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Carbon-ions are charged particles with a high linear energy transfer, and therefore, they make a better dose distribution with greater biological effects on the tumors compared with photons and protons. Since prostate cancer, renal cell carcinoma, and retroperitoneal sarcomas such as liposarcoma and leiomyosarcoma are known to be radioresistant tumors, carbon-ion radiotherapy, which provides the advantageous radiobiological properties such as an increasing relative biological effectiveness toward the Bragg peak, a reduced oxygen enhancement ratio, and a reduced dependence on fractionation and cell-cycle stage, has been tested for these urological tumors at the National Institute for Radiological Sciences since 1994. To promote carbon-ion radiotherapy as a standard cancer therapy, the Japan Carbon-ion Radiation Oncology Study Group was established in 2015 to create a registry of all treated patients and conduct multi-institutional prospective studies in cooperation with all the Japanese institutes. Based on accumulating evidence of the efficacy and feasibility of carbon-ion therapy for prostate cancer and retroperitoneal sarcoma, it is now covered by the Japanese health insurance system. On the other hand, carbon-ion radiotherapy for renal cell cancer is not still covered by the insurance system, although the two previous studies showed the efficacy. In this review, we introduce the characteristics, clinical outcomes, and perspectives of carbon-ion radiotherapy and our efforts to disseminate the use of this new technology worldwide.

A charged particle therapy was proposed by Robert R. Wilson in 1946 and a clinical study of proton radiotherapy had been started at Lawrence Berkeley National Laboratory in 1954. Clinical studies have been promoted mainly in the United States and Europe. However, in Japan as well, the University of Tsukuba (KEK Campus) and the National Institute of Radiological Sciences （NIRS） started proton radiotherapy around 1980, and NIRS started carbon-ion radiotherapy in 1994. Following pioneering clinical studies, now in Japan, many proton and carbon-ion radiotherapy facilities are in operation, and some vendors are supplying equipment. Among them, charged particle therapy technologies originating in Japan have been developed, such as a respiratory-gated irradiation technology, a spot scanning irradiation technology, and a clinical dose design for ion radiotherapy. I look back on them and discuss the future direction of research and development of the charged particle therapy.

量研関西研では,レーザー駆動イオン加速機構によって生じる炭素ビームの横方向エミッタンスを明らかにすることに取り組んでいる。同時加速される陽子ビームから炭素ビームを弁別することが困難であるために，炭素ビームの横方向エミッタンスが評価された例はない。現在, 四重極磁石による核種の磁場弁別とダブルスリット法とを組み合わせた炭素ビーム横方向エミッタンス診断系の開発を進めている。 本発表では, 数理的な考えを診断装置に組み込むことによる, 観測誤差の低減に関して報告する予定である。, 第69回応用物理学会春季学術講演会

近年，炭素イオンなどを用いた重イオンビームによるガン治療は成功を収めている．一般的に，直線もしくはシンクロトロン型の粒子加速器が高エネルギー重イオンビーム生成のために使用されるが，それらの加速器は広く医療機関に行き渡らせるにはサイズが大きすぎるという問題を持つ．そのためコンパクトな加速器の実現が求められている．レーザー粒子加速器は，未来の加速器の候補の一つである． 量子科学技術研究開発機構では，高い治療効果が明らかになっている重イオンがん治療装置の高性能化・小型化を目指す“量子メス”プロジェクトを進めている．この次世代の小型重イオンがん治療装置は，重イオンビームの鋭いブラッグピークと，少ない内部散乱による腫瘍への高い線量集中性を持っている．これによって正常組織へのダメージを少なく抑え，より多くのがんを極めて短期間で治療できることが期待され、手術に代わる可能性を秘めている． 現在提案されている第５世代重イオンがん治療装置（量子メス）は，イオン入射器・超伝導シンクロトロン・ビーム輸送系・超伝導回転ガントリーから構成されている．装置を小型化するためには，体積の大部分を占める入射器とシンクロトロンの小型化が不可欠である．レーザー駆動イオン加速は非常に大きな加速勾配を持つことからこの小型化の要求に応える技術として期待されている．既存のイオン入射器をレーザー駆動方式で置き換えるためには，小型のレーザーモジュールの開発とそれを用いたレーザー駆動による数MeV/uの炭素イオンの加速が必要である．そこで，三次元電磁粒子コードによって実験に即したシミュレーションを実施することにより，加速炭素イオンの定量評価を行った．また，加速に有利な６価の炭素イオンを生成するためのレーザー条件を理論的に求め，シミュレーションによる妥当性評価を行った．, 日本物理学会第77回年次大会

