Washout studies of 11C in rabbit thigh muscle implanted by secondary beams of HIMAC.

Heavy ion therapy has two definite advantages: good dose localization and higher biological effect. Range calculation of the heavy ions is an important factor in treatment planning. X-ray CT numbers are used to estimate the heavy ion range by looking up values in a conversion table which relates empirically photon attenuation in tissues to particle stopping power; this is one source of uncertainty in the treatment planning. Use of positron emitting radioactive beams along with a positron emission tomograph or a positron camera gives range information and may be used as a means of checking in heavy ion treatment planning. However, the metabolism of the implanted positron emitters in a living object is unpredictable because the chemical forms of these emitters are unknown and the metabolism is dependent on the organ species and may be influenced by many factors such as blood flow rate and fluid components present. In this paper, the washout rate of 11C activity implanted by injecting energetic 11C beams into thigh muscle of a rear leg of a rabbit is presented. The washout was found to consist of two components, the shorter one was about 4.2 +/- 1.1 min and the longer one ranged from 91 to 124 min. About one third of the implanted beta+ activity can be used for imaging and the rest was washed out of the target area.

Relative biological effectiveness of the 235 MeV proton beams at the National Cancer Center Hospital East.

A therapy-dedicated cyclotron was installed in the National Cancer Center Hospital East (NCCHE) at Kashiwa in 1997. Prior to the start of clinical use, we investigated the biological effectiveness of therapeutic proton beams for cell lethality. The proton beams accelerated up to 235 MeV were horizontally extracted from the cyclotron, and scattered by a bar-ridge filter to produce a Spread-Out-Bragg-Peak (SOBP) of 10-cm width. The biological systems used here were mouse intestinal crypt cells and three in vitro cell lines, including SCC61 human squamous cell carcinoma, NB1RGB human fibroblasts and V79 Chinese hamster cells. The dose responses after irradiation at either the entrance plateau or the middle portion of SOBP were compared with those after linac 6 MV X-ray irradiation. The fit of a linear quadratic model to survival curves showed that proton irradiation increased the alpha value of SCC61 and the beta value of V79 cells with a least change for alpha/beta ratio of NB1RGB cells. The isoeffect dose that reduces either cell survivals to 10% or mouse jejunum crypts to 10 per circumference was termed D10. The relative biological effectiveness (RBE) of protons obtained by comparing the D10 values between protons and X-rays ranged from 0.9 to 1.2. The depth distribution of cell lethality was measured by replating V79 cells after irradiation from a "cell stack chamber" that received a single dose of 7 Gy at the middle position of SOBP. The thus-obtained cell survivals at various depths coincided well with the estimated survivals, but tended to decrease at the distal end of SOBP. We conclude that an RBE of 1.1 would be appropriate for 235 MeV proton beams at the NCCHE.

Ridge filter design and optimization for the broad-beam three-dimensional irradiation system for heavy-ion radiotherapy.

The broad-beam three-dimensional irradiation system under development at National Institute of Radiological Sciences (NIRS) requires a small ridge filter to spread the initially monoenergetic heavy-ion beam to a small spread-out Bragg peak (SOBP). A large SOBP covering the target volume is then achieved by a superposition of differently weighted and displaced small SOBPs. Two approaches were studied for the definition of a suitable ridge filter and experimental verifications were performed. Both approaches show a good agreement between the calculated and measured dose and lead to a good homogeneity of the biological dose in the target. However, the ridge filter design that produces a Gaussian-shaped spectrum of the particle ranges was found to be more robust to small errors and uncertainties in the beam application. Furthermore, an optimization procedure for two fields was applied to compensate for the missing dose from the fragmentation tail for the case of a simple-geometry target. The optimized biological dose distributions show that a very good homogeneity is achievable in the target.

[Development of a multi-layer ion chamber for measurement of depth dose distributions of heavy-ion therapeutic beam for individual patients].

