Experimental comparison of relative stopping power evaluation between proton CT and x-ray CT for pre-clinical proton irradiation studies of small animals.

Objective. Proton therapy experiments in small animals are useful not only for pre-clinical and translational studies, but also for the development of advanced technologies for high-precision proton therapy. While treatment planning for proton therapy is currently based on the stopping power of protons relative to water (i.e. the relative stopping power (RSP)), estimated by converting the CT number into RSP (Hounsfield unit (HU)-RSP conversion) in reconstructed x-ray computed tomography (XCT) images, the HU-RSP conversion causes uncertainties in RSP, which affect the accuracy of dose simulation in patients. Proton computed tomography (pCT) has attracted a great deal of attention due to its potential to reduce RSP uncertainties in clinical treatment planning. However, as the proton energies for irradiating small animals are much lower than those used clinically, the energy dependence of RSP may negatively affect pCT-based RSP evaluation. Here, we explored whether the low-energy pCT approach provided more accurate RSPs when planning proton therapy treatment for small animals.Approach.We evaluated the RSPs of 10 water- and tissue-equivalent materials with known constituent elements based on pCT measurements conducted at 73.6 MeV, then compared them with XCT-based and calculated RSPs to investigate energy dependence and achieve more accurate RSPs for treatment planning in small animals.Main results. Despite the low proton energy, the pCT approach for RSP evaluation yields a smaller root mean square deviation (1.9%) of RSP from the theoretical prediction, compared to conventional HU-RSP conversion with XCT (6.1%).Significance.Low-energy pCT is expected to improve the accuracy of proton therapy treatment planning in pre-clinical studies of small animals if the RSP variation that can be attributed to energy dependence is identical to the variation in the clinical proton energy region.

Targeted concurrent chemoradiotherapy, by using improved microcapsules that release carboplatin in response to radiation, improves detectability by computed tomography as well as antitumor activity while reducing adverse effect in vivo.

PURPOSE: The effect of alginate-hyaluronate microcapsules that release carboplatin in response to radiation was improved by adding ascorbic acid (AA). MATERIALS AND METHODS: Four measures of the effectiveness of the microcapsules were evaluated: 1) release of carboplatin in response to radiation in vitro and in vivo; 2) detectability of their accumulation by computed tomography (CT) in vivo; 3) enhancement of antitumor effects in vivo; and 4) reduction of adverse effects in vivo. RESULTS: There were significant increases in the rupture of microcapsules by adding AA in vitro. Subcutaneously injected microcapsules around the tumor could be detected by using CT and the alteration of CT-values correlated with the accumulation of the microcapsules. Those microcapsules released carboplatin and resulted in synergistic antitumor effect with concomitant radiation. With the encapsulation of carboplatin, chemotherapeutic effects were still observed two weeks after treatment. However, addition of AA did not result in increased antitumor effect in vivo. A reduction in adverse effects was observed with the encapsulation of carboplatin, through localization of carboplatin around the tumor. CONCLUSION: Addition of AA to the materials of microcapsules did not result in increasing antitumor effect. However encapsulation of carboplatin will be useful as a clinical cancer-therapy option.

Pre-computed system matrix calculation based on a piece-wise method for PET.

A system matrix (SM) is the basic component of iterative image reconstruction algorithms. Calculation of the SM needs a considerable amount of time due to an enormous number of lines of response (LORs) being modeled. In this study, we developed a technique based on a piece-wise calculation method in which symmetry and further division of the voxels are applied. The detector response function for all detectable pairs of photons along certain LORs originating from each voxel is calculated analytically. The total number of LORs in 300 × 300 × 120 voxels (with 2 × 2 × 2 mm(3)) is ~44 billion, and the SM was calculated by the use of three different computers independently; the calculation time was 5 h. The SM took 5 days when calculated by the use of the conventional method (where symmetry and the piece-wise method are not used). The sensitivity correction factor was stored; it had a size of 42 MB in a four-byte computer memory.

Chromatographic separation of platinum group metals from simulated high level liquid waste using macroporous silica-based adsorbents.

To separate platinum group metals (PGMs) from high level liquid waste, three novel macroporous silica-based adsorbents, namely, (Crea+Dodec)/SiO2-P, (Crea+TOA)/SiO2-P and (MOTDGA+TOA)/SiO2-P, were synthesized by introducing extractants Crea (N',N'-di-n-hexyl-thiodiglycolamide), TOA (Tri-n-octylamine), MOTDGA (N,N'-dimethyl-N,N'-di-n-octyl-thiodiglycolamide) along with theirs modifier, Dodec (n-dodecyl alcohol), into 50µm diameter SiO2-P particles by impregnation. Chromatographic separation of PGMs from simulated high level liquid waste was investigated by column method. It was found that 100% of Pd(II) and Re(VII) could be eluted out from simulate HLLW in 3.0M HNO3 solution using three adsorbents. For Ru(III) and Rh(III), high temperature has distinct effect on the adsorption rate and a further study for Ru(III) and Rh(III) is necessary to separate them from HLLW completely. In all six column experiments, a relatively satisfactory chromatographic separation operating for PGMs from simulated HLLW was obtained using (Crea+TOA)/SiO2-P adsorbent packed column at 323K.

