Publications by authors named "Akira Maruhashi"

53 Publications

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.

Int J Radiat Biol 2019 12 23;95(12):1708-1717. Epub 2019 Sep 23.

Kansai BNCT Medical Center, Osaka Medical College, Osaka, Japan.

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. 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 B-carrier (-boronophenylalanine-B (BPA) or sodium mercaptoundecahydrododecaborate-B (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. 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 B-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. 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.
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http://dx.doi.org/10.1080/09553002.2019.1666214DOI Listing
December 2019

Effect of a change in reactor power on response of murine solid tumors in vivo, referring to impact on quiescent tumor cell population.

Int J Radiat Biol 2019 05 8;95(5):635-645. Epub 2019 Jan 8.

c Particle Radiation Oncology Center , Institute for Integrated Radiation and Nuclear Science, Kyoto University , Sennan-gun , Osaka , Japan.

Purpose: To examine the effect of a change in reactor power on the response of solid tumors, referring to impact on quiescent (Q) tumor cell population.

Materials And Methods: Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) tumor cells, and were treated with boronophenylalanine-B (BPA) or sodium mercaptododecaborate-B (BSH). After reactor neutron beam irradiation at a power of 1 or 5 MW with an identical beam spectrum, cells from tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled Q and total (P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU.

Results: After neutron irradiation with or without B-carrier, radio-sensitivity was reduced by decreasing reactor power in both cells, especially in Q cells and after irradiation with BPA. The values of relative and compound biological effectiveness were larger at a power of 5 MW and in Q cells than at a power of 1 MW and in total cells, respectively. The sensitivity difference between total and Q cells was widened when combined with B-carrier, especially with BPA, and through decreasing reactor power.

Conclusion: 5 MW is more advantageous than 1 MW for boron neutron capture therapy.
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http://dx.doi.org/10.1080/09553002.2019.1558300DOI Listing
May 2019

Effect of Tirapazamine, Metformin or Mild Hyperthermia on Recovery From Radiation-Induced Damage in Pimonidazole-Unlabeled Quiescent Tumor Cells.

World J Oncol 2017 Oct 5;8(5):137-146. Epub 2017 Nov 5.

Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan.

Background: The aim of the study was to examine the effect of tirapazamine (TPZ) on recovery from radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells compared with that of metformin (Met) or mild temperature hyperthermia (MTH).

Methods: Proliferating (P) cells in EL4 tumors were labeled by continuous 5-bromo-2'-deoxyuridine (BrdU) administration. Tumors received γ-rays at 1 h after pimonidazole administration followed by Met or TPZ treatment or MTH. Twenty-four hours later, the responses of Q and total (P + Q) cells and those of the pimonidazole-unlabeled cells were assessed with micronucleation and apoptosis frequencies using immunofluorescence staining for BrdU and apoptosis frequency using immunofluorescence staining for pimonidazole, respectively.

Results: With γ-rays only, the pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay, was more clearly observed in Q than total cells. Post-irradiation MTH or Met treatment more clearly repressed the decrease in radio-sensitivity in the Q than total cells. Post-irradiation TPZ administration produced a large radio-sensitizing effect on both total and Q cells, especially on Q cells. In pimonidazole-unlabeled cell fractions in both total and Q cells, TPZ suppressed the reduction in sensitivity much more efficiently than MTH or Met without any radio-sensitizing effect.

Conclusion: Post-irradiation TPZ administration has the potential to both suppress recovery from radiation-induced damage and enhance the radio-sensitivity both in total and Q tumor cells. Post-irradiation TPZ administration may be useful for controlling tumors.
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http://dx.doi.org/10.14740/wjon1058wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687893PMC
October 2017

Effect of oxygen pressure during incubation with a (10)B-carrier on (10)B uptake capacity of cultured p53 wild-type and mutated tumor cells: dependency on p53 status of tumor cells and types of (10)B-carriers.

Int J Radiat Biol 2016 18;92(4):187-94. Epub 2016 Feb 18.

d Particle Radiation Oncology, Research Reactor Institute , Kyoto University , Kumatori, Osaka , Japan.

Purpose To evaluate the effect of oxygen pressure during incubation with a (10)B-carrier on (10)B uptake capacity of cultured p53 wild-type and mutated tumor cells. Materials and methods Cultured human head and neck squamous cell carcinoma cell line transfected with mutant TP53 (SAS/mp53), or with a neo vector as a control (SAS/neo) was incubated with L-para-boronophenylalanine-(10)B (BPA) or sodium mercaptoundecahydrododecaborate-(10)B (BSH) as a (10)B-carrier at the (10)B concentration of 60 ppm for 24 h under aerobic (20.7% of oxygen) or hypoxic (0.28% of oxygen) conditions. Immediately after incubation, cultured tumor cells received reactor thermal neutron beams, and a cell survival assay was performed. (10)B concentration of cultured SAS/neo or SAS/mp53 cells incubated under aerobic or hypoxic conditions was determined with a thermal neutron guide tube. Results Hypoxic incubation significantly decreased (10)B concentration of cultured cells with a clearer tendency observed following BPA than BSH treatment in both SAS/neo and SAS/mp53 cells. Following neutron beam irradiation, SAS/mp53 cells showed significantly higher relative biological effectiveness values than SAS/neo cells because of the significantly lower radiosensitivity of SAS/mp53 to γ-rays than SAS/neo cells. Conclusion Oxygen pressure during incubation with a (10)B-carrier had a critical impact on (10)B uptake of cultured tumor cells.
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http://dx.doi.org/10.3109/09553002.2016.1137104DOI Listing
July 2016

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

Med Phys 2015 Nov;42(11):6651-7

Kyoto University Research Reactor Institute, Asashironishi 2-1010, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan.

