Arrangement of high-energy neutron irradiation field and shielding experiment using 4 m concrete at KENS.

An irradiation field of high-energy neutrons produced in the forward direction from a thick tungsten target bombarded by 500 MeV protons was arranged at the KENS spallation neutron source facility. In this facility, shielding experiment was performed with an ordinary concrete shield of 4 m thickness assembled in the irradiation room, 2.5 m downstream from the target centre. Activation detectors of bismuth, aluminium, indium and gold were inserted into eight slots inside the shield and attenuations of neutron reaction rates were obtained by measurements of gamma-rays from the activation detectors. A MARS14 Monte Carlo simulation was also performed down to thermal energy, and comparisons between the calculations and measurements show agreements within a factor of 3. This neutron field is useful for studies of shielding, activation and radiation damage of materials for high-energy neutrons, and experimental data are useful to check the accuracies of the transmission and activation calculation codes.

Improvement of depth dose distribution using multiple-field irradiation in boron neutron capture therapy.

It is important that improvements are made to depth dose distribution in boron neutron capture therapy, because the neutrons do not reach the innermost regions of the human body. Here, we evaluated the dose distribution obtained using multiple-field irradiation in simulation. From a dose volume histogram analysis, it was found that the mean and minimum tumor doses were increased using two-field irradiation, because of improved dose distribution for deeper-sited tumors.

Clinical results of fractionated proton therapy.

PURPOSE: Preliminary results of a multi-site Phase I-II clinical trial investigating the efficacy of high-energy proton beams in a wide variety of human malignancies are reported. METHODS AND MATERIALS: Since 1983 proton radiotherapy using 250 MeV proton beams produced by a booster synchrotron of the National Laboratory for High Energy Physics has been carried out at Proton Medical Research Center, University of Tsukuba. As of September 1990, a total of 147 patients received a partial or full treatment with proton beams with curative intent; 92 patients (63%) were treated with proton beams alone and 55 patients (37%) with combined photon and proton beams. There were 91 males and the mean age was 61.8 years old. The follow-up observation period ranged from 10 to 97 months. With regard to a total tumor dose, nearly 80% of patients received 70 Gy or more and 53% received 80 Gy or more. While dose-fractionations used depended upon tumor sites, the large majority of patients received substantially high radiation doses in terms of larger total doses (> 70 Gy) and larger fraction sizes (> 2.5 Gy) than those traditionally used. This fractionation regimen has been used because of limited availability of the accelerator or a shortage of machine time (27-30 weeks/year, 3-3.5 hr/day), and also by the expectation that the superior dose distribution possible with protons will permit administration of high radiation doses without increasing morbidities. In connection with this, we have determined the target volume by setting margins around the tumor boundary as practically small as possible, ranging from 5 to 10 mm. RESULTS AND CONCLUSIONS: The current trial has been based on a site and dose searching program, hence a wide variety of tumor sites including the aerodigestive organs has been treated. So far, our judgment is that proton therapy has proven of potential advantage in treatment of the lung, esophageal, liver, uterine cervix, prostate, and head and neck malignancies; and of possible value in treatment of high-grade gliomas, and gastric, urinary bladder, and pediatric tumors.

Multi-layer energy filter for realizing conformal irradiation in charged particle therapy.

A new type of filter for charged particle radiotherapy is developed to reduce unwanted dose transfer to the normal tissues around a tumor. The new filter can make a static irradiation field where the width of the spread-out Bragg peak (SOBP) is two-dimensionally adjusted. That makes the field conformal to the tumor three-dimensionally. The filter is made of many layers produced by using stereolithography. The layer has a miniaturized structure that has geometrical similarity to the conventional ridge filter. Shapes of cone and pyramid are also usable for the unit-cell constructing the layer. The spread of the field in the depth direction is decided by the thickness of the filter, or by the number of layers. The experimental result of the irradiation using the ridge-type construction shows a good agreement with an estimate by the Monte Carlo calculation. By combining this technique with intensity modulation that has lateral position dependence, the conformal irradiation can be achieved by a simple procedure.

