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Interstitial lung disease (ILD) is a common complication of connective tissue diseases (CTD), but there are few clinical trials to guide disease management. We aimed to develop expert consensus statements and an algorithm for CTD-ILD management. Based on a targeted literature review, we developed 109 statements on managing CTD-ILD across six domains. We used a modified Delphi process to survey 22 physicians in Japan involved in managing CTD-ILD (specialists in pulmonology, rheumatology, pathology, and radiology). These panelists participated in two rounds of web-based survey to establish consensus statements, which were used to define an algorithm. Consensus was defined as a mean value ≥70 on a scale of 0 (strong disagreement) to 100 (strong agreement). Between May–August 2022, consensus was reached on 93 statements on CTD-ILD management. The most important consensus statements included screening CTD patients for ILD (typically with high-resolution computed tomography), using imaging, pulmonary function testing and serum biomarkers for diagnosis and severity assessment, regularly following up patients, and multidisciplinary management of CTD-ILD. Consensus statements were interpreted into an algorithm for clinical guidance. Using the Delphi process, we have developed consensus statements and an algorithm to guide clinical decision-making for CTD-ILD.

The effects of a magnetic field longitudinal to the ion beam track on the generation of hydroxyl radicals (•OH) and hydrogen peroxide (H2O2) in water were investigated. A longitudinal magnetic field was reported to enhance the biological effects of the ion beam. However, the mechanism of the increased cell death by a longitudinal magnetic field has not been clarified. The local density of •OH generation was estimated by a method based on the EPR spin-trapping. A series of reaction mixtures containing varying concentrations (0.76‒2278 mM) of DMPO was irradiated by 16 Gy of carbon- or iron-ion beams at the Heavy-Ion Medical Accelerator in Chiba (HIMAC, NIRS/QST, Chiba, Japan) with or without a longitudinal magnetic field (0.0, 0.3, or 0.6 T). The DMPO-OH yield in the sample solutions was measured by X-band EPR and plotted versus DMPO density. O2-dependent and O2-independent H2O2 yields were measured. An aliquot of ultra-pure water was irradiated by carbon-ion beams with or without a longitudinal magnetic field. Irradiation experiments were performed under air or hypoxic conditions. H2O2 generation in irradiated water samples was quantified by an EPR spin-trapping, which measures •OH synthesized from H2O2 by UVB irradiation. Relatively sparse •OH generation caused by particle beams in water were not affected by loading a magnetic field on the beam track. O2-dependent H2O2 generation decreased and oxygen-independent H2O2 generation increased after loading a magnetic field parallel to the beam track. Loading a magnetic field to the beam track made •OH generation denser or made dense •OH more reactive.

Background and Purpose The purpose is to verify experimentally whether application of magnetic fields longitudinal and perpendicular to a proton beam alters the biological effectiveness of the radiation. Methods and Materials Proton beams with linear energy transfer (LET) of 1.1 and 3.3 keV/μm were irradiated onto human cancer and normal cells under the longitudinal (perpendicular) magnetic field of BL (BP) = 0, 0.3, or 0.6 T. Cell survival curves were constructed to evaluate the effects of the magnetic fields on the biological effectiveness. The ratio of dose that would result in a survival fraction of 10% without the magnetic field Dwo to the dose with the magnetic field Dw, R10 = Dwo / Dw, was determined for each cell line and magnetic field. Results For cancer cells exposed to the 1.1- (3.3-) keV/μm proton beams, R10s were increased to 1.10±0.07 (1.11±0.07) and 1.11±0.07 (1.12±0.07) by the longitudinal magnetic fields of BL = 0.3 and 0.6 T, respectively. For normal cells, R10s were increased to 1.13±0.06 (1.17±0.06) and 1.17±0.06 (1.30±0.06) by the BLs. In contrast, R10s were not changed significantly from 1 by the perpendicular magnetic fields of BP = 0.3 and 0.6 T for both cancer and normal cells exposed to 1.1- and 3.3-keV/μm proton beams. Conclusions The biological effectiveness of proton beams was significantly enhanced by the longitudinal magnetic fields of BL = 0.3 and 0.6 T, while the biological effectiveness was not altered by the perpendicular magnetic fields of the same strengths. This enhancement effect should be taken into account in MRI guided proton therapy with a longitudinal magnetic field.