Purpose: 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.

Methods: 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.

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 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.

Conclusions: 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.
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http://dx.doi.org/10.1118/1.4934243DOI Listing
November 2015

The Effect of p53 Status of Tumor Cells on Radiosensitivity of Irradiated Tumors With Carbon-Ion Beams Compared With γ-Rays or Reactor Neutron Beams.

World J Oncol 2015 Aug 27;6(4):398-409. Epub 2015 Aug 27.

Particle Radiation Oncology, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan.

Background: The aim of the study was to clarify the effect of p53 status of tumor cells on radiosensitivity of solid tumors following accelerated carbon-ion beam irradiation compared with γ-rays or reactor neutron beams, referring to the response of intratumor quiescent (Q) cells.

Methods: Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector (SAS/neo) were injected subcutaneously into hind legs of nude mice. Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received γ-rays or accelerated carbon-ion beams at a high or reduced dose-rate. Other tumor-bearing mice received reactor thermal or epithermal neutrons at a reduced dose-rate. Immediately or 9 hours after the high dose-rate irradiation (HDRI), or immediately after the reduced dose-rate irradiation (RDRI), the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU.

Results: The difference in radiosensitivity between the total (P + Q) and Q cells after γ-ray irradiation was markedly reduced with reactor neutron beams or carbon-ion beams, especially with a higher linear energy transfer (LET) value. Following γ-ray irradiation, SAS/neo tumor cells, especially intratumor Q cells, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q cells within SAS/mp53 tumors that showed little repair capacity. In both total and Q cells within both SAS/neo and SAS/mp53 tumors, carbon-ion beam irradiation, especially with a higher LET, showed little recovery capacity through leaving an interval between HDRI and the assay or decreasing the dose-rate. The recovery from radiation-induced damage after γ-ray irradiation was a p53-dependent event, but little recovery was found after carbon-ion beam irradiation. With RDRI, the radiosensitivity to reactor thermal and epithermal neutron beams was slightly higher than that to carbon-ion beams.

Conclusion: For tumor control, including intratumor Q-cell control, accelerated carbon-ion beams, especially with a higher LET, and reactor thermal and epithermal neutron beams were very useful for suppressing the recovery from radiation-induced damage irrespective of p53 status of tumor cells.
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http://dx.doi.org/10.14740/wjon941wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624688PMC
August 2015

The dependency of compound biological effectiveness factors on the type and the concentration of administered neutron capture agents in boron neutron capture therapy.

Springerplus 2014 7;3:128. Epub 2014 Mar 7.

Particle Radiation Biology, Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka, 590-0494 Japan.

Purpose: To examine the effect of the type and the concentration of neutron capture agents on the values of compound biological effectiveness (CBE) in boron neutron capture therapy.

Methods And Materials: After the subcutaneous administration of a (10) B-carrier, boronophenylalanine- (10) B (BPA) or sodium mercaptododecaborate- (10) B (BSH), at 3 separate concentrations, the (10) B concentrations in tumors were measured by γ-ray spectrometry. SCC VII tumor-bearing C3H/He mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells, then treated with BPA or BSH. Immediately after reactor neutron beam irradiation, during which intratumor (10) B concentrations were kept at levels similar to each other, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled quiescent (Q) and total (= P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU.

Results: The CBE values were higher in Q cells and in the use of BPA than total cells and BSH, respectively. In addition, the higher the administered concentrations were, the smaller the CBE values became, with a clearer tendency in the use of BPA than BSH. The values for neutron capture agents that deliver into solid tumors more dependently on uptake capacity of tumor cells became more changeable.

Conclusion: Tumor characteristics, such as micro-environmental heterogeneity, stochastic genetic or epigenetic changes, or hierarchical organization of tumor cells, are thought to partially influence on the value of CBE, meaning that the CBE value itself may be one of the indices showing the degree of tumor heterogeneity.
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http://dx.doi.org/10.1186/2193-1801-3-128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320213PMC
February 2015

Significance of Fractionated Administration of Thalidomide Combined With γ-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis.

World J Oncol 2014 Aug 25;5(4):155-165. Epub 2014 Aug 25.

Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan.

Background: The aim of this study was to evaluate the significance of fractionated administration of thalidomide combined with γ-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.

Methods: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received γ-ray irradiation after thalidomide treatment through a single or two consecutive daily intraperitoneal administrations up to a total dose of 400 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) 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: Thalidomide raised the sensitivity of the total cell population more remarkably than Q cells in both single and daily administrations. Daily administration of thalidomide elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases.

Conclusion: Daily fractionated administration of thalidomide in combination with γ-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential.
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http://dx.doi.org/10.14740/wjon855wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649741PMC
August 2014

Effect of bevacizumab combined with boron neutron capture therapy on local tumor response and lung metastasis.

Exp Ther Med 2014 Jul 8;8(1):291-301. Epub 2014 May 8.