Adsorption and separation behavior of yttrium and strontium in nitric acid solution by extraction chromatography using a macroporous silica-based adsorbent.

To separate (90)Y from the fission product (90)Sr-(90)Y group, a silica-based TODGA/SiO(2)-P adsorbent was prepared by impregnating N,N,N',N'-tetraoctyl-3-oxapentane-1,5-diamide (TODGA) extractant into the macroporous SiO(2)-P support with a mean diameter of 60 µm. The adsorption behavior of Sr(II) and Y(III) onto TODGA/SiO(2)-P adsorbent from HNO(3) solution and their mutual separation were investigated. Under the experimental conditions, this adsorbent showed high adsorption affinity to Y(III) and weak adsorption to Sr(II). It was found that the adsorption process of Y(III) could be expressed by both of Langmuir monomolecular layer adsorption mode and the pseudo-second order model. From the results of stability experiments, it became clear that TODGA/SiO(2)-P adsorbent is stable in 3M HNO(3) solution for 1 month contact time at 298 K. Using a column packed with TODGA/SiO(2)-P adsorbent, Sr(II) and Y(III) were eluted by distilled water and diethylenetriamine pentaacetic acid (DTPA) solution, respectively. The separation of Y(III) from Sr(II)-Y(III) group was achieved successfully.

Precise practical measurements of 90Y used in radiopharmaceuticals using re-entrant ionization chambers.

For diagnostic nuclear medicine, radiopharmaceuticals are labeled with γ-ray emitting nuclides. Routine activity measurements for these drugs are mainly performed with re-entrant ionization chambers. For radiotherapeutic applications, ß-ray emitting nuclides are also used. Since very few gamma transitions are involved in these nuclides, an ionization chamber responds only to weak bremsstrahlung. In order to apply the re-entrant chamber method to routine activity assay for these ß-ray emitting nuclides, detailed studies were carried out. It was determined that the response was strongly affected by the choice of thickness of the inner wall of the well in the measurement of high energy beta particle emitting nuclides. The geometrical dependences were successfully reduced. Accordingly, routine assay of radioactivity of (90)Y therapeutic pharmaceuticals can be performed within an acceptable uncertainty with ordinary re-entrant dose calibrators that are commercially available and equipped in most hospitals.

Delivery of Na/I symporter gene into skeletal muscle using nanobubbles and ultrasound: visualization of gene expression by PET.

UNLABELLED: The development of nonviral gene delivery systems is essential in gene therapy, and the use of a minimally invasive imaging methodology can provide important clinical endpoints. In the current study, we present a new methodology for gene therapy-a delivery system using nanobubbles and ultrasound as a nonviral gene delivery method. We assessed whether the gene transfer allowed by this methodology was detectable by PET and bioluminescence imaging. METHODS: Two kinds of reported vectors (luciferase and human Na/I symporter [hNIS]) were transfected or cotransfected into the skeletal muscles of normal mice (BALB/c) using the ultrasound-nanobubbles method. The kinetics of luciferase gene expression were analyzed in vivo using bioluminescence imaging. At the peak of gene transfer, PET of hNIS expression was performed using our recently developed PET scanner, after (124)I injection. The imaging data were confirmed using reverse-transcriptase polymerase chain reaction amplification, biodistribution, and a blocking study. The imaging potential of the 2 methodologies was evaluated in 2 mouse models of human pathology (McH/lpr-RA1 mice showing vascular disease and C57BL/10-mdx Jic mice showing muscular dystrophy). RESULTS: Peak luciferase gene activity was observed in the skeletal muscle 4 d after transfection. On day 2 after hNIS and luciferase cotransfection, the expression of these genes was confirmed by reverse-transcriptase polymerase chain reaction on a muscle biopsy. PET of the hNIS gene, biodistribution, the blocking study, and autoradiography were performed on day 4 after transfection, and it was indicated that hNIS expression was restricted to the site of plasmid administration (skeletal muscle). Similar localized PET and (124)I accumulation were successfully obtained in the disease-model mice. CONCLUSION: The hNIS gene was delivered into the skeletal muscle of healthy and disease-model mice by the ultrasound-nanobubbles method, and gene expression was successfully visualized with PET. The combination of ultrasound-nanobubble gene transfer and PET may be applied to gene therapy clinical protocols.

Long-term performance evaluation of positron emission tomography: analysis and proposal of a maintenance protocol for long-term utilization.

