Development and evaluation of dose calculation algorithm with a combination of Monte Carlo and point-kernel methods for boron neutron capture therapy

We developed a 'hybrid algorithm' that combines the Monte Carlo (MC) and point-kernel methods for fast dose calculation in boron neutron capture therapy. The objectives of this study were to experimentally verify the hybrid algorithm and to verify the calculation accuracy and time of a 'complementary approach' adopting both the hybrid algorithm and the full-energy MC method. In the latter verification, the results were compared with those obtained using the full-energy MC method alone. In the hybrid algorithm, the moderation process of neutrons is simulated using only the MC method, and the thermalization process is modeled as a kernel. The thermal neutron fluxes calculated using only this algorithm were compared with those measured in a cubic phantom. In addition, a complementary approach was used for dose calculation in a geometry simulating the head region, and its computation time and accuracy were verified. The experimental verification indicated that the thermal neutron fluxes calculated using only the hybrid algorithm reproduced the measured values at depths exceeding a few centimeters, whereas they overestimated those at shallower depths. Compared with the calculation using only the full-energy MC method, the complementary approach reduced the computation time by approximately half, maintaining nearly same accuracy. When focusing on the calculation only using the hybrid algorithm only for the boron dose attributed to the reaction of thermal neutrons, the computation time was expected to reduce by 95% compared with the calculation using only the full-energy MC method. In conclusion, modeling the thermalization process as a kernel was effective for reducing the computation time

Intensity-modulated irradiation for superficial tumors by overlapping irradiation fields using intensity modulators in accelerator-based BNCT

The distribution of the thermal neutron flux has a significant impact on the treatment efficacy. We developed an irradiation method of overlapping irradiation fields using intensity modulators for the treatment of superficial tumors with the aim of expanding the indications for accelerator-based boron neutron capture therapy (BNCT). The shape of the intensity modulator was determined and Monte Carlo simulations were carried out to determine the uniformity of the resulting thermal neutron flux distribution. The intensity modulators were then fabricated and irradiation tests were conducted, which resulted in the formation of a uniform thermal neutron flux distribution. Finally, an evaluation of the tumor dose distribution showed that when two irradiation fields overlapped, the minimum tumor dose was 27.4 Gy-eq, which was higher than the tumor control dose of 20 Gy-eq. Furthermore, it was found that the uniformity of the treatment was improved 47% as compared to the treatment that uses a single irradiation field. This clearly demonstrates the effectiveness of this technique and the possibility of expanding the indications to superficially located tumors

Development of optimization method for uniform dose distribution on superficial tumor in an accelerator-based boron neutron capture therapy system

To treat superficial tumors using accelerator-based boron neutron capture therapy (ABBNCT), a technique was investigated, based on which, a single-neutron modulator was placed inside a collimator and was irradiated with thermal neutrons. In large tumors, the dose was reduced at their edges. The objective was to generate a uniform and therapeutic intensity dose distribution. In this study, we developed a method for optimizing the shape of the intensity modulator and irradiation time ratio to generate a uniform dose distribution to treat superficial tumors of various shapes. A computational tool was developed, which performed Monte Carlo simulations using 424 different source combinations. We determined the shape of the intensity modulator with the highest minimum tumor dose. The homogeneity index (HI), which evaluates uniformity, was also derived. To evaluate the efficacy of this method, the dose distribution of a tumor with a diameter of 100 mm and thickness of 10 mm was evaluated. Furthermore, irradiation experiments were conducted using an ABBNCT system. The thermal neutron flux distribution outcomes that have considerable impacts on the tumor’s dose confirmed a good agreement between experiments and calculations. Moreover, the minimum tumor dose and HI improved by 20 and 36%, respectively, compared with the irradiation case wherein a single-neutron modulator was used. The proposed method improves the minimum tumor volume and uniformity. The results demonstrate the method’s efficacy in ABBNCT for the treatment of superficial tumors