Department of Radiation Life and Medical Science, Research Reactor Institute, Kyoto University, Osaka 590-0494, Japan.

The aim of the present study was to evaluate the effect of bevacizumab on local tumor response and lung metastatic potential during boron neutron capture therapy (BNCT) and in particular, the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously administered bromodeoxyuridine (BrdU) to label all proliferating (P) tumor cells. The tumors were irradiated with thermal neutron beams following the administration of a B-carrier [L--boronophenylalanine-B (BPA) or sodium mercaptoundecahydrododecaborate-B (BSH)], with or without the administration of bevacizumab. This was further combined with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH, 40°C for 60 min). Immediately following the irradiation, cells from certain tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q cells and the total (P+Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days following irradiation, lung metastases were enumerated. Three days following bevacizumab administration, the sensitivity of the total tumor cell population following BPA-BNCT had increased more than that following BSH-BNCT. The combination with MTH, but not with nicotinamide, further enhanced total tumor cell population sensitivity. Regardless of the presence of a B-carrier, MTH enhanced the sensitivity of the Q cell population. Regardless of irradiation, the administration of bevacizumab, as well as nicotinamide treatment, demonstrated certain potential in reducing the number of lung metastases especially in BPA-BNCT compared with BSH-BNCT. Thus, the current study revealed that BNCT combined with bevacizumab has the potential to sensitize total tumor cells and cause a reduction in the number of lung metastases to a similar level as nicotinamide.
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http://dx.doi.org/10.3892/etm.2014.1704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061189PMC
July 2014

Pilot clinical study of boron neutron capture therapy for recurrent hepatic cancer involving the intra-arterial injection of a (10)BSH-containing WOW emulsion.

Appl Radiat Isot 2014 Jun 30;88:32-7. Epub 2014 Jan 30.

Department of Surgery, Shin-Yamate Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.

A 63-year-old man with multiple HCC in his left liver lobe was enrolled as the first patient in a pilot study of boron neutron capture therapy (BNCT) involving the selective intra-arterial infusion of a (10)BSH-containing water-in-oil-in-water emulsion ((10)BSH-WOW). The size of the tumorous region remained stable during the 3 months after the BNCT. No adverse effects of the BNCT were observed. The present results show that (10)BSH-WOW can be used as novel intra-arterial boron carriers during BNCT for HCC.
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http://dx.doi.org/10.1016/j.apradiso.2014.01.014DOI Listing
June 2014

Development of a simple and rapid method of precisely identifying the position of 10B atoms in tissue: an improvement in standard alpha autoradiography.

J Radiat Res 2014 Mar 18;55(2):373-80. Epub 2013 Oct 18.

Kyoto University Research Reactor Institute, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan.

Boron neutron capture therapy (BNCT) can be utilized to selectively kill cancer cells using a boron compound that accumulates only in cancer cells and not in normal cells. Tumor-bearing animals treated by BNCT are routinely used to evaluate long-term antitumor effects of new boron compounds. Alpha-autoradiography is one of the methods employed in the evaluation of antitumor effects. However, a standard alpha-autoradiography cannot detect the microdistribution of (10)B because of the difficulty associated with the superposition of a tissue sample image and etched pits on a track detector with the etching process. In order to observe the microdistribution of (10)B, some special methods of alpha-autoradiography have been developed that make use of a special track detector, or the atomic force microscope combined with X-ray and UV light irradiation. In contrast, we propose, herein, a simple and rapid method of precisely identifying the position of (10)B using the imaging process and the shape of etched pits, such as their circularity, without the need to use special track detectors or a microscope. A brief description of this method and its verification test are presented in this article. We have established a method of detecting the microdistribution of (10)B with submicron deviation between the position of etched pits and the position of reaction in a tissue sample, for a given circularity of etched pits.
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http://dx.doi.org/10.1093/jrr/rrt110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951073PMC
March 2014

Boron neutron capture therapy outcomes for advanced or recurrent head and neck cancer.

J Radiat Res 2014 Jan 16;55(1):146-53. Epub 2013 Aug 16.

Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan.

We retrospectively review outcomes of applying boron neutron capture therapy (BNCT) to unresectable advanced or recurrent head and neck cancers. Patients who were treated with BNCT for either local recurrent or newly diagnosed unresectable head or neck cancers between December 2001 and September 2007 were included. Clinicopathological characteristics and clinical outcomes were retrieved from hospital records. Either a combination of borocaptate sodium and boronophenylalanine (BPA) or BPA alone were used as boron compounds. In all the treatment cases, the dose constraint was set to deliver a dose <10-12 Gy-eq to the skin or oral mucosa. There was a patient cohort of 62, with a median follow-up of 18.7 months (range, 0.7-40.8). A total of 87 BNCT procedures were performed. The overall response rate was 58% within 6 months after BNCT. The median survival time was 10.1 months from the time of BNCT. The 1- and 2-year overall survival (OS) rates were 43.1% and 24.2%, respectively. The major acute Grade 3 or 4 toxicities were hyperamylasemia (38.6%), fatigue (6.5%), mucositis/stomatitis (9.7%) and pain (9.7%), all of which were manageable. Three patients died of treatment-related toxicity. Three patients experienced carotid artery hemorrhage, two of whom had coexistent infection of the carotid artery. This study confirmed the feasibility of our dose-estimation method and that controlled trials are warranted.
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http://dx.doi.org/10.1093/jrr/rrt098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885131PMC
January 2014

Usefulness of Daily Fractionated Administration of Wortmannin Combined With γ-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis.