ObjectiveTo stratify patients with polymyositis/dermatomyositis-associated interstitial lung disease (ILD) who were initially treated with an intensive regimen consisting of high-dose corticosteroids, a calcineurin inhibitor, and intravenous cyclophosphamide (triple-combo therapy) into subgroups based on mortality outcomes by a cluster analysis using a large-scale multicenter retrospective cohort of Japanese patients with myositis-associated ILD (JAMI).MethodsTwo-step cluster analysis of preclustering and subsequent hierarchical clustering was conducted in 185 patients who received triple-combo therapy in an unbiased manner. Initial predictors for mortality previously reported in patients with myositis-associated ILD were used as variables and included age, sex, disease duration, classification of myositis, requirement of supplemental oxygen, anti-aminoacyl tRNA synthetase (ARS) antibody, anti-melanoma differentiation-associated gene 5 (MDA5) antibody, and serum levels of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6). The cluster model was further applied to 283 patients who received conventional regimens consisting of corticosteroids with or without a single immunosuppressive agent (dual-combo therapy or monotherapy). Cumulative survival rates were compared using Kaplan-Meier analysis, and the log-rank test was used to test for significant differences between two groups.ResultsWe developed a cluster model consisting of 6 clusters, which were categorized by age at onset, clinically amyopathic dermatomyositis, CRP, KL-6, requirement of supplemental oxygen, anti-ARS antibody, and anti-MDA5 antibody. This model was judged to be of good quality based on the silhouette measure of cohesion and separation of 0.6. These clusters were regrouped into three subsets based on low (50%) mortality rates. The performance of the clustering was generally replicated in patients who received initial dual-combo therapy or monotherapy. Survival benefits of triple-combo therapy over dual-combo therapy or monotherapy were not observed in any of the clusters.ConclusionWe successfully developed a cluster model that stratified patients with myositis-associated ILD who were treated with initial triple-combo therapy into subgroups with different prognoses, although this model failed to identify a patient subgroup that showed survival benefits from triple-combo therapy over dual-combo therapy or monotherapy.

The incidence of male reproductive system disorders, especially hypospadias, has been increasing in developed countries since the latter half of the 20th century. Endocrine-disrupting chemicals from the environment are considered to be involved in hypospadias onset through epigenetic alterations. This pilot study aimed to explore disease-specific methylated CpGs in human patient samples using the methylated-site display-amplified fragment length polymorphism (MSD-AFLP) technique developed by our research group [1]. We compared clinical samples from hypospadias and phimosis patients. Foreskin and blood samples were collected from one- to two-year-old patients with hypospadias (N = 3) and phimosis (N = 3) during surgical treatment. MSD-AFLP analysis showed significantly decreased CpG-methylation levels of genes such as MYH11 and increased CpG-methylation levels of genes such as PLA2G15 in hypospadias patients. Hierarchical clustering analysis showed that genes with significantly altered CpG levels were more markedly altered in DNA from blood than from foreskin. Because of the small number of samples, further investigation is necessary to elucidate the association between variations in CpG levels in foreskin and blood DNA and male genital abnormalities. However, our MSD-AFLP method appears to be a useful tool for exploring disease-specific methylated-CpGs in human epidemiological studies.

Previous studies have revealed application of a magnetic field longitudinal to a carbon-ion beam enhances its biological effectiveness. This communication investigated how timing of the magnetic field application with respect to beam irradiation influenced this effect. Human cancer cells were exposed to carbon-ion beams with linear energy transfer (LET) of 12 and 50 keV/μm. The longitudinal magnetic field of 0.3 T was applied to the cells just before, during, or right after the beam irradiation. The effects of the timing on the biological effectiveness were evaluated by cell survival. The biological effectiveness increased only if the magnetic field was applied during beam irradiation for both LET beams.

A study of multiple-ion therapy with charged heavy-ion beams was performed to improve outcomes of refractory cancer treatments. We proposed the accelerator operation method for applying the multiple-ion therapy, to quickly switch the ion species and energies of the output beams. In this method, the irradiation ion species can be changed only by switching the selected ion source and the injector parameters, and the output beam energies can be varied without changing the magnetic operation patterns of the synchrotron. We verified the effectiveness of our approach by conducting experiments at the Heavy Ion Medical Accelerator in Chiba (HIMAC) and confirmed that the approach can provide the fast switching of both the ion species and the beam energies. The experimental results also demonstrated that our approach will greatly reduce the commissioning time and the routine adjustments for multiple-ion beams.