Heavy ion radiotherapy with the Heavy-Ion Medical Accelerator in Chiba (HIMAC) has been carried out more than 13000 patients since 1994. In 2010, a new particle therapy research facility connected to HIMAC was built, and we started heavy-ion radiotherapy using a 3D scanning irradiation system in 2011 and using a superconducting rotating gantry in 2017 at the new facility. In 2016, we began a project of "quantum scalpel", a next-generation heavy-ion radiotherapy machine that applies a compact superconducting synchrotron and rotating gantry currently under development. This paper outlines R&Ds for a new project and current facility as well as the present status of HIMAC.

Carbon-ion radiotherapy using the Heavy-Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS) has been conducted on more than 12,000 patients since 1994. We started the heavy-ion radiotherapy with a 3D scanning irradiation system in 2011 and using a superconducting rotating gantry in 2017, at a new treatment research facility in NIRS. We have continued some R&Ds on HIMAC to enhance the treatment quality and to improve the treatment results. From 2016, we have started developments of a compact superconducting rotating gantry and synchrotron to be applied for a newly started project of a “quantum scalpel” that is a next generation of the heavy-ion radiotherapy machine. This paper outlines those R&Ds as well as the present status of HIMAC facility.

We confirmed the effect of ion recombination using a parallel-plate ionization chamber: dose monitor for clinical use and the Advanced Markus chamber. A 290 MeV/u carbon-ion beam was irradiated using the continuous spot-scanning method in a field size of 5 cm by 5 cm with 2 mm spacing. We tested three beam intensities (1.35×10^8, 2.69×10^9, and 4.03×10^9 particle per second (pps)) at two linear energy transfers (12 keV/μm and 200 keV/μm). The charge (Q) was measured by changing the voltage of the Advanced Markus chamber and that of the dose monitor. Then, Boag’s method was used to calculate the saturated charge (Qsat ). For the Advanced Markus chamber, 300 V is a sufficient potential to collect charge. For the dose monitor, Qsat/Q at 2500 V was 1.024 for 4.03×10^9 pps, indicating that the general recombination correction cannot be ignored when high dose rate treatment is performed using a carbon-ion scanning beam.

We confirmed the effect of ion recombination using a parallel-plate ionization chamber: dose monitor for clinical use and the Advanced Markus chamber. A 290 MeV/u carbon-ion beam was irradiated using the continuous spot-scanning method in a field size of 5 cm by 5 cm with 2 mm spacing. We tested three beam intensities (1.35 × 108, 2.69 × 109, and 4.03 × 109 particle per second (pps)) at two linear energy transfers (12 keV/μm and 200 keV/μm). The charge ( Q ) was measured by changing the voltage of the Advanced Markus chamber and that of the dose monitor. Then, Boag’s method was used to calculate the saturated charge ( Q sat ). For the Advanced Markus chamber, 300 V is a sufficient potential to collect charge. For the dose monitor, Q sat / Q at 2500 V was 1.024 for 4.03 × 109 pps, indicating that the general recombination correction cannot be ignored when high dose rate treatment is performed using a carbon-ion scanning beam.