OBJECTIVE: Positron emission tomography (PET) scanners require periodic monitoring in order to maintain scanner performance. The aim of the present study was to examine the deterioration of PET scanner performance caused by aging. METHODS: We retrospectively examined PET scanner performance alterations in terms of sensitivity, spatial resolution, false coincidences due to scatter and random coincidences based on 13 years of follow-up data, including data when the PET scanner underwent an overhaul at the 10th year after installation. Sensitivity and scatter fraction were calculated by using cross calibration factor (CCF) measurement data, which are collected routinely. Efficacy of the examining the sensitivity and scatter was confirmed by NEMA measurements. Trans-axial resolution was measured as full width at half-maximum (FWHM) and full width at tenth-maximum (FWTM) at 0-20 cm offset from the field of view (FOV) center at the time of installation, 8 years after installation, and immediately after the overhaul. Random coincidence rate fraction was measured in a wide range of count rates before and after the overhaul. RESULTS AND DISCUSSION: The results indicated that the total reduction of sensitivity during the first 10 years was 41% of the initial value in terms of NEMA measurement, and that the annual reduction of sensitivity progressed at a rate of 4.7% per year in terms of CCF measurement data. The changes in sensitivity can be calculated using CCF measurement data. Regarding the spatial resolution, mean FWHM and FWTM values were increased by 1.7 and 3.6%, respectively, in 8 years after installation. The relative scatter fraction was significantly increased compared with that before the overhaul. The random fraction decreased by 10-15% after the overhaul within a certain range of random count rates (1-120 kcps). In the case of our scanner, the parameter that displayed the largest change was the sensitivity, and this change was thought to be caused by the reduction of photomultiplier tube (PMT) gain, although the changes in PMT gain can cause various types of performance deterioration, as investigated in this study. CONCLUSION: We observed that the sensitivity of our PET scanner generally deteriorated due to aging. Sensitivity monitoring using CCF measurements can be an easy and useful method for monitoring and maintaining the performance of PET scanners against aging. Since the data were obtained from a single scanner, the authors would encourage the initiation of a follow-up study involving various scanners.

Targeted delivery of chemotherapeutic agents using improved radiosensitive liquid core microcapsules and assessment of their antitumor effect.

PURPOSE: Radiation-sensitive microcapsules composed of alginate and hyaluronic acid are being developed. We report the development of improved microcapsules that were prepared using calcium- and yttrium-induced polymerization. We previously reported on the combined antitumor effect of carboplatin-containing microcapsules and radiotherapy. METHODS AND MATERIALS: We mixed a 0.1% (wt/vol) solution of hyaluronic acid with a 0.2% alginate solution. Carboplatin (l mg) and indocyanine green (12.5 microg) were added to this mixture, and the resultant material was used for capsule preparation. The capsules were prepared by spraying the material into a mixture containing a 4.34% CaCl(2) solution supplemented with 0-0.01% yttrium. These capsules were irradiated with single doses of 0.5, 1.0, 1.5, or 2 Gy (60)Co gamma-rays. Immediately after irradiation, the frequency of microcapsule decomposition was determined using a microparticle-induced X-ray emission camera. The amount of core content released was estimated by particle-induced X-ray emission and colorimetric analysis with 0.25% indocyanine green. The antitumor effect of the combined therapy was determined by monitoring its effects on the diameter of an inoculated Meth A fibrosarcoma. RESULTS: Microcapsules that had been polymerized using a 4.34% CaCl(2) solution supplemented with 5.0 x 10(-3)% (10(-3)% meant or 10%(-3)) yttrium exhibited the maximal decomposition, and the optimal release of core content occurred after 2-Gy irradiation. The microcapsules exhibited a synergistic antitumor effect combined with 2-Gy irradiation and were associated with reduced adverse effects. CONCLUSION: The results of our study have shown that our liquid core microcapsules can be used in radiotherapy for targeted delivery of chemotherapeutic agents.

Development of an irradiation method with lateral modulation of SOBP width using a cone-type filter for carbon ion beams.

Passive irradiation methods deliver an extra dose to normal tissues upstream of the target tumor, while in dynamic irradiation methods, interplay effects between dynamic beam delivery and target motion induced by breathing or respiration distort the dose distributions. To solve the problems of those two irradiation methods, the authors have developed a new method that laterally modulates the spread-out Bragg peak (SOBP) width. By reducing scanning in the depth direction, they expect to reduce the interplay effects. They have examined this new irradiation method experimentally. In this system, they used a cone-type filter that consisted of 400 cones in a grid of 20 cones by 20 cones. There were five kinds of cones with different SOBP widths arranged on the frame two dimensionally to realize lateral SOBP modulation. To reduce the number of steps of cones, they used a wheel-type filter to make minipeaks. The scanning intensity was modulated for each SOBP width with a pair of scanning magnets. In this experiment, a stepwise dose distribution and spherical dose distribution of 60 mm in diameter were formed. The nonflatness of the stepwise dose distribution was 5.7% and that of the spherical dose distribution was 3.8%. A 2 mm misalignment of the cone-type filter resulted in a nonflatness of more than 5%. Lateral SOBP modulation with a cone-type filter and a scanned carbon ion beam successfully formed conformal dose distribution with nonflatness of 3.8% for the spherical case. The cone-type filter had to be set to within 1 mm accuracy to maintain nonflatness within 5%. This method will be useful to treat targets moving during breathing and targets in proximity to important organs.

