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.     

硼中子俘获疗法治疗脑胶质瘤及难治性垂体腺瘤的现状及展望

硼中子俘获疗法在脑胶质瘤治疗研究中已经取得很大进展,但由于脑胶质瘤的特性以及缺乏与肿瘤高亲和力的掺硼药物,硼中子俘获治疗的效果并不十分理想.此外,难治性垂体腺瘤具有很多与脑胶质瘤相同的特点,硼中子俘获疗法可能具有一定的意义.文章重点介绍硼中子俘获疗法治疗脑胶质瘤的研究现状和治疗难治性垂体腺瘤的可能性.     

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.     

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.     

The microdosimetry of boron neutron capture therapy in a randomised ellipsoidal cell geometry

Two reactions deliver the majority of local dose in boron neutron capture therapy. The ionised particles (protons, alpha particles and lithium nuclei) produced in the two reactions, 10B(n,alpha,gamma)7Li and 14N(n,p)14O, have short ranges that are less than -14 microm (which is on the order of the diameter of a typical human cell). The ionised particles are heavy and are in the 2+ charge state in the case of the boron reactions. These heavy 2+ ions will do significant damage to molecules near their tracks. Thus, the distribution of nitrogen and, in particular, of boron determines the spatial characteristics of the radiation field. Since the distribution of nitrogen is nearly homogeneous in the brain and is not easily altered for the purpose of radiotherapy, the spatial variation in the radiation dose is due mainly to the spatial distribution of boron. This implies that the spatial distribution of boron determines the microscopic energy deposition and therefore the spatial characteristics of the microscopic dose. The microscopic dose from the (n,alpha) and (n,p) reactions has been examined in detail and, as averred, the proton dose is relatively homogeneous except for statistical variability. The statistical variability in essence adds a false spatial variability that would not be seen if a large number of histories were performed. Since the majority of spatial variability occurs in the boron distribution, the (n,p) reaction can be suppressed to better understand the spatial distribution effects on the microscopic dose. Programs have been written in FORTRAN using Monte Carlo techniques to model ellipsoidal cells that are either randomly sized and located in the region of interest or are arranged in a face centred cubic array and are identical except for the location of the nuclei, which may be random. It is shown that closely packed prolate ellipsoidal cells with a large eccentricity in one dimension will receive a larger nuclear dose than cells that are more sparsely packed. This demonstrates that the boron content of a cell and its nucleus can have a significant impact upon the dose to neighbouring cells. The local boron distribution in a region of interest can be shown to affect the macrodosimetric dose, with possible implications for clinical outcomes.     

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.     

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.     

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.     

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.     

Alanine and TLD coupled detectors for fast neutron dose measurements in neutron capture therapy (NCT)

A method was investigated to measure gamma and fast neutron doses in phantoms exposed to an epithermal neutron beam designed for neutron capture therapy (NCT). The gamma dose component was measured by TLD-300 [CaF2:Tm] and the fast neutron dose, mainly due to elastic scattering with hydrogen nuclei, was measured by alanine dosemeters [CH3CH(NH2)COOH]. The gamma and fast neutron doses deposited in alanine dosemeters are very near to those released in tissue, because of the alanine tissue equivalence. Couples of TLD-300 and alanine dosemeters were irradiated in phantoms positioned in the epithermal column of the Tapiro reactor (ENEA-Casaccia RC). The dosemeter response depends on the linear energy transfer (LET) of radiation, hence the precision and reliability of the fast neutron dose values obtained with the proposed method have been investigated. Results showed that the combination of alanine and TLD detectors is a promising method to separate gamma dose and fast neutron dose in NCT.     

Improved oral delivery of paclitaxel following administration in nanoemulsion formulations

Nanoemulsion formulations were designed for enhancing the oral bioavailability of hydrophobic drugs. Paclitaxel was selected as a model hydrophobic drug, which is also a substrate for the P-glycoprotein efflux system. The oil-in-water (o/w) nanoemulsions were formulated with pine nut oil as the internal oil phase, egg lecithin as the primary emulsifier, and water as the external phase. Stearylamine and deoxycholic acid were used to impart positive and negative charge to the emulsions, respectively. Nanoemulsions were prepared by sonication method and characterized for particle size and surface charge. The control and nanoemulsion formulations with tritiated [3H]-paclitaxel were administered orally to female C57BL/6 mice and the distribution of the drug was examined. The formulated nanoemulsions had a particle size range of approximately 90-120 nm (laser diffraction method) and zeta potential values ranging from -56 mV to +34 mV. Following oral administration, a significantly higher concentration of paclitaxel was observed in the systemic circulation when administered in the nanoemulsion relative to control aqueous solution. The absorbed drug was found to be distributed in the liver, kidneys, and lungs. The results of this study suggest that nanoemulsions are promising novel formulations that can enhance the oral bioavailability of hydrophobic drugs, like paclitaxel.     

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.     

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.     

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.     

Nanodosimetric measurements and calculations in a neutron therapy beam

A comparison of calculated and measured values of the dose mean lineal energy (y(D)) for the former neutron therapy beam at Louvain-la-Neuve is reported. The measurements were made with wall-less tissue-equivalent proportional counters using the variance-covariance method and simulating spheres with diameters between 10 nm and 15 microm. The calculated y(D)-values were obtained from simulated energy distributions of neutrons and charged particles inside an A-150 phantom and from published y(D)-values for mono-energetic ions. The energy distributions of charged particles up to oxygen were determined with the SHIELD-HIT code using an MCNPX simulated neutron spectrum as an input. The mono-energetic ion y(D)-values in the range 3-100 nm were taken from track-structure simulations in water vapour done with PITS/KURBUC. The large influence on the dose mean lineal energy from the light ion (A > 4) absorbed dose fraction, may explain an observed difference between experiment and calculation. The latter being larger than earlier reported result. Below 50 nm, the experimental values increase while the calculated decrease.     

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.     

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.     

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.     

Pharmacokinetics and tissue distribution of amphotericin B following oral administration of three lipid-based formulations to rats

The objective of this study was to assess the pharmacokinetics and tissue distribution of amphotericin B (AmB) in rats following oral administration of three lipid-based formulations (iCo-009, iCo-010 and iCo-011). The lipid-based formulations were administered to rats at a dose of 10?mg/kg and blood samples were withdrawn at predose, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72?h, after which the animals were sacrificed and the body organs were collected for AmB quantification using a validated HPLC method. Plasma pharmacokinetics parameters were determined using non-compartmental analysis. The disappearance of AmB from plasma was the slowest following the administration of iCo-010 with MRT of 63?h followed by iCo-009 then iCo-011 (36 and 27?h). The AUC_0-24h of iCo-009 and iCo-010 was 1.5–2-fold higher than that of iCo-011. The kidney exposure was comparable between iCo-009 and iCo-010 and was higher than that of iCo-011. The lung exposure was the highest following iCo-010 administration as compared to that of iCo-009. The distribution of AmB from plasma to tissues resulted in a high accumulation of AmB overtime with slow back-distribution to plasma. The pharmacokinetics profiles varied among the three formulations, despite the similarity in lipid composition between iCo-010 and iCo-011 and the presence of Peceol® as a common component in the formulations. The administration of oral iCo-010 could lead to higher steady state concentrations in the tissues after multiple dosing, which could lead to enhanced eradication of tissue borne fungal and parasitic infections.