In heavy-ion radiotherapy, an accelerated beam is modified to realize a desired dose distribution in patients. The setup of the beam-modifying devices in the irradiation system is changed according to the patient, and it is important to check the depth dose distributions in the patient. In order to measure dose distributions realized by an irradiation system for heavy-ion radiotherapy, a multi-layer ionization chamber(MLIC) was developed. The MLIC consists of 64 ionization chambers, which are stacked mutually. The interval between each ionization chamber is about 4.1 mm water. There are signal and high voltage plates in the MILC, which are used as electrodes of the ionization chambers and phantom. Depth dose distribution from 5.09 mm to 261.92 mm water can be measured in about 30 seconds using this MLIC. Thus, it is possible to check beam quality in a short amount of time.

Proton dosimetry intercomparison based on the ICRU report 59 protocol.

BACKGROUND AND PURPOSE: A new protocol for calibration of proton beams was established by the ICRU in report 59 on proton dosimetry. In this paper we report the results of an international proton dosimetry intercomparison, which was held at Loma Linda University Medical Center. The goals of the intercomparison were, first, to estimate the level of consistency in absorbed dose delivered to patients if proton beams at various clinics were calibrated with the new ICRU protocol, and second, to evaluate the differences in absorbed dose determination due to differences in 60Co-based ionization chamber calibration factors. MATERIALS AND METHODS: Eleven institutions participated in the intercomparison. Measurements were performed in a polystyrene phantom at a depth of 10.27 cm water equivalent thickness in a 6-cm modulated proton beam with an accelerator energy of 155 MeV and an incident energy of approximately 135 MeV. Most participants used ionization chambers calibrated in terms of exposure or air kerma. Four ionization chambers had 60Co-based calibration in terms of absorbed dose-to-water. Two chambers were calibrated in a 60Co beam at the NIST both in terms of air kerma and absorbed dose-to-water to provide a comparison of ionization chambers with different calibrations. RESULTS: The intercomparison showed that use of the ICRU report 59 protocol would result in absorbed doses being delivered to patients at their participating institutions to within +/-0.9% (one standard deviation). The maximum difference between doses determined by the participants was found to be 2.9%. Differences between proton doses derived from the measurements with ionization chambers with N(K)-, or N(W) - calibration type depended on chamber type. CONCLUSIONS: Using ionization chambers with 60Co calibration factors traceable to standard laboratories and the ICRU report 59 protocol, a distribution of stated proton absorbed dose is achieved with a difference less than 3%. The ICRU protocol should be adopted for clinical proton beam calibration. A comparison of proton doses derived from measurements with different chambers indicates that the difference in results cannot be explained only by differences in 60Co calibration factors.

Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy.

PURPOSE: The irradiation system and biophysical characteristics of carbon beams are examined regarding radiation therapy. METHODS AND MATERIALS: An irradiation system was developed for heavy-ion radiotherapy. Wobbler magnets and a scatterer were used for flattening the radiation field. A patient-positioning system using X ray and image intensifiers was also installed in the irradiation system. The depth-dose distributions of the carbon beams were modified to make a spread-out Bragg peak, which was designed based on the biophysical characteristics of monoenergetic beams. A dosimetry system for heavy-ion radiotherapy was established to deliver heavy-ion doses safely to the patients according to the treatment planning. A carbon beam of 80 keV/microm in the spread-out Bragg peak was found to be equivalent in biological responses to the neutron beam that is produced at cyclotron facility in National Institute Radiological Sciences (NIRS) by bombarding 30-MeV deuteron beam on beryllium target. The fractionation schedule of the NIRS neutron therapy was adapted for the first clinical trials using carbon beams. RESULTS: Carbon beams, 290, 350, and 400 MeV/u, were used for a clinical trial from June of 1994. Over 300 patients have already been treated by this irradiation system by the end of 1997.

Relationship between CT number and electron density, scatter angle and nuclear reaction for hadron-therapy treatment planning.

The precise conversion of CT numbers to their electron densities is essential in treatment planning for hadron therapy. Although some conversion methods have already been proposed, it is hard to check the conversion accuracy during practical therapy. We have estimated the CT numbers of real tissues by a calculational method established by Mustafa and Jackson. The relationship between the CT numbers and the electron densities was investigated for various body tissues as well as some tissue-equivalent materials used for a conversion to check the accuracy of the current conversion methods. The result indicates a slight disagreement at the high-CT-number region. A precise estimation of the multiple scattering, nuclear reaction and range straggling of incident particles has been considered as being important to realize higher-level conformal therapy in the future. The relationship between these parameters and the CT numbers was also investigated for tissues and water. The result shows that it is sufficiently practical to replace these parameters for real tissues with those for water by adjusting the density.