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 of 1.1 and 3.3 keV/μm irradiated human cancer and normal cells under a 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 longitudinal magnetic fields of BL = 0.3 and 0.6 T, whereas the biological effectiveness was not altered by perpendicular magnetic fields of the same strengths. This enhancement effect should be taken into account in magnetic resonance imaging guided proton therapy with a longitudinal magnetic field.

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.

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.

Three-dimensional (3D) pencil-beam scanning is an ideal irradiation technique to make the best use of the characteristics of a carbon-ion beam and to provide flexible dose delivery. To suppress beam spread due to multiple scattering and nuclear reactions, we developed a full energy scanning method. In some cases, such as eye treatments, the irradiation fields are very small and short ranged. Accordingly, we prepared a minimum low-energy carbon-ion beam corresponding to water-equivalent residual ranges of less than 2 mm. We performed experimental verification for low-energy carbon-ion beams ranging from 55.6 to 96.0 MeV/u. The accuracy of 3D dose delivery with the low-energy carbon-ion beam was verified by measuring the dose distributions for different target volumes. The results confirmed that the measured dose distributions agree well with the calculated ones. Then, the first eye treatment with low-energy carbon-ion beam to a patient was performed in 2018.

Three-dimensional (3D) pencil-beam scanning is an ideal irradiation technique to make the best use of the characteristics of a carbon-ion beam and to provide flexible dose delivery. To suppress beam spread due to multiple scattering and nuclear reactions, we developed a full energy scanning method. In some cases, such as eye treatments, the irradiation fields are very small and short ranged. Accordingly, we prepared a minimum low-energy carbon-ion beam corresponding to water-equivalent residual ranges of less than 2 mm. We performed experimental verification for low-energy carbon-ion beams ranging from 55.6 to 96.0 MeV/u. The accuracy of 3D dose delivery with the low-energy carbon-ion beam was verified by measuring the dose distributions for different target volumes. The results confirmed that the measured dose distributions agree well with the calculated ones. Then, the first eye treatment with low-energy carbon-ion beam to a patient was performed in 2018.

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.

A project to develop a compact heavy ion therapy device has been initiated at the National Institutes for Quantum and Radiological Science and Technology . The therapy device uses a 430 MeV/u synchrotron with superconducting bending magnets as a main accelerator. In order to reach the required output of the heavy ion beam, the bending magnets have been designed to be operate d alternately from 0.3 T (for to 3.5 T maximum (for extraction) at the ramping rate of 0.6 T/s. The 3D electromagnetic design of the synchrotron bending magnet has been performed. The magnetic length is 1.49 m for 45 degree bending angle, and curvature radius is 1.89 m. The superconducting coil consists of a low loss NbTi wire with a 1 mm diameter , and t he maximum operating current is 265A. To suppress the magnetomotive force, t he cross sectional coil design adopt ed an elliptical shaped arrangement. The coil and iron yoke designs were optimized for the uniformity of the magnetic field in the required area In addition, a short straight model with a magnetic length of 400 mm w as fabricated for the feasibility demonstration. The results of the excitation test as well as the electromagnetic design will be reported., 27th International Conference on Magnet Technology

現在の炭素線治療施設は臨床研究型の大型施設だが、炭素線治療の平均分割照射回数の少なさ（～12回）を考慮すると、1治療室でも比較的多くの患者の治療が可能なため、次世代治療装置では、シングルガントリーの小型治療装置が主流となると考えられる。また、現在の粒子線治療は陽子線と炭素線の2種類だが、世界的にはヘリウムイオンや酸素イオンの臨床研究が始まりつつあり、次世代治療装置は、ヘリウムから酸素（ネオン）までのイオン種が供給可能である必要がある。量子科学技術研究開発機構（QST）では、これらの要件を満たす次世代治療装置を「量子メス」と名付け、2017年より研究開発を進めてきた。 このプロジェクトでは、産学連携により液体ヘリウムを使用しない3.5Ｔ超伝導磁石を開発し、陽子線治療装置のサイズに近い小型装置の設計を進めるとともに、ヘリウムからネオンまでのイオンを、1分以内で切り替えられるシステムの開発を進めてきた。後者については、治療計画の高度化により、患者毎にイオン種を変えるだけでなく、1照射の中でイオンを切り替える研究もおこなっている。これらの技術は、基礎研究の段階から、QST病院に実証機を建設し、臨床試験を実施する段階に入りつつある。さらにQSTでは、次世代技術として高強度の超短パルスレーザーを使用したテーブルトップイオン加速器の研究も実施している。本講演ではこれらの研究の現在と今後について報告する。, 日本放射線腫瘍学会第34回学術大会 シンポジウム14