Purpose: Our previous study revealed application of a magnetic field longitudinal to a carbon-ion beam of 0.1 ≤ B// ≤ 0.6 T enhances the biological effectiveness of the radiation. The purpose of this study is to experimentally verify whether application of a magnetic field perpendicular to the beam also alters the biological effectiveness. Methods and Materials: Most experimental conditions other than the magnetic field direction were the same as those used in the previous study to allow comparison of their results. Human cancer and normal cells were exposed to low (12 keV/μm) and high (50 keV/μm) linear energy transfer (LET) carbon-ion beams under the perpendicular magnetic fields of = 0, 0.15, 0.3, or 0.6 T generated by a dipole magnet. The effects of the magnetic fields on the biological effectiveness were evaluated by clonogenic cell survival. Doses that would result in the survival of 10%, D10s, were determined for the exposures and analyzed using Student’s t-tests. Results: For both cancer and normal cells treated by low- and high-LET carbon-ion beams, the D10s measured in the presence of the perpendicular magnetic fields of ≥ 0.15 T were not statistically different (p >> 0.05) from the D10s measured in the absence of the magnetic fields, = 0 T. Conclusions: Exposure of human cancer and normal cells to the perpendicular magnetic fields of ≤ 0.6 T did not alter significantly the biological effectiveness of the carbon-ion beams, unlike the exposure to longitudinal magnetic fields of the same strength. Although the mechanisms underlying the observed results still require further exploration, these findings indicate that the influence of the magnetic field on biological effectiveness of the carbon-ion beam depends on the applied field direction with respect to the beam.

Purpose: A magnetic field longitudinal to an ion beam will potentially affect the biological effectiveness of the radiation. The purpose of this study is to experimentally verify the significance of such effects. Methods and Materials: Human cancer and normal cell lines were exposed to low (12 keV/μm) and high (50 keV/μm) linear energy transfer (LET) carbon-ion beams under the longitudinal magnetic fields of B// = 0, 0.1, 0.2, 0.3, or 0.6 T generated by a solenoid magnet. The effects of the magnetic fields on the biological effectiveness were evaluated by clonogenic cell survival. Doses that would result in a survival fraction of 10% (D10s) were determined for each cell line and magnetic field. Results: For cancer cells exposed to the low (high)-LET beams, D10 decreased from 5.2 (3.1) Gy at 0 T to 4.3 (2.4) Gy at 0.1 T, while no further decrease in D10 was observed for higher magnetic fields. For normal cells, decreases in D10 of comparable magnitudes were observed by applying the magnetic fields. Conclusions: Significant decreases in D10, i.e., significant enhancements of the biological effectiveness, were observed in both cancer and normal cells by applying longitudinal magnetic fields of B// ≥ 0.1 T. These effects were enhanced with LET. Further studies are required to figure out the mechanism underlying the observed results.

The effect of a magnetic field loaded parallel to the ion-beam track on the generations of reactive oxygen species (ROS) in water was investigated. It was reported that loading magnetic field parallel to the particle beam track exaggerate the biological effects, i.e. cell lethality, of the particle beam. However, the mechanism of the enhanced cell death delivered by a logigudinal magnetic field to the beam track has not been clarified yet. Local density of •OH generation was estimated by a method based on EPR spin-trapping technique. A series of reaction mixtures containing varying concentrations (0.76‒2278 mM) of DMPO was prepared, and transferred to a polyethylene bag for irradiation. Then, the samples were irradiated 16 Gy of carbon- or iron-beam at the Heavy-Ion Medical Accelerator in Chiba (HIMAC, NIRS/QST, Chiba, Japan) with or without longitudinal magnetic field (0.0, 0.3, or 0.6 T). O2-dependent and O2-independent H2O2 yield was measured. An aliquot of ultra-pure water was irradiated by carbon-ion beam with or without longitudinal magnetic field. Irradiation experiments were performed under air or hypoxic (, 20th Biennial Meeting of SFRR International (SFRR-I 2021)

放射線医学総合研究所（放医研）は、1993年に重粒子線がん治療用加速器HIMACを建設し、炭素イオンを用いた重粒子線がん治療を行ってきた。1994年の治療開始から今年で27年目を迎え、現在までの重粒子がん治療の登録患者数は延べ12000人以上となっている。2010年にはHIMACの既存施設に連結する形で新治療研究棟を建設し、複雑な腫瘍形状や治療期間中における腫瘍形状の変化にも対応可能な三次元スキャニング照射法を適用した治療を2011年から開始している。また、2017年からは超伝導電磁石を用いた回転ガントリー照射装置による治療も開始され、0-360度の角度範囲から任意の方向を選択して照射できるようになり、より良い治療成果が期待されている。 現在放医研では、レーザー駆動イオン加速技術を用いた入射器やシンクロトロンへの超伝導電磁石技術の適用などによって実現される次世代重粒子線治療装置「量子メス」の研究開発を進めている。量子メスでは、複数のイオン種を組み合わせて照射するマルチイオン照射法の確立による難治性がんの治療成績向上や治療期間の短縮などの治療高度化も目指しており、それに関連した研究開発もあわせて進められている。本発表では、最近の研究開発の概要を紹介するとともに、運用の現状について報告を行う。, 第17回日本加速器学会年会