Characteristics of proton beams after field shaping at PMRC.

The proton irradiation control system was developed for cancer radiotherapy at the Proton Medical Research Center, with the extension of a beam line connected to a synchrotron at the High Energy Physics Laboratory. The initial energy of the 500 MeV proton beam supplied by the accelerator is degraded down to 243 MeV after passing through a graphite rod. In the control system, a proton beam is scattered to form a large field, its Bragg peak width is spread out, and its energy is degraded to the optimum value with a range covering tumour depth. The characteristics of the devices required for these procedures have been investigated from the viewpoint of the relationship between dose rate and field flatness, taking the setting-up geometry of these devices into consideration.

DNA-lesion and cell death by alpha-particles and nitrogen ions.

When the natural logarithm of the surviving fraction is plotted against the dose of radiation, curves with shoulders at relatively high survival levels are obtained after gamma-rays. The curves were practically linear in case of HMV-I and HA-1 cells irradiated by charged particle beams. These cells were derived from human malignant melanoma and Chinese hamster cells, respectively. The amount of DNA single strand breaks (ssb) by gamma-rays or nitrogen-ions (LET=530KeV/micrometers) in HMV-I cells increases linearly with increment in dose, when the ssb is detected using the alkaline elution technique. There is no close relationship between the dose-response curve of the ssb and the dose-survival curves after gamma-rays or N-ions. The amount of DNA double strand breaks (dsb) by gamma-rays increases quadratically with increment of dose, in both HMV-I cells and HA-1 cells, when the dsb is detected using the neutral elution technique. The survival fraction for HA-1 cells is slightly higher than that for HMV-I cells, at the same dose, and the amount of dsb for HA-1 cells is considerably greater than that for HMV-I cells. These results suggest that the radiosensitivities to gamma-rays in different cell lines do not correspond to the number of DNA strand breaks. The amount of both non-repairable ssb and dsb also increases quadratically with increment of dose for gamma-rays and almost linearly with increment of dose for N-ions and alpha-particles (LET=36keV/micrometers for HA-1 cells and LET=77keV/micrometers for HMV-I cells). The dose-response curves for non-repairable dsb in case of these radiations seemed to mirror image the dose-survival curves for these radiations, in both cell lines. The number of non-repairable DNA strand breaks in the two cell lines, at the same level of survival was much the same. These results show the close relationship between the induction of non-repairable DNA strand breaks and cell killing.

The irradiation system and dose estimation joint-system for NCT wider application in Kyoto University.

The research for neutron capture therapy (NCT) at the Kyoto University Research Reactor (KUR) has been remarkably developing after December 2001. However, the most important subject is the preparations for the KUR provisional shutdown coming in March 2006. In this paper, our present concept and plan are reported about the novel irradiation system and dose estimation system for wider applications of NCT. For the irradiation field, the target nuclear reaction was selected to (7)Li(p,n)(7)Be and the neutron moderator was selected to heavy water. The minimum proton current was about 13 mA for epi-thermal neutron irradiation, and about 9 mA for mix-neutron irradiation. In thermal neutron irradiation, the proton current needed more than 18 mA for 2.5-MeV protons, but only 4 mA for 5.0-MeV protons. For the dose estimation system, we are aiming at the completion of the "dose estimation joint-system". The data from the on-line measurement systems such as beam monitors and gamma-ray telescopes are fed back to the results for the in-body dose estimation, and then the dose estimations for irradiation field and a living body are jointed. For the beam-monitor system, multi-chamber method was adopted. The surveys were performed for the wall materials and chamber gases.

The usefulness of 2-nitroimidazole-sodium borocaptate-10B conjugates as 10B-carriers in boron neutron capture therapy.