World J Oncol 2013 Feb 6;4(1):26-36. Epub 2013 Mar 6.

Radiation Life and Medical Science Research Division, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka, 590-0494, Japan.

Background: To evaluate the usefulness of fractionated administration of wortmannin combined with γ-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.

Methods: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received γ-ray irradiation after wortmannin treatment through a single or 4 consecutive daily intraperitoneal administrations up to a total dose of 4 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) 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: Wortmannin raised the sensitivity of Q cells more remarkably than the total cell population in both single and daily administrations. Daily administration of wortmannin elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases.

Conclusion: Daily fractionated administration of wortmannin in combination with γ-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential.
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http://dx.doi.org/10.4021/wjon640wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649916PMC
February 2013

Wortmannin efficiently suppresses the recovery from radiation-induced damage in pimonidazole-unlabeled quiescent tumor cell population.

J Radiat Res 2013 Mar 24;54(2):221-9. Epub 2012 Oct 24.

Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka, 590-0494, Japan.

Labeling of proliferating (P) cells in mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2'-deoxyuridine (BrdU). Tumors were irradiated with γ-rays at 1 h after pimonidazole administration followed by caffeine or wortmannin treatment. Twenty-four hours later, assessment of the responses of quiescent (Q) and total (= P + Q) cell populations were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. The pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using an assay performed 24 hours after irradiation, was more clearly observed in Q cells than total cells. In both the pimonidazole-unlabeled and the whole cell fractions, wortmannin efficiently suppressed the reduction in sensitivity due to delayed assay. Wortmannin combined with γ-ray irradiation is useful for suppressing the recovery from radiation-induced damage especially in the pimonidazole-unlabeled cell fraction within the total and Q tumor cell populations.
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http://dx.doi.org/10.1093/jrr/rrs094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589932PMC
March 2013

Usefulness of combined treatment with continuous administration of tirapazamine and mild temperature hyperthermia in γ-ray irradiation in terms of local tumour response and lung metastatic potential.

Int J Hyperthermia 2012 4;28(7):636-44. Epub 2012 Sep 4.

Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Osaka, Japan.

Purpose: To evaluate the usefulness of combined treatment with continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ), and mild temperature hyperthermia (MTH) in γ-ray irradiation in terms of local tumour response and lung metastatic potential, referring to the response of intratumour quiescent (Q) cells.

Materials And Methods: B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumour-bearing mice then received γ-ray irradiation after a single intraperitoneal injection or 24 h continuous subcutaneous infusion of TPZ, either with or without MTH. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated.

Results: Continuous administration elevated the sensitivity of both the total and Q cells, especially the total cells. MTH raised the sensitivity of Q cells more remarkably in both single and continuous administrations, probably because of more exposure to TPZ in intermediately hypoxic areas derived mainly from chronic hypoxia through MTH. With or without irradiation, TPZ, especially administered continuously and combined with MTH, decreased the number of lung metastases.

Conclusion: The combination of continuous long-term administration of TPZ and MTH in γ-ray irradiation was thought to be promising because of its potential to enhance local tumour response and repress lung metastatic potential.
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http://dx.doi.org/10.3109/02656736.2012.714517DOI Listing
March 2013

Evaluating the Usefulness of a Novel B-Carrier Conjugated With Cyclic RGD Peptide in Boron Neutron Capture Therapy.

World J Oncol 2012 Jun 5;3(3):103-112. Epub 2012 Jul 5.

Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nichi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan.

Background: To evaluate the usefulness of a novel B-carrier conjugated with an integrin-binding cyclic RGD peptide (GPU-201) in boron neutron capture therapy (BNCT).

Methods: GPU-201 was synthesized from integrin-binding Arg-Gly-Asp (RGD) consensus sequence of matrix proteins and a B cluster 1, 2-dicarba--dodecaborane-B. Mercaptododecaborate-B (BSH) dissolved in physiological saline and BSH and GPU-201 dissolved with cyclodextrin (CD) as a solubilizing and dispersing agent were intraperitoneally administered to SCC VII tumor-bearing mice. Then, the B concentrations in the tumors and normal tissues were measured by γ-ray spectrometry. Meanwhile, tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with GPU-201, BSH-CD, or BSH. Immediately after reactor neutron beam or γ-ray irradiation, during which intratumor B concentrations were kept at levels similar to each other, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU.

Results: The B from BSH was washed away rapidly in all these tissues and the retention of B from BSH-CD and GPU-201 was similar except in blood where the B concentration from GPU-201 was higher for longer. GPU-201 showed a significantly stronger radio-sensitizing effect under neutron beam irradiation on both total and Q cell populations than any other B-carrier.

Conclusion: A novel B-carrier conjugated with an integrin-binding RGD peptide (GPU-201) that sensitized tumor cells more markedly than conventional B-carriers may be a promising candidate for use in BNCT. However, its toxicity needs to be tested further.
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http://dx.doi.org/10.4021/wjon477wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649788PMC
June 2012

Phase II clinical study of boron neutron capture therapy combined with X-ray radiotherapy/temozolomide in patients with newly diagnosed glioblastoma multiforme--study design and current status report.