We developed a time-of-flight (TOF) detector for mass measurements of rare radioactive isotopes (RIs) with a storage ring, called the Rare-RI Ring, in RIKEN. For successful mass measurements, a time resolution of less than 100 ps and a detection efficiency close to 100% are required. Additionally, the change of ion velocity in the detector should be as small as possible ( ). To satisfy these requirements, the TOF detector utilizes ion-induced secondary electrons emitted from a thin foil and the crossed static electric and magnetic fields to transport the electrons isochronously to the microchannel plate detectors. The TOF detector was tested in both offline test with an alpha source and online test with heavy ions. In the online test with 84Kr ions of 200 MeV/nucleon, a time resolution of 38.6(2) ps in sigma and a position-averaged detection efficiency of 95.2(2)% were achieved in the entire area of 45-mm-diameter aluminum-coated Mylar foil. This good performance is attributed to the electromagnetic field achieved, which is the strongest thus far for a detector with this design.

Heavy ion cancer therapy with the Heavy ion Medical Accelerator synchrotron in Chiba (HIMAC) has been administered to more than 10,000 patients since 1994. We started the heavy-ion cancer therapy using a 3D scanning irradiation system in May 2011, at New Particle Therapy Research Facility in NIRS. To enhance the treatment quality by achieving a precise dose control, we have continued some R&Ds on HIMAC and its irradiation system including a superconductingrotating gantry. Since 2016, we have started developments of a compact superconducting rotating gantry and a compact superconducting synchrotron to be applied for a newly started project of a “quantum scalpel” that is a next generation of the heavy-ion cancer therapy machine. We also started R&Ds for the intensity modulated multi-ion therapy that is applied to improve outcomes of the refractory cancer treatment. This paper outlines those R&Ds as well as the present status of HIMAC accelerator facility.

Technical innovation in radiation science enable us to develop the new therapies, such as the stereotactic irradiation, the adaptive radiation therapy of the intensity-modulated radiation therapy and the image-guided radiation therapy. They make it possible to deliver the ideal distribution of radiation doses to the target volume with great accuracy, sparing the neighboring normal organs at risk. It should be necessary for developing radiotherapy to understand fundamental biological responses concerning the combined effects between static magnetic fields and radiations. In this study we examined the cell-killing effect by carbon-ion irradiations in combination with static magnetic fields. Normal human skin fibroblasts and cervical epitheloid carcinoma cells were irradiated with carbon ions (LET~ 12 and 50keV/µm) accelerated with the Heavy Ion Medical Accelerator in Chiba under the longitudinal magnetic fields of 0, 0.3 and 0.6 T generated by a solenoid magnet. The cell-killing effects, which were detected using the colony-forming assay, treated with the magnetic fields of 0.3T and 0.6T during the irradiations were 1.3 ~ 1.5 times higher than those of carbon ions alone. There is evidence that the carbon-ion induced cell death is enhanced by combining with the longitudinal magnetic fields. We set up the hypothesis from the data using X-ray microbeams generated with the synchrotron radiations at Photon Factory as follows; “When cytoplasm of targeted cells are irradiated with low-LET radiations, unknown cellular response(s) is induced in the cell and in consequence the cell becomes protective to radiation damage.” We will discuss a possible mechanism based on our hypothesis., 日本放射線影響学会第62回大会

Technical innovation enables us to develop the new radiotherapy, such as the image-guided radiation therapy (IGRT), and makes it possible to deliver the ideal distribution of radiation doses to the target volume with accuracy, sparing the neighboring normal organs at risk. However, the limited reports are available concerning the combined effects between static magnetic fields and radiations. This year, we examined cell-killing effect in a human tumor cell line by carbon ions in combination with static magnetic fields. Cervical epitheloid carcinoma cell line was irradiated with carbon-ion beams (LET~12 and 50keV/µm) accelerated with the HIMAC under the longitudinal magnetic fields of 0.3 and 0.6 T generated by a solenoid magnet. The cell-killing effects treated with the magnetic fields during the irradiation were 1.3 times higher for the low-LET and 1.5 times higher for the high-LET beams than those of carbon ions alone. There is clear evidence that the cell-killing effect irradiated with carbon ions is enhanced by combining with the longitudinal magnetic fields., 第78回日本癌学会学術総会

