaging of two different cell types within the same ion microscopy field of imaging

A co-culture, cryogenic SIMS methodology is presented for the quantitative analysis of cell type-dependent accumulation of boron delivered by BPA-F and BSH, two clinically approved drugs used in boron neutron capture therapy of cancer. T98G human glioblastoma cells were co-cultured with morphologically different normal LLC-PK1 epithelial cells or GM3348 human skin fibroblasts. Our freeze-fracture method of cryogenic sample preparation successfully fractured the different cell types grown together in co-cultures. Quantitative observations revealed an active uptake of boron from BPA-F in both T98G and LLC-PK1 cells but did not show cell type-dependent differences. Accumulation of BSH in all three cell types examined also did not reveal any cell type-dependent differences in co-cultures. As this method relies on the analysis, within the same field of SIMS imaging, of two different cell types that have been maintained under identical conditions of growth, drug exposure, sample preparation, and instrumental analysis, it provides the most effective approach for comparing cell type-specific differences in boron concentrations. The most effective applications of this method will be realized in testing the selectivity of experimental boronated compounds designed to specifically target tumor cells.     

Solid state microdosimetry in hadron therapy

A report of recent developments in silicon microdosimetry is presented. SOI based microdosemeters have shown promise as a viable alternative to traditional tissue-equivalent proportional counters. The application of these silicon microdosemeters to such radiation therapy modalities as boron neutron capture therapy (BNCT), boron neutron capture synovectomy (BNCS), proton therapy (PT), and fast neutron therapy (FNT) has been performed. Several shortcomings of the current silicon microdosemeter were identified and will be taken into account in the design of a second-generation device.     

Self-shielding effects in neutron spectra measurements for neutron capture therapy by means of activation foils

The design and optimisation of a neutron beam for neutron capture therapy (NCT) is accompanied by the neutron spectra measurements at the target position. The method of activation detectors was applied for the neutron spectra measurements. Epithermal neutron energy region imposes the resonance structure of activation cross sections resulting in strong self-shielding effects. The neutron self-shielding correction factor was calculated using a simple analytical model of a single absorption event. Such a procedure has been applied to individual cross sections from pointwise ENDF/B-VI library and new corrected activation cross sections were introduced to a spectra unfolding algorithm. The method has been verified experimentally both for isotropic and for parallel neutron beams. Two sets of diluted and non-diluted activation foils covered with cadmium were irradiated in the neutron field. The comparison of activation rates of diluted and non-diluted foils has demonstrated the correctness of the applied self-shielding model.     

硼中子俘获治疗人脑胶质母细胞瘤的前景和困惑

硼中子俘获疗法是一种可以选择性杀伤肿瘤细胞的放射疗法,其产生的α粒子对临床治疗新诊断和复发的脑胶质母细胞瘤有较好的疗效.发达国家20世纪五六十年代就已进入临床试验,但一直受到硼携带载体和中子源发展的限制.现就其治疗脑胶质母细胞瘤的前景做一综述.     

Boron microquantification in oral muscosa and skin following administration of a neutron capture therapy agent

Clinical trials of boron neutron capture therapy (BNCT) for intracranial tumours using boronophenylalanine-fructose undertaken at Harvard-MIT and Brookhaven National Laboratory have observed acute normal tissue reactions in the skin and oral mucosa. Because the range of the 10B(n, alpha)7Li reaction products is very short, 10-14 microns combined, knowledge of the 10B microdistribution in tissue is critical for understanding the microdosimetry and radiobiology of BNCT. This paper reports measurements of the microdistribution of 10B in an animal model, rat skin and tongue, using high resolution quantitative autoradiography (HRQAR), a neutron-induced etched track autoradiographic technique. The steep spatial gradient and high absolute value relative to blood of the 10B concentration observed in some strata of the rat tongue epithelium and skin are important for properly evaluating the radiobiology and the biological effectiveness factors for normal tissue reactions such as oral mucositis, which are generally assessed using the blood boron concentration rather than the tissue boron concentration.     

叶酸靶向含硼脂质体的制备及其包封率的测定

制备具有良好靶向性及包封率高的硼脂质体,为硼中子俘获治疗方法的研究与应用建立了一个有效的靶向给药途径.采用复乳法及薄膜—超声分散法制备叶酸靶向硼脂质体,利用高效液相色谱法检测4—羟基苯硼酸4—Hydroxyphenylboronicacid (HBA)脂质体、2—噻吩硼酸2—thiophenylboric acid(TBA)脂质体、4—叔丁基苯硼酸4—tert-Butylphenylboronic Acid(BBA)脂质体的含量及包封率,以包封率为评价指标,采用单因素法优化脂质体的制备处方和工艺条件.筛选出HBA、TBA、BBA最优的色谱条件,分别绘制出标准曲线,结果表明在1 ～ 100 μg/mL范围内线性关系良好.HBA、TBA、BBA脂质体在最优制备处方和工艺条件下包封率分别为25.7％、38.9％、94.8％.BBA脂质体优化后的制备处方和工艺条件如下:胆固醇与磷脂质量比为1∶1,药脂比为1∶50,pH值为7.4,按该处方工艺制备的BBA脂质体包封率在94.8％.制备叶酸靶向脂质体的优选处方和制备工艺稳定可行,质量控制方法简单、准确,包封率高.