Appl Radiat Isot 2011 Dec 21;69(12):1796-9. Epub 2011 Mar 21.

Department of Neurosurgery, Osaka Medical College, Takatsuki, Osaka, Japan.

Recently, we reported our clinical experiences of boron neutron capture therapy (BNCT) for the newly diagnosed glioblastoma. The major differences of our protocol from the other past studies were simultaneous use of both sodium borocapate and boronophenylalanine, and combination with fractionated X-ray irradiation. These results showed the efficacy of combination therapy with external beam X-ray irradiation and BNCT. For our future study, we planned the multi-centric phase II clinical study for newly diagnosed glioblastoma patients in Japan (OSAKA-TRIBRAIN0902, NCT00974987).
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http://dx.doi.org/10.1016/j.apradiso.2011.03.014DOI Listing
December 2011

Radiosensitivity and Capacity to Recover from Radiation-Induced Damage in Pimonidazole-Unlabeled Intratumor Quiescent Cells Depend on Status.

World J Oncol 2011 Feb 26;2(1):1-9. Epub 2011 Feb 26.

Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan.

Background: Using our method for selectively detecting the response of intratumor quiescent (Q) cells to irradiation, the Q cells was shown to have a much larger hypoxic fraction (HF) than total (= proliferating (P) + Q) tumor cell population irrespective of the status of tumor cells. However, the size of the HF was clearly less than 100%, meaning the Q cell population was never fully hypoxic. Thus, the dependency of the radio-sensitivity and recovery capacity from radiation-induced damage on status was investigated in pimonidazole-unlabeled oxygenated Q tumor cells.

Methods: Human head and neck squamous cell carcinoma cells transfected with mutant (SAS/mp53), or with neo vector as a control (SAS/neo), were inoculated subcutaneously into left hind legs of Balb/cA nude mice. The tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor P cells. Tumors were irradiated with γ-rays at a high dose-rate or a reduced dose-rate at 1 h after the administration of pimonidazole. The responses of Q and total cell populations were evaluated with the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of pimonidazole unlabeled tumor cell fractions was assessed with apoptosis frequency using immunofluorescence staining for pimonidazole.

Results: The pimonidazole-unlabeled tumor cell fraction showed significantly enhanced radio-sensitivity compared with the whole tumor cell fraction more remarkably in Q cells and -mutated tumors than total cells and -wild type tumors, respectively. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using a delayed assay or a decrease in radiation dose rate, was more clearly observed in Q cells and -wild type tumors than total cells and -mutated type tumors, respectively. Concerning the whole tumor cell fraction, the Q cells showed significantly greater radio-resistance and recovery capacity from radiation-induced damage than the total cells both in -wild and -mutated type tumors.

Conclusions: The pimonidazole-unlabeled sub-fraction of the Q tumor cells, probably oxygenated, may be a critical target in the control of solid tumors, although its radio-sensitivity and recovery capacity from radiation-induced damage depend on status of the tumor cell.
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http://dx.doi.org/10.4021/wjon272wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649882PMC
February 2011

New algorithm to simulate organ movement and deformation for four-dimensional dose calculation based on a three-dimensional CT and fluoroscopy of the thorax.

Med Phys 2009 Oct;36(10):4328-39

Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

Purpose: The aim of this study was to develop a 4D-modeling algorithm, designated "3D+," to simulate organ movement and deformation for 4D dose calculation without the need for 4D-CT or deformable image registration and to assess the validity of this algorithm.

Methods: This 3D+ algorithm virtually creates 4D-CT images by deforming static 3D-CT data according to a typical motion model and motion data at multiple observation points collected via fluoroscopy. A typical motion model intended for patients with lung tumors immobilized with a vacuum pillow inside a stereotactic body frame was constructed. The geometric accuracy of virtual 4D-CT images created using this 3D+ algorithm was evaluated in eight patients by comparing the simulated results with actual 4D-CT images in terms of visual assessment, landmark analysis, and comparison of the radial distance from the tumor centroid to the body or lung surface.

Results: The average accuracy for all patients, as determined via landmark analysis, was 2.8 +/- 1.8 mm, very similar to results obtained through 4D-CT and deformable image registrations. Error in the radial distance from the tumor centroid to the body or lung surface was generally within 1.0 or 2.0 mm, respectively, in virtual versus actual 4D-CT images. Therefore, it is assumed that these geometric errors would have only negligible effects on dose calculation.

Conclusions: 4D modeling of the thorax utilizing the 3D+ algorithm shows acceptable accuracy and is more suited for routine clinical use in terms of processing time than conventional 4D-CT and deformable image registration. The 3D+ algorithm may be useful for simulating dose distribution for advanced beam delivery techniques, such as real-time tumor tracking irradiation and adaptive radiation therapy.
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http://dx.doi.org/10.1118/1.3213083DOI Listing
October 2009

Gamma-ray irradiation enhanced boron-10 compound accumulation in murine tumors.

J Radiat Res 2009 Nov 3;50(6):553-7. Epub 2009 Oct 3.

Research Reactor Institute, Kyoto University, Sennan-gun, Osaka, Japan.