Introduction: Merging MR imaging and charged-particle therapy (MRiPT) has gained interest to increase the targeting accuracy of radiations. The radiochromic films are suited to measure the 2D dose distribution of charged particle beams with high special resolution. However, the dose response of the films under magnetic fields to the charged-particle beams has never been studied intensively. The purpose of this study is to investigate the effect of longitudinal and perpendicular magnetic fields, BL and BP, on radiochromic EBT3 file response to therapeutic carbon-ion beams. Methods and Materials: A water-cooled solenoid (dipole) magnet was used to produce a magnetic field longitudinal (perpendicular) to the carbon-ion beams. The radiochromic EBT3 films placed within the bore (gap)of the magnet were exposed t0 low (12 keV/μm) and high (50 keV/μm) linear energy transfer (LET) carbon-ion beams of 5 Gy dose under BL (BP) of 0, 0.3, and 0.6 T. The dose-monitor output was calibrated with the ionization chamber for each LET beams without the magnetic field. The optical density (OD) of the films was measured in red color channels of a scanner. The change in ODs by the orientation and the strength of magnetic fields were investigated for each LET beams based on t-test. Results: Under BL of 0.3 and 0.6 T, the ODs decreased significantly by l .0% and 0.6% for low LET beams and by 1.4% and 1.3% for high LET beams from the ODs without BL. Similarly, under BP of 0.3 and 0.6 T, the ODs decreased significantly by 1.0% and 0.8% for low LET beams and by 1.3% and 1.1% for high LET beams from the ODs without BP. Conclusion: We observed small (~ 1%) but significant reductions in ODs of radiochromlc EBT3 films exposed to low and high LET carbon-ion beams by the longitudinal and perpendicular magnetic fields., 24th International conference on Medical physics (ICMP2019)

National Institute of Radiological Sciences (NIRS) has performed carbon-ion radiotherapy since 1994 using the Heavy Ion Medical Accelerator in Chiba (HIMAC) which is the world’s first heavy-ion accelerator facility dedicated to medical use. The treatments with the carbon-ion beams have been successfully carried out for more than 10000 patients in the NIRS. Now, the NIRS has investigated multiple-ion therapy with the energetic beams of more than two ion species to improve outcomes of the refractory cancer treatment. By appling the multiple-ion beams for treatment irradiation, we become controllable not only the dose but also the linear energy transfer (LET), which concerns with the biological effect, in the target volume. To realize multiple-ion therapy, it is required that the accelerator control system can switch the ion species, energy and intensity of the output beams quickly in the treatment session. For this purpose, we have studied the switching method of the multiple-ion beams using multiple-energy operation at the HIMAC. Since this method accelerates the multiple-ion beams with the charge-to-mass ratio Q/A of 1/2 without changing the magnetic operation pattern of the synchrotron, the irradiation ion species can be changed only by switching the ion sources and the injector parameters. Therefore, this method can perform the fast switching of the irradiation ion species. In addition, because of the use of the same magnetic operation pattern, we can reduce the time for the commissioning and daily adjustments of the multiple-ion beams. In this paper, we describe our accelerator control method for multi-ion therapy operation and the results of the beam experiments at the HIMAC., 13th European Conference on Accelerators in Applied Research and Technology (ECAART13)

A development project for hypo-fractionated multi-ion therapy has been initiated at the National Institute of Radiological Sciences in Japan. In the treatment, helium, carbon, oxygen, and neon ions will be used as primary beams with pencil beam scanning. A ripple filter (RiFi), consisting of a thin plastic or aluminum plate with a fine periodic ridge and groove structure, has been used to broaden the Bragg peak of heavy-ion beams in the beam direction. To sufficiently broaden the Bragg peak of helium-, carbon-, oxygen-, and neon-ion beams with suppressed lateral scattering and surface dose inhomogeneity, in this study, we tested a plate made of a lung substitute material, Gammex LN300, as the RiFi. The planar integrated dose distribution of a 183.5-MeV/u neon-ion beam was measured behind a 3-cm-thick LN300 plate in water. The Bragg peak of the pristine beam was broadened following the normal distribution with the standard deviation value of 1.29 mm, while the range of the beam was reduced by 8.8 mm by the plate. To verify the LN300 performance as the RiFi in multi-ion therapy, we measured the pencil beam data of helium-, carbon-, oxygen, and neon-ion beams penetrating the 3-cm-thick LN300 plate. The data were then modeled and used in a treatment planning system to achieve a uniform 10% survival of human undifferentiated carcinoma cells within a cuboid target by the beam for each of the different ion species. The measured survival fractions were reasonably reproduced by the planned ones for all the ion species. No surface dose inhomogeneity was observed for any ion species even when the plate was placed close to the phantom surface. The plate made of lung substitute material, Gammex LN300, is applicable as the RiFi in multi-ion therapy with helium-, carbon-, oxygen, and neon-ion beams.

