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Biomedical subjects

A Maruhashi

Publications and source records attributed to A Maruhashi.

At least 19 recordsLinked to original sources

The usefulness of a continuous administration of tirapazamine combined with reduced dose-rate irradiation using {gamma}-rays or reactor thermal neutrons.

We clarified the usefulness of the continuous administration of tirapazamine (TPZ) in combination with reduced dose-rate irradiation (RDRI) using gamma-rays or reactor thermal neutrons. Squamous cell carcinoma (SCC) VII tumour-bearing mice received a continuous administration of 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. Then, they received a single intraperitoneal injection or 24 h continuous subcutaneous infusion of TPZ in combination with conventional dose-rate irradiation (CDRI) or RDRI using gamma-rays or thermal neutrons. After irradiation, the tumour cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labelling ( = quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. The MN frequency in the total tumour cells was determined using tumours that were not pre-treated with BrdU. The sensitivity of both total and Q cells, especially of Q cells, was significantly reduced with RDRI compared with CDRI. Combination of TPZ increased the sensitivity of both populations, with a slightly more remarkable increase in Q cells. Furthermore, the continuous administration of TPZ raised the sensitivity of both total and Q cell populations, especially the former, more markedly than the single administration, whether combined with CDRI or RDRI using gamma-rays or thermal neutrons. From the viewpoint of solid tumour control as a whole, including intratumour Q-cell control, the use of TPZ, especially when administered continuously, combined with RDRI, is useful for suppressing the reduction in the sensitivity of tumour cells caused by the decrease in irradiation dose rate in vivo.

Animals↗

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.

Computer Simulation↗

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.

Animals↗

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.

Boron Neutron Capture Therapy↗

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.

Equipment Design↗

[Dose-volume histogram analysis of patients with hepatocellular carcinoma regarding changes in liver function after proton therapy].

Seventy-five patients with hepatocellular carcinoma were treated with proton beams from 1983-1993 at the Proton Medical Research Center, University of Tsukuba. For the purpose of confirming the feasibility of proton therapy for hepatocellular carcinoma, we investigated the influence of proton therapy on liver function and also tried to evaluate the possibility of optimization using dose-volume histogram (DVH) analysis. The results indicated that proton therapy did not cause clinically symptomatic damage in liver function and the only notable change after proton therapy was the transient increase of transminase. DVH analysis showed that this transient increase of transaminase was well correlated to the normal tissue complication probability (NTCP). These results indicate that localized high dose radiation using proton beams is feasible for the treatment of liver cancers and optimization of this treatment may be possible using DVH analysis.

Adult↗

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.

Humans↗

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.

Adolescent↗

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.

Chordoma↗

[Proton irradiation synchronized with respiratory cycle].

A sensitive strain gauge was used to detect the movement of the chest wall in order to synchronize an irradiation control system with the respiratory cycle. The output timing signal from the system is transferred to the proton accelerator for synchronized irradiation. The timing signal is set during the expiratory phase at a duration of 1.5 to 2 seconds. The efficacy of this method was evaluated by dose volume histogram based on the treatment planning program with CT images. The volume spared by this novel method was calculated in several cases, and results suggest that the method was highly effective.

Humans↗

[Development of a moving target aiming system using an ultrasound imaging unit].

We developed an ultrasound imaging unit for gating the irradiation of proton beams or acquiring CT scan data for treatment planning according to the motion of tumors in the abdomen. In proton therapy, it is essential that the maximum region of dose rate distribution in a body always coincide with the volume of the tumor in motion during irradiation. Gated proton bean irradiation based on tumor motion could solve this problem and minimize undesirable dose distribution to normal tissues in the vicinity of the tumor. This device can generate the TTL level signal of time width corresponding to the period that the tumor would be sited in a region determined in advance, to control the various kinds of machines. Results of our preliminary experiment using X-ray irradiation showed that this aiming device was able to make the width of the gated irradiation area coincide with that of the planned area within a difference of about 0.5 mm.

Humans↗

[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.

Aortic Valve↗

[Field localization and verification system for proton beam radiotherapy in deep-seated tumors].

It has been recognized that, for precise localization and verification of radiation fields, a marking drawn on the skin surface is not entirely reliable because its position relative to bony structures or internal organs is not stationary. This is especially true when treating deep-seated tumors located below the clavicle. In proton beam radiotherapy at the University of Tsukuba, we ristrict the margins around the target volume. Therefore, special care in field localization and verification is needed, and we make it a rule to take X-ray pictures on each treatment day. To accomplish this, we have developed a localize-and-verify system by using fluoroscopic techniques and combining it with a real-time digital image processing device. This allows for the formation of a digital image of the proton field and storage it in the optic disc. By using this system as well as verification films, filed placement errors were measured in 10 patients with deep-seated tumors. Out of a total of 190 localizations, 22% exhibited a field placement error of more than 5 mm, where patient positioning and field localization were done by using skin drawings aligned with laser beams. This result strongly suggests the necessity for daily localization and verification of radiation fields, as is being done by us, for precision in the execution of proton beam radiation therapy.

Adult↗

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.

Alpha Particles↗

[Clinical investigation of indications in proton therapy].

The indications for curative treatment with proton therapy were investigated by the clinical results of 31 cancer patients treated with proton beams between 1983 and 1985 at the Particle Radiation Medical Science Center of Tsukuba University. Many locally extended, radioresistant lesions, lesions with large volume and small radiocurable lesions in this series revealed sufficient improvement without definite late damage in the surrounding normal tissues. This clinical result suggests that proton beam treatment could be applied to lesions in a much wider range for curative purposes as compared with conventional radiotherapy. This study is to be continued further.

Adult↗

Synchrotron radiation at the Photon Factory for non-invasive coronary angiography: experimental studies.

Synchrotron radiation available at the Photon Factory, National Laboratory for High Energy Physics, provides a new X-ray source which is highly suitable for K-edge subtraction. This is due to its high intensity, its parallelism and its monochromaticity, available in a monochromator system. Experiments were performed using wiggler synchrotron radiation. Since the beam size is relatively-small for in-vivo imaging, a phantom coupled with a detector was moved horizontally using a scanning table. K-edge subtraction was successfully applied both to the coronary artery phantom filled with barium sulphate, and to rat angiography using iodine contrast material. The potential use and value of energy subtraction was successfully demonstrated.

Animals↗