Previous studies have demonstrated that X-ray irradiation affects angiogenesis in tumors. Here, we studied the effects of gamma-ray irradiation on boron-10 compound accumulation in a murine tumor model. The mouse squamous cell carcinoma was irradiated with gamma-ray before BSH ((10)B-enriched borocaptate sodium) administration. Then, the boron-10 concentrations in tumor and normal muscle tissues were measured by prompt gamma-ray spectrometry (PGA). A tumor blood flow assay was performed, and cell killing effects of neutron irradiation with various combinations of BSH and gamma-rays were also examined. BSH concentrations of tumor tissues were 16.1 +/- 0.6 microg/g, 16.7 +/- 0.5 microg/g and 17.8 +/- 0.5 microg/g at 72 hours after gamma-ray irradiation at doses of 5, 10, and 20 Gy, compared with 13.1 +/- 0.5 microg/g in unirradiated tumor tissues. The enhancing inhibition of colony formation by neutron irradiation with BSH was also found after gamma-ray irradiation. In addition, increasing Hoechst 33342 perfusion was also observed. In this study, we demonstrated that gamma-ray irradiation enhances BSH accumulation in tumors. The present results suggest that the enhancement of (10)B concentration that occurs after gamma-ray irradiation may be due to the changes in the extracellular microenvironment, including in tumor vessels, induced by gamma-ray irradiation.
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http://dx.doi.org/10.1269/jrr.09071DOI Listing
November 2009

A simple and rapid method for measurement of (10)B-para-boronophenylalanine in the blood for boron neutron capture therapy using fluorescence spectrophotometry.

J Radiat Res 2009 Jul 9;50(4):377-82. Epub 2009 Jun 9.

Particle Radiation Oncology Research Centre, Research Reactor Institute, Kyoto University.

Background and Purpose; (10)B deriving from (10)B-para-boronophenylalanine (BPA) and (10)B-borocaptate sodium (BSH) have been detected in blood samples of patients undergoing boron neutron capture therapy (BNCT) using prompt gamma ray spectrometer or Inductively Coupled Plasma (ICP) method, respectively. However, the concentration of each compound cannot be ascertained because boron atoms in both molecules are the target in these assays. Here, we propose a simple and rapid method to measure only BPA by detecting fluorescence based on the characteristics of phenylalanine. Material and Methods; (10)B concentrations of blood samples from human or mice were estimated by the fluorescence intensities at 275 nm of a BPA excited by light of wavelength 257 nm using a fluorescence spectrophotometer. Results; The relationship between fluorescence to increased BPA concentration showed a positive linear correlation. Moreover, we established an adequate condition for BPA measurement in blood samples containing BPA, and the estimated (10)B concentrations of blood samples derived from BPA treated mice were similar between the values obtained by our method and those by ICP method. Conclusion; This new assay will be useful to estimate BPA concentration in blood samples obtained from patients undergoing BNCT especially in a combination use of BSH and BPA.
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http://dx.doi.org/10.1269/jrr.09015DOI Listing
July 2009

Effectiveness of boron neutron capture therapy for recurrent head and neck malignancies.

Appl Radiat Isot 2009 Jul 2;67(7-8 Suppl):S37-42. Epub 2009 Apr 2.

Department of Oral and Maxillofacial Surgery, II Osaka University, Graduate School of Dentistry, Osaka, Japan.

It is necessary to explore new treatments for recurrent head and neck malignancies (HNM) to avoid severe impairment of oro-facial structures and functions. Boron neutron capture therapy (BNCT) is tumor-cell targeted radiotherapy that has significant superiority over conventional radiotherapies in principle. We have treated with BNCT 42 times for 26 patients (19 squamous cell carcinomas (SCC), 4 salivary gland carcinomas and 3 sarcomas) with a recurrent and far advanced HNM since 2001. Results of (1) (10)B concentration of tumor/normal tissue ratios (T/N ratio) of FBPA-PET studies were SCC: 1.8-5.7, sarcoma: 2.5-4.0, parotid tumor: 2.5-3.7. (2) Therapeutic effects were CR: 12 cases, PR: 10 cases, PD: 3 cases NE (not evaluated): 1 case. Response rate was 85%. (3) Improvement of QOL such as a relief of severe pain, bleeding, and exudates at the local lesion, improvement of PS, disappearance of ulceration, covered with normal skin and preserved oral and maxillofacial functions and tissues. (4) Survival periods after BNCT were 1-72 months (mean: 13.6 months). Six-year survival rate was 24% by Kaplan-Meier analysis. (5) Adverse-events were transient mucositis and alopecia in most of the cases; three osteomyelitis and one brain necrosis were recognized. These results indicate that BNCT represents a new and promising treatment approach for advanced HNM.
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http://dx.doi.org/10.1016/j.apradiso.2009.03.103DOI Listing
July 2009

Survival benefit from boron neutron capture therapy for the newly diagnosed glioblastoma patients.

Appl Radiat Isot 2009 Jul 25;67(7-8 Suppl):S15-8. Epub 2009 Mar 25.

Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka, Japan.

Objective: Since 2002-2007, we applied boron neutron capture therapy (BNCT) to >50 cases of malignant gliomas (MGs) with epithermal neutron irradiations. Recently, we showed the early radiographical improvement of malignant glioma patients by our modified BNCT, with simultaneous use of BPA (borono-phenylalanine) and BSH (sodium borocaptate). In this time, we focused on the survival benefit from BNCT for the newly diagnosed glioblastoma patients.