We measured the energy dependence of the total reaction cross sections (σR) for the proton-drip-line nucleus, 17Ne, using a solid hydrogen target. We compared the experimental data with theoretical calculations using the Glauber model. We found that the theoretical cross sections overestimate the experimental ones in the low-energy region (∼100A MeV), whereas they significantly underestimate the experimental data in the intermediate-energy region (∼300-500A MeV). These trends are the same as those for σR for carbon–proton collisions, which were measured previously. We discuss several possibilities for resolving this discrepancy. This work demonstrates the necessity of additional careful investigations of the energy dependence of σR for various nuclei on proton targets in order to determine nuclear size properties precisely.

Radioactive ion (RI) beams combined with in-beam positron emission tomography enable accurate in situ beam range verification in heavy ion therapy. However, the energy spread of the radioactive beams generated as secondary beams is wider than that of conventional stable heavy ion beams which causes Bragg peak region and distal falloff region broadening. Therefore, the energy spread of the RI beams should be measured carefully for their quality control. Here, we proposed an optical imaging technique for the energy spread estimation of radioactive oxygen ion beams. A polymethyl methacrylate phantom (10.0 × 10.0 × 9.9 cm3) was irradiated with an 15O beam (mean energy = 247.7 MeV u−1, standard deviation = 6.8 MeV u−1) in the Heavy Ion Medical Accelerator in Chiba. Three different momentum acceptances of 1%, 2% and 4% were used to get energy spreads of 1.9 MeV u−1, 3.4 MeV u−1 and 5.5 MeV u−1, respectively. The in-beam luminescence light and offline beam Cerenkov light images were acquired with an optical system consisting of a lens and a cooled charge-coupled device camera. To estimate the energy spread of the 15O ion beams, we proposed three optical parameters: (1) distal-50% falloff length of the prompt luminescence signals; (2) full-width at half maximum of the Cerenkov light signals in the beam direction; and (3) positional difference between the peaks of the Cerenkov light and the luminescence signals. These parameters estimated the energy spread with the respective mean squared errors of 2.52 × 10−3 MeV u−1, 5.91 × 10−3 MeV u−1, and 0.182 MeV u−1. The distal-50% falloff length of the luminescence signals provided the lowest mean squared error among the optical parameters. From the findings, we concluded optical imaging using luminescence and Cerenkov light signals offers an accurate energy spread estimation of 15O ion beams. In the future, the proposed optical parameters will be used for energy spread estimation of other RI beams as well as stable ion beams.

This paper proposes accurate CMOS device de-embedding and modeling methods. For millimeter-wave circuit design, accurate simulation models are required. For this reason, an accurate measurement is a key technique for device characterization, and de-embedding and modeling methods are also very important. In this work, a three-parameter pad model based on L-2L de-embedding method and a transistor model with frequency and bias dependency are proposed. The pad model is derived from the assumption that the capacitance of PADs becomes constant at high frequencies. In the transistor modeling, parasitic elements are extracted mathematically. A five-stage low-noise amplifier is fabricated by 65–nm CMOS technology to confirm the accuracy of simulation, and the simulation and measurement results match well with each other.

Positron emission tomography (PET) has been used for dose verification in charged particle therapy. The causes of washout of positron emitters by physiological functions should be clarified for accurate dose verification. In this study, we visualized the distribution of irradiated radioactive beams, 11C and 15O beams, in the rabbit whole-body using our original depth-of-interaction (DOI)-PET prototype to add basic data for biological washout effect correction. Time activity curves of the irradiated field and organs were measured immediately after the irradiations. All data were corrected for physical decay before further analysis. We also collected expired gas of the rabbit during beam irradiation and the energy spectrum was measured with a germanium detector. Irradiated radioactive beams into the brain were distributed to the whole body due to the biological washout process, and the implanted 11C and 15O ions were concentrated in the regions which had high blood volume. The 11C-labelled 11CO2 was detected in expired gas under the 11C beam irradiation, while no significant signal was detected under the 15O beam irradiation as a form of C15O2. Results suggested that the implanted 11C ions form molecules that diffuse out to the whole body by undergoing perfusion, then, they are incorporated into the blood-gas exchange in the respiratory system. This study provides basic data for modelling of the biological washout effect.

