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.

Efficacy of Boron Neutron Capture Therapy in Primary Central Nervous System Lymphoma: In Vitro and In Vivo Evaluation.

BACKGROUND: Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation method. High-dose methotrexate and whole-brain radiation therapy (WBRT) are the recommended treatments for primary central nervous system lymphoma (PCNSL). This tumor responds well to initial treatment but relapses even after successful treatment, and the prognosis is poor as there is no safe and effective treatment for relapse. In this study, we aimed to conduct basic research to explore the possibility of using BNCT as a treatment for PCNSL. METHODS: The boron concentration in human lymphoma cells was measured. Subsequently, neutron irradiation experiments on lymphoma cells were conducted. A mouse central nervous system (CNS) lymphoma model was created to evaluate the biodistribution of boron after the administration of borono-phenylalanine as a capture agent. In the neutron irradiation study of a mouse PCNSL model, the therapeutic effect of BNCT on PCNSL was evaluated in terms of survival. RESULTS: The boron uptake capability of human lymphoma cells was sufficiently high both in vitro and in vivo. In the neutron irradiation study, the BNCT group showed a higher cell killing effect and prolonged survival compared with the control group. CONCLUSIONS: A new therapeutic approach for PCNSL is urgently required, and BNCT may be a promising treatment for PCNSL. The results of this study, including those of neutron irradiation, suggest success in the conduct of future clinical trials to explore the possibility of BNCT as a new treatment option for PCNSL.

BNCT for primary synovial sarcoma.

Synovial sarcoma is a rare tumor requiring new treatment methods. A 46-year-old woman with primary monophasic synovial sarcoma in the left thigh involving the sciatic nerve, declining surgery because of potential dysfunction of the affected limbs, received two courses of BNCT. The tumor thus reduced was completely resected with no subsequent recurrence. The patient is now able to walk unassisted, and no local recurrence has been observed, demonstrating the applicability of BNCT as adjuvant therapy for synovial sarcoma. Further study and analysis with more experience accumulation are needed to confirm the real impact of BNCT efficacy for its application to synovial sarcoma.

Usefulness of combination with both continuous administration of hypoxic cytotoxin and mild temperature hyperthermia in boron neutron capture therapy in terms of local tumor response and lung metastatic potential.

Purpose: To evaluate the usefulness of combined treatment with both continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ) and mild temperature hyperthermia (MTH) in boron neutron capture therapy (BNCT) in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.Materials and methods: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumors received reactor thermal neutron beam irradiation following the administration of a 10B-carrier (L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)) after single intraperitoneal injection of an acute hypoxia-releasing agent (nicotinamide), MTH (40 °C for 60 min), and 24-h continuous subcutaneous infusion of TPZ or combined treatment with both TPZ and MTH. Immediately after irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (=P + Q) tumor cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated.Results: BPA-BNCT increased the sensitivity of the total tumor cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a 10B-carrier, combination with continuously administered TPZ with or without MTH enhanced the sensitivity of the both total and Q cells, especially Q cells. Even without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with combined treatment with both TPZ and MTH as well as nicotinamide treatment, showed the potential to reduce the number more than BSH-BNCT.Conclusion: BSH-BNCT combined with TPZ with or without MTH improved local tumor control, while BPA-BNCT in combination with both TPZ and MTH as well as nicotinamide is thought to reduce the number of lung metastases. It was elucidated that control of the chronic hypoxia-rich Q cell population in the primary solid tumor has the potential to impact the control of local tumors as a whole and that control of the acute hypoxia-rich total tumor cell population in the primary solid tumor has the potential to impact the control of lung metastases.

Localized dose delivering by ion beam irradiation for experimental trial of establishing brain necrosis model.

Localized dose delivery techniques to establish a brain radiation necrosis model are described. An irradiation field was designed by using accelerated protons or helium ions with a spread-out Bragg peak. Measurement of the designed field confirmed that a high dose can be confined to a local volume of an animal brain. The irradiation techniques described here are very useful for establishing a necrosis model without existence of extraneous complications.

Influence of manipulating hypoxia in solid tumors on the radiation dose-rate effect in vivo, with reference to that in the quiescent cell population.

PURPOSE: The aim of this study was to clarify the effect of manipulating intratumor hypoxia on radiosensitivity under reduced dose-rate (RDR) irradiation. MATERIALS AND METHODS: Tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. They received gamma-rays or accelerated carbon-ion beams at high dose-rate (HDR) or RDR with or without tumor clamping to induce hypoxia. Some mice without clamping received nicotinamide, an acute hypoxia-releasing agent or misonidazole, a hypoxic cell radio-sensitizer before irradiation. The responses of quiescent (Q) and total (= P + Q) cells were assessed by the micronucleus frequency using immunofluorescence staining for BrdU. RESULTS: The clearer decrease in radiosensitivity in Q than total cells after RDR gamma-ray irradiation was suppressed with carbon-ion beams, especially with a higher linear energy transfer value. Repressing the decrease in the radiosensitivity under RDR irradiation through keeping tumors hypoxic during irradiation and enhancing the decrease in the radiosensitivity by nicotinamide were clearer with gamma-rays and in total cells than with carbon-ion beams and in Q cells, respectively. Inhibiting the decrease in the radiosensitivity by misonidazole was clearer with gamma-rays and in Q cells than with carbon-ion beams and in total cells, respectively. CONCLUSION: Manipulating hypoxia during RDR as well as HDR irradiation influences tumor radiosensitivity, especially with gamma-rays.