We evaluated the usefulness of five new (10)B-compounds (TX-2016, TX-2017, TX-2018, TX-2041, and TX-2042) as (10)B-carriers in boron neutron capture therapy (BNCT). They are 2-nitroimidazole-sodium borocaptate-(10)B (BSH) conjugates, that is, hybrid compounds that have both hypoxic tumor cell sensitizing unit under gamma-ray irradiation, 2-nitroimidazoles, and thermal neutron-sensitizing unit, BSH. (10)B distribution analyses in tumors and blood indicated that TX-2041 has the most favorable characteristics for localizing a sufficient amount of (10)B into tumors and keeping the (10)B concentration high during neutron beam irradiation. In addition, TX-2041 showed a significantly higher radio-sensitization effect with reactor thermal neutron beams than BSH on both total (=proliferating (P) + quiescent (Q)) and hypoxia-rich Q cell populations in solid tumors. Further, TX-2041 clearly demonstrated a radio-sensitization effect with gamma-rays on both cell populations, which could never be achieved by BSH. (10)B-carriers with a hypoxic tumor cell-sensitizing effect on tumors with gamma-rays as well as the potential to selectively localize and keep (10)B in tumors, such as TX-2041, are promising for use in actual BNCT.

Proton radiation therapy for clivus chordoma--case report.

A 57-year-old male with clival chordoma developed severe hoarseness, dysphagia, and dysphonia 1 month after a second removal of the tumor. Magnetic resonance imaging demonstrated a mass 10 cm in diameter in the region of the middle clivus enhanced inhomogeneously by gadolinium-diethylenetriaminepentaacetic acid, and a defect in the skull base. There was evidence of compression of the anterior surface of the pons. He received proton irradiation employing a pair of parallel opposed lateral proton beams. The dose aimed at the tumor mass was 75.5 Gy, to the pharyngeal wall less than 38 Gy, and to the anterior portion of the pons less than 30 Gy. Time dose and fractionation factor was calculated at 148. Thirty-one months following treatment, he was free of clinical neurological sequelae. Proton therapy should be considered in treatment planning following initial surgical removal or for inoperable clivus chordoma.

[A case report of two mitral valve aneurysms with one perforation after two attacks of infective endocarditis].

Aneurysms of the mitral valve complicating infective endocarditis (IE) are uncommon. The patient was a 57-year-old man who was admitted to our hospital for a precise examination of heart failure. One year before, the first two-dimensional echocardiography showed an aneurysm of the anterior mitral leaflet possibly due to a previous attack of IE. Doppler color flow mapping detected a regurgitant jet from the mitral valve aneurysm into the left atrium during systole, which suggested perforation of the aneurysm, and an aortic regurgitant jet flowing against the anterior mitral leaflet. Because the patient's family refused cardiac catheter examination and surgery, we treated him in the out-patient clinic. A few weeks before his admission, he had discontinued taking diuretics because of uncomfortable urinary frequency. He gradually developed the symptoms of heart failure and entered our hospital. IE was suspected because of leucocytosis and slight fever. Two-dimensional echocardiography revealed a new aneurysm of the anterior mitral leaflet without perforation, located in the distal part of the old aneurysm. This time, his family consented to the surgical treatment. Aortic and mitral valve replacement was successfully performed. It was pathologically confirmed that the two mitral aneurysms had been caused by IE.

Dose estimation for internal organs during boron neutron capture therapy for body-trunk tumors.

Radiation doses during boron neutron capture therapy for body-trunk tumors were estimated for various internal organs, using data from patients treated at Kyoto University Research Reactor Institute. Dose-volume histograms were constructed for tissues of the lung, liver, kidney, pancreas, and bowel. For pleural mesothelioma, the target total dose to the normal lung tissues on the diseased side is 5Gy-Eq in average for the whole lung. It was confirmed that the dose to the liver should be carefully considered in cases of right lung disease.

Evaluation of thermal neutron irradiation field using a cyclotron-based neutron source for alpha autoradiography.