A superconducting magnet gantry has been used at HIMAC in NIRS, transporting beams for carbon ion radiotherapy. A second superconducting gantry, with a different design, is under construction in Yamagata University. This invited talk presents an overview of these gantry designs, their advantages for light ion radiotherapy, their operational experiences, and future perspectives for superconducting radiotherapy gantries., Proceedings of the 9th Int. Particle Accelerator Conf., IPAC2018, Vancouver, BC, Canada

Table S1. The pup number and sex ratio. Figure S1. Effect of prenatal BPA exposure on body weight and anogenital distance (AGD). Figure S2. A typical MSD-AFLP peak chart after electrophoresis obtained by a selective primer set. Figure S3. MSRE-PCR analysis of representative CpGs (Chr 4: 35339023 and Chr X: 74707008) showing the minimum q-value obtained from the MSD-AFLP data. Table S2. The KEGG enrichment analysis of the effect on the DNA methylation. (DOCX 289Â kb)

Most important ingredients of reliability in particle-therapy accelerators like HIMAC are reproducibility of a treatment beam as well as prevention of unexpected down time. In order to realize reliable operations of medical accelerators, we take trend data of many parameters. For example, water flow of magnets has been readjusted during biweekly maintenance according to recent trend data, so that we could prevent interlock by flow-meters. Analyzing trend data in the long term may be more important and rewarding. It was known that a treatment beam has faint fluctuations in a beam position, as measured by beam monitors. Due to this fluctuation, correction of a position had to be frequently made by steering magnets. By taking long-term trends and analyzing them, we found that this fluctuation would have seasonal characteristic. Thus, we optimized parameters of the steering magnets to minimize the effect of the fluctuation, and hence eliminated frequently retuning. This and other cases will be discussed in the present report, together with future prospects., ARW 2017 (Accelerator Reliability Workshop)

Additional file 1: Table S1. Oligonucleotides used for MSD-AFLP. Table S2. Locus-specific primers used for MSRE-PCR. Table S3. Locus-specific primers used for bisulfite genomic sequencing. Table S4. Chromosomal nucleotide position of methylated cytosine predicted using the Genome DNA Fragment Database (GFDB) and gene name identified by actual sequencing analysis. Figure S1. Genome DNA Fragment Database (GFDB). Figure S2. Length data of SbfI-HpaII/MspI fragments in the mouse and human reference genome sequences, retrieved using the GFDB system. Figure S3. Analysis with bisulfite genome sequencing. Figure S4. Comparison of genome wide methylation patterns among tissues using MSD-AFLP data.

Heavy ion therapy is a promising cancer therapy technique due to the sharper Bragg peak and smaller lateral scattering characteristics of heavy ion beams as compared to a proton therapy. Recently, the potential for radioactive ion beam therapy has been investigated in combination with the OpenPET system to improve the accuracy of in vivo beam range verification. However, the characteristics of the radioactive ion beams have not been investigated thoroughly. Optical imaging has been proposed as a novel high-resolution beam range estimation method for heavy ion beams. In this study, high-resolution luminescence imaging and Cerenkov light imaging were performed for the range estimation of radioactive ion beams such as 11C and 15O in the Heavy Ion Medical Accelerator in Chiba (HIMAC) secondary beam line. A polymethyl methacrylate (PMMA) phantom (10.0 × 10.0 × 9.9 cm3) was irradiated by 11C and 15O ion beams. In order to obtain the in-beam luminescence and off-line beam Cerenkov light images, an optical system was used that consisted of a lens and a cooled CCD camera. The Bragg peaks and stopping positions of the 11C and 15O ion beams could be visualized by using the luminescence and Cerenkov light imaging, respectively. The Bragg peaks showed a good correlation with the peak of the luminescence profile with a positional discrepancy of 1 mm and 0.4 mm for the 11C and 15O ion beams, respectively. In conclusion, optical imaging using luminescence and Cerenkov light could be used for the precise range estimation of radioactive ion beams.

A superconducting rotating-gantry for carbon radiotherapy was developed. This isocentric rotating gantry can transport carbon ions with the maximum energy of 430 MeV/u to an isocenter with irradiation angles of over 0-360 degrees, and is further capable of performing three-dimensional raster-scanning irradiation. The combined-function superconducting magnets were employed for the rotating gantry. The superconducting magnets with optimized beam optics allowed a compact gantry design with a large scan size at the isocenter; the length and the radius of the gantry are approximately 13 and 5.5 m, respectively, which are comparable to those for the existing proton gantries. The total weight of the gantry is estimated to be approximately 300 tons, which is roughly half of the existing gantry for carbon radiotherapy. A construction of the gantry structure begun since early 2014, and the installation of the entire gantry system to the Heavy Ion Medical Accelerator in Chiba (HIMAC) complex at National Institute of Radiological Sciences (NIRS) completed by the end of September, 2015. Beam commissioning subsequently begun since October, 2015, and carbon beams, as accelerated by the HIMAC upper synchrotron, having kinetic energy of between 430-48 MeV/u were successfully transported with the rotating gantry to the isocenter. The size and shape of the beam spots at the isocenter were finely tuned over various combinations of the beam energies and the gantry angle. We will present the recent progress as well as the current status of the superconducting rotating-gantry., The Workshop on Accelerator Operations 2016 (WAO2016)