Carbon beam dosimetry intercomparison at HIMAC.

To verify international uniformity in carbon beam dosimetry, an intercomparison programme was carried out at the heavy ion medical accelerator (HIMAC). Dose measurements with ionization chambers were performed for both unmodulated and 6 cm modulated 290 MeV/nucleon carbon beams. Although two different dosimetry procedures were employed, the evaluated values of absorbed dose were in good agreement. This comparison established a common framework for ionization chamber dosimetry between two different carbon beam therapy facilities.

Initial recombination in a parallel-plate ionization chamber exposed to heavy ions.

For exact determination of absorbed dose in heavy-ion irradiation fields which are used in radiation therapy and biological experiments, ionization chambers have been characterized with defined heavy-ion beams and correction factors. The LET (linear energy transfer) dependence of columnar recombination in a parallel-plate ionization chamber has been examined. Using 135 MeV/u carbon and neon beams, the ion collection efficiency was measured for several gases (air, carbon dioxide, argon and tissue-equivalent gas). 95 MeV/u argon beams and 90 MeV/u iron beams were also used for measurements of columnar recombination in air. As expected by Jaffe theory, the inverse of the ratio of the ionization charge to the saturated ionization charge had a linear relationship with the inverse of the electric field strength in the region below 0.002 V(-1) cm. The gradient of the line increases as the LET of the heavy ions increases. A strong LET dependence of the gradient was observed in air and carbon dioxide. The LET dependence was not observed in tissue-equivalent gas, nitrogen or argon. The exact depth-dose distribution of the heavy-ion beam was obtained by this correction of the initial recombination effect for the collected ionization charge. The columnar recombination in air was analysed using Jaffe theory; the obtained parameter b (a track radius) should be in the range between 0.001 cm and 0.005 cm, whereas the value obtained by Jaffe is 0.00179 cm. The value of the parameter b should increase as the LET of the heavy-ion beam increases in order to reproduce the experimental values of the initial recombination.

L-arginine-nitric oxide pathway and chronic nephropathy in aged rats.

Effects of aging and dietary protein on the L-arginine-nitric oxide (Arg-NO) pathway and the progress of chronic nephropathy were examined. At 6-7 months of age, 10 male Fischer 344 rats were fed a 23% protein diet until 24 or 25 months of age, and another 10 were fed a 12% protein diet until that age. Twenty male Fischer 344 rats that were fed the 23% protein diet from 6 to 8 months of age were used as a control. Urinary excretion of nitrite/nitrate (NOx) at the age of 24 months in the 23% protein group was remarkably decreased, whereas in the 12% protein group, urinary NOx remained comparable to that of the control. Histological examination revealed that chronic nephropathy was highly progressive in the 23% protein group, accompanied by lowered renal function, but these changes were obviously suppressed in the 12% protein group. These results suggest that an age-related decrease in the synthesis of NO could be associated with the progress of chronic nephropathy.

Effects of dietary protein restriction on nitrogen balance and cardiovascular functions in aged rats.

Effects of aging and dietary protein restriction on nitrogen balance and cardiovascular functions were examined. Male Fischer 344 rats 6-7 months old were fed ad libitum until 24 or 25 months old with either a 12% or a 23% protein diet, respectively. The nitrogen balance measured at the age of 24 months old demonstrated a significant difference between the two groups: the group with the 23% protein diet had a negative balance, while the group with the 12% protein diet had a positive balance. Endothelium-dependent relaxation with acetylcholine of the thoracic aortas was impaired by age but to a lesser extent to the protein-restricted animals. In addition, increased ability of platelet aggregation according to aging was also significantly suppressed by protein restriction. These observations demonstrate that protein restriction delays the aging effects of nitrogen loss and reduced cardiovascular function.