Methods: BNCT group including 21 newly histological confirmed glioblastoma patients treated with surgical removal followed by BNCT in Osaka Medical College during 2002-2006 period. Ten patients were treated with BNCT only, and in the other 11 patients, 20-30 Gy fractionated external beam X-ray irradiation therapy (XRT) was performed after BNCT. No chemotherapy was administered until tumor progression was observed.

Results: Treatments were well tolerated. Any kind of acute systemic or local severe toxicity were not demonstrated. Mean over all survival of the patients treated by BNCT was 20.7 and the median was 15.6 months with 2-years survival of 25%. Stratification by RPA criteria showed 6, 6, 8 and 1 patients, respectively, in classes III-VI. Three patients out of six in class III and one out of eight in class V are alive at the end point of this study. All the patients in classes IV and VI died. Median survival time for the BNCT group compared to the RTOG database was as follows: 20.6 months vs. 17.9 months for class III; 16.9 months vs. 11.1 months for class IV; 13.2 months vs. 8.9 months for class V.

Conclusion: The RTOG RPA prognostic criteria were helpful in establishing which class of glioma patients could potentially benefit from BNCT. BNCT showed a survival benefit in all of the RPA classes of the RTOG database not only for the good prognosis group.
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http://dx.doi.org/10.1016/j.apradiso.2009.03.015DOI Listing
July 2009

Survival benefit of boron neutron capture therapy for recurrent malignant gliomas.

Appl Radiat Isot 2009 Jul 27;67(7-8 Suppl):S22-4. Epub 2009 Mar 27.

Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan.

We have applied boron neutron capture therapy (BNCT) to malignant brain tumors. Here we evaluated the survival benefit of BNCT for recurrent malignant glioma (MG). Since 2002, we have treated 22 cases of recurrent MG with BNCT. Survival time was analyzed with special reference to recursive partitioning analysis (RPA) classification, by Carson et al. Median survival times (MSTs) after BNCT for all patients and for glioblastoma as on-study histology at recurrence was 10.8 months (n=22; 95% CI, 7.3-12.8 months) and 9.6 months (n=19; 95% CI, 6.9-11.4 months), respectively. In our study, MST for the high-risk RPA classes was 9.1 months (n=11; 95% CI, 4.4-11.0 months). By contrast, the original journal data showed that the MST of the same RPA classes was 4.4 months (n=129; 95% CI, 3.6-5.4 months). BNCT showed a survival benefit for recurrent MG, especially in the high-risk group.
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http://dx.doi.org/10.1016/j.apradiso.2009.03.032DOI Listing
July 2009

Induction of DNA double-strand breaks and cellular migration through bystander effects in cells irradiated with the slit-type microplanar beam of the spring-8 synchrotron.

Int J Radiat Oncol Biol Phys 2009 May;74(1):229-36

Research Reactor Institute, Kyoto University, Osaka, Japan.

Purpose: To determine whether glioma cells irradiated with a microplanar X-ray beam exert bystander effects.

Methods And Materials: Microplanar beam irradiation of glioma cells in vitro was done using the SPring-8 synchrotron radiation facility. The amount of DNA double-strand breaks (dsbs) was measured by the fluorescence intensity of phosphorylated H2AX or the number of 53BP1 foci. The dose distribution in a cell population exposed to a single microplanar beam was determined by the amount of phosphorylated H2AX-positive cells. Bystander effects were determined by counting the number of 53BP1 foci in nonirradiated cells treated with conditioned medium from cultures of irradiated cells.

Results: More DNA dsbs were detected in cells adjacent to an area irradiated by the single beam than in cells in distant, nonirradiated areas as a result of bystander effects caused by scattered X-rays and DNA dsbs. In support of this, more 53BP1 foci were observed in nonirradiated, conditioned medium-treated cells than in control cells (i.e., cells not treated with irradiation or conditioned medium). These results suggest that DNA dsbs were induced in nonirradiated cells by soluble factors in the culture medium. In addition, we observed cellular migration into areas irradiated with peak doses, suggesting that irradiated cells send signals that cause nonirradiated cells to migrate toward damaged cells.

Conclusions: Bystander effects are produced by factors secreted as a result of slit-type microplanar X-ray beam irradiation.
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http://dx.doi.org/10.1016/j.ijrobp.2008.09.060DOI Listing
May 2009

Impact of accelerator-based boron neutron capture therapy (AB-BNCT) on the treatment of multiple liver tumors and malignant pleural mesothelioma.

Radiother Oncol 2009 Jul 28;92(1):89-95. Epub 2009 Mar 28.

Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Osaka, Japan.

Background And Purpose: To confirm the feasibility of accelerator-based BNCT (AB-BNCT) for treatment of multiple liver tumors and malignant pleural mesothelioma (MPM), we compared dose distribution and irradiation time between AB-BNCT and reactor-based BNCT (RB-BNCT).

Material And Methods: We constructed treatment plans for AB-BNCT and RB-BNCT of four multiple liver tumors and six MPM. The neutron beam data on RB-BNCT were those from the research reactor at Kyoto University Research Reactor Institute (KURRI). The irradiation time and dose-volume histogram data were assessed for each BNCT system.