It is important to measure the microdistribution of (10)B in a cell to predict the cell-killing effect of new boron compounds in the field of boron neutron capture therapy. Alpha autoradiography has generally been used to detect the microdistribution of (10)B in a cell. Although it has been performed using a reactor-based neutron source, the realization of an accelerator-based thermal neutron irradiation field is anticipated because of its easy installation at any location and stable operation. Therefore, we propose a method using a cyclotron-based epithermal neutron source in combination with a water phantom to produce a thermal neutron irradiation field for alpha autoradiography. This system can supply a uniform thermal neutron field with an intensity of 1.7×10(9) (cm(-2)s(-1)) and an area of 40mm in diameter. In this paper, we give an overview of our proposed system and describe a demonstration test using a mouse liver sample injected with 500mg/kg of boronophenyl-alanine.

Radiosensitivity of pimonidazole-unlabelled intratumour quiescent cell population to γ-rays, accelerated carbon ion beams and boron neutron capture reaction.

OBJECTIVES: To detect the radiosensitivity of intratumour quiescent (Q) cells unlabelled with pimonidazole to accelerated carbon ion beams and the boron neutron capture reaction (BNCR). METHODS: EL4 tumour-bearing C57BL/J mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumour proliferating (P) cells. After the administration of pimonidazole, tumours were irradiated with γ-rays, accelerated carbon ion beams or reactor neutron beams with the prior administration of a (10)B-carrier. Responses of intratumour Q and total (P+Q) cell populations were assessed based on frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of pimonidazole-unlabelled tumour cells was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. RESULTS: Following γ-ray irradiation, the pimonidazole-unlabelled tumour cell fraction showed significantly enhanced radiosensitivity compared with the whole tumour cell fraction, more remarkably in the Q than total cell populations. However, a significantly greater decrease in radiosensitivity in the pimonidazole-unlabelled cell fraction, evaluated using a delayed assay or a decrease in radiation dose rate, was more clearly observed among the Q than total cells. These changes in radiosensitivity were suppressed following carbon ion beam and neutron beam-only irradiaton. In the BNCR, the use of a (10)B-carrier, especially L-para-boronophenylalanine-(10)B, enhanced the sensitivity of the pimonidazole-unlabelled cells more clearly in the Q than total cells. CONCLUSION: The radiosensitivity of the pimonidazole-unlabelled cell fraction depends on the quality of radiation delivered and characteristics of the (10)B-carrier used in the BNCR. ADVANCES IN KNOWLEDGE: The pimonidazole-unlabelled subfraction of Q tumour cells may be a critical target in tumour control.

Effects of employing a ¹°B-carrier and manipulating intratumour hypoxia on local tumour response and lung metastatic potential in boron neutron capture therapy.

OBJECTIVES: To evaluate the effects of employing a (10)B-carrier and manipulating intratumour hypoxia on local tumour response and lung metastatic potential in boron neutron capture therapy (BNCT) by measuring the response of intratumour quiescent (Q) cells. METHODS: B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumours received reactor thermal neutron beam irradiation following the administration of a (10)B-carrier [L-para-boronophenylalanine-(10)B (BPA) or sodium mercaptoundecahydrododecaborate-(10)B (BSH)] in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (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, macroscopic lung metastases were enumerated 17 days after irradiation. RESULTS: BPA-BNCT increased the sensitivity of the total tumour 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 (10)B-carrier, MTH enhanced the sensitivity of the Q cell population. Without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with nicotinamide treatment, showed the potential to reduce the number of metastases more than BSH-BNCT. CONCLUSION: BSH-BNCT in combination with MTH improves local tumour control, while BPA-BNCT in combination with nicotinamide may reduce the number of lung metastases.

Study on optimization of multiionization-chamber system for BNCT.

In order to monitor stability of doses from the four components such as thermal, epi-thermal, fast neutron and gamma-ray during BNCT irradiation, we are developing a multiionization-chamber system. This system is consisted of four kinds of ionization chamber, which have specific sensitivity for each component, respectively. Since a suitable structure for each chamber depends on the energy spectrum of the irradiation field, the optimization study of the chamber structures for the epi-thermal neutron beam of cyclotron-based epi-thermal neutron source (C-BENS) was performed by using a Monte Carlo simulation code "PHITS" and suitable chamber-structures were determined.