Mechanical circulatory assist by a roller pump system using hydrophilic heparinized polymer coated tubing.

We developed a circulatory assist system driven by a roller pump using hydrophilic heparinized polymer coated tubing. This system is easy to handle and does not require systemic heparinization. We applied it to 11 patients who failed to be weaned from cardiopulmonary bypass after open heart surgery. Left heart bypass was employed in 5 patients, right heart bypass in 1, combined left and right heart bypass in 2, and venoarterial bypass without oxygenation was done in 3 patients. The assisting flow rate ranged from 0.8 to 3.2 L/min, and the duration of the assist ranged from 5 h to 21 days. Six patients were weaned from this support, and 5 were discharged from the hospital. This system is beneficial for patients who failed to wean from cardiopulmonary bypass after cardiac surgery because of its simplicity and antithrombogenicity.

Nonfamilial and unusual cases of Leber's hereditary optic neuropathy identified by mitochondrial DNA analysis.

Peripheral blood mitochondrial DNA (mtDNA) samples from 11 patients with acute optic neuritis or insidious optic atrophy were examined for the mutation at nt 11778 and nt 3460 in polymerase chain reaction products. The mtDNA mutation at nt 11778 was evident in 8 cases, which led to a definite diagnosis of Leber's hereditary optic neuropathy (LHON); 4 of the cases were familial and the remaining 4 cases were nonfamilial. None of the 11 patients showed the nt 3460 mutation. The symptoms and signs were variable among the LHON cases with nt 11778 mutation. Assessment of mtDNA provides a useful diagnostic aid for clinically undefined, seemingly nonfamilial or atypical cases of Leber's hereditary optic neuropathy, particularly in bilateral, insidious optic nerve disease in early childhood.

[Transarterial segmental hepatic chemo-embolization in patients with hepatocellular carcinoma].

We can administer a Lipiodol-adriamycin emulsion transarterially into the portal vein, because more than a certain amount of Lipiodol injected into the hepatic artery enters the portal vein through arterioportal communications without arterioportal shunting. When Gelfoam embolization is followed by portal venous administration of this emulsion, hepatic chemoembolization is performed from both artery and portal vein simultaneously. But this chemoembolization must be in a limited area of the liver, since such treatment of the whole liver is lethal. We encountered a segmental hepatic chemoembolization in four patients with hepatocellular carcinoma by the catheterization of a hepatic segmental artery. In two cases operated after segmental chemoembolization, complete necrosis was certified in the main tumor and daughter nodules. Hepatic segmental atrophy and infarctions were also noted in the treated segment. In two non-operated cases, hepatic segmental atrophy and excellent antitumor effects were demonstrated by CT and radioisotope liver scan. Thus, we call this treatment "transarterial partial hepatectomy".

Evidence for guanylate cyclase activity associated with hemagglutinating virus of Japan (Sendai virus).

Purified virions of HVJ (Sendai virus) were found to contain a guanylate cyclase activity that converts GTP to cyclic GMP. Activities of adenylate cyclase and 5'-nucleotidase which are frequently used as marker enzymes of cell membranes were not detected in the virus. Guanylate cyclase and virion-associated activities, neuraminidase and hemagglutinin, were co-purified during a purification of virions. Guanylate cyclase activity was not detected without disruption of the virions with a detergent, Triton X-100 or Nonident P-40. Treatment of intact HVJ with a proteolytic enzyme, trypsin or chymotrypsin, destroyed both neuraminidase and hemagglutinin; however, most of the guanylate cyclase ws retained. Guanylate cyclase activity was found in fractions containing nucleocapsids after sucrose density gradient centrifugation of disrupted virions. These results indicated that the enzyme was tightly bound to cores of HVJ and, therefore, its presence could not be explained by binding of host cell enzyme to the surface of virions. Properties of the virus-derived enzyme and particulate fractions of host cell homogenates were similar. Antiserum against nucleocapsids of HVJ inhibited guanylate cyclase activity of HVJ and particulate fractions of cells such as chorioallantoic membrane and rat liver, while soluble guanylate cyclase was not inhibited by antiserum. The biological significance and origin of guanylate cyclase found in HVJ are obscure and await further study.