Role of p53 mutation in the effect of boron neutron capture therapy on oral squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Boron neutron capture therapy (BNCT) is a selective radiotherapy, being effective for the treatment of even advanced malignancies in head and neck regions as well as brain tumors and skin melanomas. To clarify the role of p53 gene, the effect of BNCT on oral squamous cell carcinoma (SCC) cells showing either wild- (SAS/neo) or mutant-type (SAS/mp53) p53 was examined.</p> <p>Methods</p> <p>Cells were exposed to neutron beams in the presence of boronophenylalanine (BPA) at Kyoto University Research Reactor. Treated cells were monitored for modulations in colony formation, proliferation, cell cycle, and expression of cell cycle-associated proteins.</p> <p>Results</p> <p>When SAS/neo and SAS/mp53 cells were subjected to BNCT, more suppressive effects on colony formation and cell viability were observed in SAS/neo compared with SAS/mp53 cells. Cell cycle arrest at the G1 checkpoint was observed in SAS/neo, but not in SAS/mp53. Apoptotic cells increased from 6 h after BNCT in SAS/neo and 48 h in SAS/mp53 cells. The expression of p21 was induced in SAS/neo only, but G2 arrest-associated proteins including Wee1, cdc2, and cyclin B1 were altered in both cell lines.</p> <p>Conclusion</p> <p>These results indicate that oral SCC cells with mutant-type are more resistant to BNCT than those with wild-type p53, and that the lack of G1 arrest and related apoptosis may contribute to the resistance. At a physical dose affecting the cell cycle, BNCT inhibits oral SCC cells in p53-dependent and -independent manners.</p

Design, Synthesis, and Biological Applications of Boron-Containing Polyamine and Sugar Derivatives

Boron (B), an element that is present in ultratrace amounts in animal cells and tissues, is expected to be useful in many scientific fields. We have found the hydrolysis of C–B bond in phenylboronic acid-pendant cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) and the full decomposition of ortho-carborane attached with cyclen and ethylenediamines in aqueous solution at neutral pH upon complexation with intracellular metals. The change in the chemical shift of the 11B signals in 11B-NMR spectra of these boron-containing metal chelators can be applied to the magnetic resonance imaging (MRI) of metal ions in solutions and in living cells

Theoretical Studies for Molecular Modeling of New Camptothecin Analogues

Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino carbonyloxycamptothecin: CPT-11) is a widely used potent antitumor drug that is developed based on camptothecin. However, overexpression of ABCG2 (BCRP/MXR/ABCP) confers cancer cells resistance to SN-38, that is, the active metabolite of irinotecan. In the present study to develop a platform for the molecular modeling to circumvent cancer drug resistance associated with ABCG2, we have characterized a total of fourteen new SN-38 analogues by some typical properties, which were evaluated by molecular orbital (MO) calculations and neural network (NN) QSAR technique

Development of a dual phantom technique for measuring the fast neutron component of dose in boron neutron capture therapy.

[Purpose]: Research and development of various accelerator-based irradiation systems for boron neutroncapture 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 irradiationconditions 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 fastneutrons. 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. [Methods]: One phantom was filled with pure water. The other phantom was filled with a water solution of lithiumhydroxide (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. % [6]LiOH solution for 95%-enriched Li-6. A phantom was constructed containing 10 wt. % [6]LiOH solution based on the simulation results. Experimental characterization of the depth dose distributions of the neutron andgamma-ray components along the central axis was performed at Heavy Water Neutron IrradiationFacility installed at Kyoto University Reactor using activation foils and thermoluminescent dosimeters, respectively. [Results]: 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 [6]LiOH with a solubility approaching its upper limit. Experiments confirmed that the thermalneutron flux and secondary gamma-ray dose rate decreased substantially; however, the fastneutron flux and primary gamma-ray dose rate were hardly affected in the 10%-[6]LiOH 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%-[6]LiOH phantom. [Conclusions]: The dual phantom technique using the combination of a pure water phantom and a 10%-[6]LiOH phantom developed in this work provides an effective method for dose estimation of the fast neutroncomponent in BNCT. Improvement in the accuracy achieved with the proposed technique results in improved RBE estimation for biological experiments and clinical practice