The optimization study of Bonner sphere in the epi-thermal neutron irradiation field for BNCT.

The optimization study on the Bonner sphere in the epi-thermal neutron irradiation field for BNCT was done for the moderator material, moderator size, and activation foils as a neutron detector in the sphere. The saturated activity for the activation foil was obtained from the calculated response, and the effective energy range for each Bonner sphere was determined from the saturated activity. We can see that boric acid solution moderator is suitable for the spectrum measurement of a epi-thermal neutron irradiation field.

A phantom experiment for the evaluation of whole body exposure during BNCT using cyclotron-based epithermal neutron source (C-BENS).

At Kyoto University Research Reactor Institute (KURRI), cyclotron-based epithermal neutron source was installed in December 2008, and the supplementary construction works have been performed. As of December 2010, the various irradiation characteristics important for BNCT were mostly evaluated. The whole body exposure during BNCT medical irradiation is one of the important characteristics. In this article, measurements of absorbed dose for thermal and fast neutrons and gamma-ray at ten positions corresponding to important organs are reported.

Evaluation for activities of component of Cyclotron-Based Epithermal Neutron Source (C-BENS) and the surface of concrete wall in irradiation room.

The workers employed in BNCT must enter the irradiation room just after an irradiation under the condition of remaining activities. To reduce the radiation exposure for the workers, it is important to identify the origins of the activities. In this research, the activities induced on the concrete wall surface were evaluated using MCNP-5 and the measurement results of thermal neutron distribution. Furthermore, the radioisotopes produced in the moderator were identified with a High Purity Germanium detector. It was found that the activities of the wall were mainly caused by (46)Sc, (60)Co and (152)Eu, and that (24)Na and (56)Mn were mainly produced in the moderator.

Reducing intratumour acute hypoxia through bevacizumab treatment, referring to the response of quiescent tumour cells and metastatic potential.

OBJECTIVES: The aim was to evaluate the influence of bevacizumab on intratumour oxygenation status and lung metastasis following radiotherapy, with specific reference to the response of quiescent (Q) cell populations within irradiated tumours. METHODS: B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray irradiation following treatment with the acute hypoxia-releasing agent nicotinamide or local mild temperature hyperthermia (MTH) with or without the administration of bevacizumab under aerobic conditions or totally hypoxic conditions, achieved by clamping the proximal end of the tumours. 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 the other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation. RESULTS: 3 days after bevacizumab administration, acute hypoxia-rich total cell population in the tumour showed a remarkably enhanced radiosensitivity to γ-rays, and the hypoxic fraction (HF) was reduced, even after MTH treatment. However, the hypoxic fraction was not reduced after nicotinamide treatment. With or without γ-ray irradiation, bevacizumab administration showed some potential to reduce the number of lung metastases as well as nicotinamide treatment. CONCLUSION: Bevacizumab has the potential to reduce perfusion-limited acute hypoxia and some potential to cause a decrease in the number of lung metastases as well as nicotinamide.

Experimental verification of beam characteristics for cyclotron-based epithermal neutron source (C-BENS).

A cyclotron-based epithermal neutron source has been developed for boron neutron capture therapy. This system consists of a cyclotron accelerator producing 1.1-mA proton beams with an energy of 30 MeV, a beam transport system coupled with a beryllium neutron production target, and a beam-shaping assembly (BSA) with a neutron collimator. In our previous work, the BSA was optimized to obtain sufficient epithermal neutron fluxes of ~10(9) cm(-2) s(-1) using a Monte Carlo simulation code. In order to validate the simulation results, irradiation tests using multi-foil activation at the surface of a gamma-ray shield located behind the collimator and water phantom experiments using a collimated epithermal neutron beam were performed. It was confirmed experimentally that the intensity of the epithermal neutrons was 1.2×10(9) cm(-2) s(-1).