Results: In BNCT for multiple liver tumors, when the 5 Gy-Eq dose was delivered as the mean dose to the healthy liver tissues, the mean dose delivered to the liver tumors by AB-BNCT and RB-BNCT was 68.1 and 65.1 Gy-Eq, respectively. In BNCT for MPM, when the mean lung dose to the normal ipsilateral lung was 5 Gy-Eq, the mean dose delivered to the MPM tumor by AB-BNCT and RB-BNCT was 20.2 and 19.9 Gy-Eq, respectively. Dose distribution analysis revealed that AB-BNCT is superior to RB-BNCT for treatment of deep-seated tumors.

Conclusions: The feasibility of the AB-BNCT system constructed at our institute was confirmed from a clinical viewpoint in BNCT for multiple liver tumors and MPM.
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http://dx.doi.org/10.1016/j.radonc.2009.01.010DOI Listing
July 2009

Boron neutron capture therapy for newly diagnosed glioblastoma.

J Radiat Res 2009 Jan 29;50(1):51-60. Epub 2008 Oct 29.

Department of Neurosurgery, Osaka Medical College, Takatsuki, Japan.

We evaluate the clinical results of a form of tumor selective particle radiation known as boron neutron capture therapy (BNCT) for newly-diagnosed glioblastoma (NDGB) patients, especially in combination with X-ray treatment (XRT). Between 2002 and 2006, we treated 21 patients of NDGB with BNCT utilizing sodium borocaptate and boronophenylalanine simultaneously. The first 10 were treated with only BNCT (protocol 1), and the last 11 were treated with BNCT followed by XRT of 20 to 30 Gy (protocol 2) to reduce the possibility of local tumor recurrence. No chemotherapy was applied until tumor progression was observed. The patients treated with BNCT (protocol 1 plus 2) showed a significant survival prolongation compared with the institutional historical controls. BNCT also showed favorable results in correspondence with the RTOG- and EORTC-RPA subclasses. The median survival time (MST) was 15.6 months for protocols 1 and 2 together. For protocol 2, the MST was 23.5 months. The main causes of death were cerebrospinal fluid dissemination as well as local recurrence. Our modified BNCT protocol showed favorable results of patients with NDGB not only for those with good prognoses but also for those with poor prognoses.
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http://dx.doi.org/10.1269/jrr.08043DOI Listing
January 2009

Survival benefit of Boron neutron capture therapy for recurrent malignant gliomas.

J Neurooncol 2009 Jan 24;91(2):199-206. Epub 2008 Sep 24.

Department of Neurosurgery, Osaka Medical College, Takatsuki, Osaka, 569-8686, Japan.

We have applied boron neutron capture therapy (BNCT) to malignant brain tumors. Here we evaluated the survival benefit of BNCT for recurrent malignant glioma (MG). Since 2002, we have treated 22 cases of recurrent MG with BNCT. Survival time was analyzed with special reference to recursive partitioning analysis (RPA) classification, by Carson et al. (J Clin Oncol 25:2601-2606, 2007). Median survival times (MSTs) after BNCT for all patients and for glioblastoma as on-study histology at recurrence was 10.8 months (n = 22; 95% CI, 7.3-12.8 months) and 9.6 months (n = 19; 95% CI, 6.9-11.4 months), respectively. In our study, MST for the high-risk RPA classes was 9.1 months (n = 11; 95% CI, 4.4-11.0 months). By contrast, the original journal data showed that the MST of the same RPA classes was 4.4 months (n = 129; 95% CI, 3.6-5.4 months). BNCT showed a survival benefit for recurrent MG, especially in the high-risk group.
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http://dx.doi.org/10.1007/s11060-008-9699-xDOI Listing
January 2009

Spectromicroscopic film dosimetry for high-energy microbeam from synchrotron radiation.

Appl Radiat Isot 2009 Jan 6;67(1):155-9. Epub 2008 Aug 6.

Japan Synchrotron Radiation Research Institute, Kouto 1-1-1, Sayo, Hyogo 679-5198, Japan.

A microscope with band-pass filters was used to measure the optical-density distribution of GafChromic films irradiated with multi-slit microbeam X-rays. The planar width was 25 microm, and the center-to-center distance was 200 microm. The peak and valley dose rates in air were found to be 120 and 0.7Gy/s, respectively. In a polymethylmethacrylate phantom, the peak-to-valley dose ratio decreased to 80 at a 1-mm depth. Doses calculated with the PENELOPE code agreed with those around the peak but became smaller in the valley.
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http://dx.doi.org/10.1016/j.apradiso.2008.08.002DOI Listing
January 2009

A novel concept of treatment of diffuse or multiple pleural tumors by boron neutron capture therapy (BNCT).

Radiother Oncol 2008 Aug 22;88(2):192-5. Epub 2008 Jul 22.

Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Kumatori-cho, Sennan-gun, Osaka, Japan.

Two patients, one with malignant pleural mesothelioma and one with a malignant short spindle cell tumor, received boron neutron capture therapy (BNCT). In each case, the tumors regressed or remained stable in size for 3-6 months following BNCT. No acute or late adverse events higher than grade 2 were observed.
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http://dx.doi.org/10.1016/j.radonc.2008.06.009DOI Listing
August 2008
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