Calorimetric study on interaction of water-soluble copolymers with ionic surfactant.

Using isothermal titration microcalorimetry (ITC), we examined the aggregation behavior of water-soluble copolymers, poly(methoxypolyethylene glycol methacrylate-co-ethyl acrylate)s (PME-EA)s, with ionic surfactant, sodium dodecyl sulfate (SDS). From ITC measurements the values of critical aggregation concentration (cac) and saturation concentration (C(2)), the concentration at which the aggregation of the copolymers starts to form and reaches saturation, respectively, were determined. Thermodynamic parameters such as DeltaG(0)(agg), DeltaH(agg), and TDeltaS(0)(agg) of the aggregation were deduced. Results indicate that cac of the PME-EA remained constant with increase in the concentration of the copolymers, while C(2) increased linearly. On the other hand, the effect of the weight ratio of the EA unit in the copolymer was such that cac of the PME400-EA decreased, while C(2) increased with increase in the weight ratio. The results suggested that the EA units are the main binding sites of the copolymer with SDS.

Use of reference tissue models for quantification of histamine H1 receptors in human brain by using positron emission tomography and [11c]doxepin.

The aim of the present study is to evaluate the validity of the simplified reference tissue model (SRTM) and of Logan graphical analysis with reference tissue (LGAR) for quantification of histamine H1 receptors (H1Rs) by using positron emission tomography (PET) with [11C]doxepin. These model-based analytic methods (SRTM and LGAR) are compared to Logan graphical analysis (LGA) and to the one-tissue model (1TM), using complete datasets obtained from 5 healthy volunteers. Since HIR concentration in the cerebellum can be regarded as negligibly small, the cerebellum was selected as the reference tissue in the present study. The comparison of binding potential (BP) values estimated by LGAR and 1TM showed good agreement; on the other hand, SRTM turned out to be unstable concerning parameter estimation in several regions of the brain. By including the results of noise analysis, LGAR became a reliable method for parameter estimation of [11C]doxepin data in the cortical regions.

[The examination of optimal positron emitting nuclide in the estimation of attainment depth within the body of RI beams by positron camera].

The (10)C and (11)C beam stop position in a homogeneous phantom was measured using the range verification system in HIMAC. This system was developed to clear uncertainty of beam range within the patient body in heavy ion radiotherapy. In this system, a target is irradiated with RI beams ((11)C or (10)C) and the distribution of the beam end-points are measured by a positron camera. To inspect the precision of the measurement, three experiments were done, simple PMMA phantom irradiation, empirical beam stop position measurements using a range shifter and boundary irradiation using PMMA and lung phantom. Results of the first two experiments were consistent. Consequently, a 0.2 mm standard deviation of statistical error measurement was possible with 250 determinations. For the third experiment, we compared the precision using (10)C and (11)C beams. The boundary of the PMMA and lung phantom was irradiated with both beams to maximize the positron range effect in the beam range measurement. Consequently, no significant difference was observed between the two beams in spite of the different positron range. Thus, we conclude that the (10)C beam was useful for clinical application because of its good statistics owing to the short half-life.

[Reliability of a positron emission tomography system (CTI:PT931/04-12)].

PURPOSE: The maintenance data of a PET system (PT931/04-12 CTI Inc.) was analyzed to evaluate its reliability. METHOD: We examined whether the initial performance for the system resolution and efficiency is kept. The reliability of the PET system was evaluated from the value of MTTF (mean time to failure) and MTBF (mean time between failures) for each part of the system obtained from the maintenance data for 13 years. RESULTS: The initial performance was kept for the resolution, but the efficiency decreased to 72% of the initial value. The 83% of the troubles of the system was for detector block (DB) and DB control module (BC). The MTTF of DB and BC were 2,733 and 3,314 days, and the MTBF of DB and BC per detector ring were 38 and 114 days. The MTBF of the system was 23 days. We found seasonal dependence for the number of troubles of DB and BC. This means that the trouble may be related the humidity. CONCLUSION: The reliability of the PET system strongly depends on the MTBF of DB and BC. The improvement in quality of these parts and optimization of the environment in operation may increase the reliability of the PET system. For the popularization of PET, it is effective to evaluate the reliability of the system and to show it to the users.