A superconducting rotating-gantry for carbon radiotherapy was developed. This isocentric rotating gantry can transport carbon ions with the maximum energy of 430 MeV/u to an isocenter with irradiation angles of over ±180 degrees, and is further capable of performing three-dimensional raster-scanning irradiation. The combined-function superconducting magnets were employed for the rotating gantry. The superconducting magnets with optimized beam optics allowed a compact gantry design with a large scan size at the isocenter; the length and the radius of the gantry are approximately 13 and 5.5 m, respectively, which are comparable to those for the existing proton gantries. The total weight of the gantry was estimated to be approximately 300 tons, which is roughly half of the existing gantry for carbon radiotherapy. A construction of the gantry structure begun by 2014, and the installation of the entire gantry system to the Heavy Ion Medical Accelerator in Chiba (HIMAC) complex at National Institute of Radiological Sciences (NIRS) completed by the end of September, 2015. Beam turning begun by October, 2015, and carbon beams, as accelerated by the HIMAC synchrotron, having maximum energy of 430 MeV/u are transported with the rotating gantry to the isocenter. The size and shape of the beam spots at the isocenter were finely tuned over various combinations of the beam energies and the gantry angle. We will present the recent progress as well as the current status of the superconducting rotating-gantry., The 12th European Conference on Accelerators in Applied Research and Technology (ECAART12)

The National Institute of Radiological Sciences (NIRS) has performed carbon-ion radiotherapy on more than 9000 patients since 1994 and began the treatment with pencil beam scanning from 2011. Multiple-energy synchrotron operation was developed to realize fast 3D scanning irradiation at the Heavy Ion Medical Accelerator in Chia (HIMAC) in NIRS. It can provide carbon-ion beams with various energies ranging from 48 to 430 MeV/n in a single synchrotron cycle. To make use of its advantage, a fast beam chopper system has been installed in the high-energy beam transport (HEBT). This system is used to prevent uncontrollable spilled beams, which is caused by varying the beam energy, being delivered to the irradiation port. The changes of the beam energy can be performed quickly and reliably by using the HEBT chopper system. In addition, the intensity control system of the extracted beam has been equipped to save the irradiation time. It can lead a fast scanning sequence by keeping the beam intensity high within the limits determined by the performance of the magnet power supplies and so on. The irradiation tests were carried out to verify the performance of the beam control system using multiple-energy operation. The system could output the beams of more than 140 different energies in 60 seconds. The output beam intensity could be controlled for their energies without large ripple and overshoot. Experimental irradiation for prostate cancer treatment was also successfully performed, and its result proved that our system can greatly reduce the irradiation time., The 12th European Conference on Accelerators in Applied Research and Technology (ECAART12)

A 34-year-old woman with primary antiphospholipid syndrome was admitted to the Gastroenterology Department of our hospital with fever, acute abdomen, watery diarrhea, and extremely high levels of inflammatory parameters. She had a history of left lower limb deep vein thrombosis and pulmonary embolism and was taking warfarin potassium. Acute gastroenteritis was suspected and an antibiotic was administered, but symptoms progressed. Abdominal ultrasonography showed occlusion of the left hepatic vein and the middle hepatic vein and her D-dimer level was high. Accordingly, Budd-Chiari syndrome was diagnosed and high-dose intravenous infusion of heparin was initiated. Her abdominal symptoms improved and the levels of inflammatory parameters and D-dimer decreased rapidly. It is known that antiphospholipid syndrome can be complicated by Budd-Chiari syndrome that usually occurs as subacute or chronic onset, but acute onset is rare. It is difficult to diagnose acute Budd-Chiari syndrome complicating antiphospholipid syndrome and this complication generally has a poor outcome. However, the present case can get early diagnosis and successful treatment with tight anticoagulant therapy.

A superconducting rotating-gantry for carbon therapy is being developed. This isocentric rotating gantry can transport carbon ions with the maximum energy of 430 MeV/u to an isocenter with irradiation angles of over 0-360 degrees, and is further capable of performing three-dimensional raster-scanning irradiation. The combined-function superconducting magnets were employed for the rotating gantry. The superconducting magnets with optimized beam optics allowed a compact gantry design with a large scan size at the isocenter; the length and the radius of the gantry are approximately 13 and 5.5 m, respectively, which are comparable to those for the existing proton gantries. Furthermore, the maximum scan size at the isocenter is calculated to be as large as approximately 200 mm square for heavy-ion beams at the maximum energy of 430 MeV/u. A construction and installation of the superconducting gantry is in progress, and beam commissioning will begin from this autumn. We will present a status of the superconducting rotating-gantry., Proceedings of the 13th Heavy Ion Accelerator Technology Conference, HIAT2015, Yokohama, Japan