A charged particle therapy was proposed by Robert R. Wilson in 1946 and a clinical study of proton radiotherapy had been started at Lawrence Berkeley National Laboratory in 1954. Clinical studies have been promoted mainly in the United States and Europe. However, in Japan as well, the University of Tsukuba (KEK Campus) and the National Institute of Radiological Sciences (NIRS) started proton radiotherapy around 1980, and NIRS started carbon-ion radiotherapy in 1994. Following pioneering clinical studies, now in Japan, many proton and carbon-ion radiotherapy facilities are in operation, and some vendors are supplying equipment. Among them, charged particle therapy technologies originating in Japan have been developed, such as a respiratory-gated irradiation technology, a spot scanning irradiation technology, and a clinical dose design for ion radiotherapy. I look back on them and discuss the future direction of research and development of the charged particle therapy.

Methamphetamine (MA) is used worldwide and causes serious public health and social problems. MA affects the central nervous, cardiac, and immune systems, which causes neuropsychiatric and cardiovascular diseases and infection. Epigenetic changes, including DNA methylation (DNAm), are associated with various clinical phenotypes of MA abuse. DNAm is related to biological aging and health risks; hence, we aimed to assess the changes in biological aging in MA dependence using the DNAm age and DNA methylation-based telomere length (DNAmTL). We used five measures of DNAm age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAmTL, and DNAm-based age-predictive factors (plasma proteins and blood cell composition). We compared patients with MA dependence and healthy controls (n = 24 each) using the DNAm profiles obtained from whole-blood samples. Patients with MA dependence showed significant acceleration in PhenoAge and GrimAge, as well as a trend for significant acceleration in DNAmTL. Following adjustment for confounding factors, MA dependence was significantly associated with accelerations in PhenoAge, GrimAge, and DNAmTL, as well as alterations in DNAm-based age-predictive factors (beta-2-microglobulin, granulocytes, and naive cluster of differentiation 4+ T cells). Our results suggested an acceleration of biological aging and specific changes in the DNAm of age- predictive factors in MA dependence.

日本量子医科学会 発足記念シンポジウム

The National Institute of Radiological Sciences in Japan started clinical studies of carbon-ion radiotherapy (CIRT) in 1994. Due to the high linear energy transfer (LET) of highly charged particles, carbon-ion beams show high relative biological effectiveness in cell killing, especially at the Bragg peak of dose near the beam range, which is controlled to conform to a tumor. Recent technological developments for CIRT include fast pencil-beam scanning, fluoroscopic respiratory motion management, advanced beam modeling for treatment planning, and a superconducting rotating gantry, which have contributed to accuracy, precision, and conformation of dose, operational efficiency, and patient comfort. With technological maturity, CIRT facilities are rapidly increasing in Asia and Europe. Ongoing developments include extension to multiple ion species and facility downsizing to raise the quality and availability of ion-beam therapy in medical care.

Purpose: Our previous study revealed that the 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. T...

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 o...

2020年度量子医科学研究所 重粒子線がん治療装置等共同利用研究報告書

This study reports the commissioning methodology and results of a respiratory gating system [AZ – 733 V/733 VI (Anzai Medical Co., Japan)] using a pressure sensor in carbon‐ion scanning radiotherapy. Commissioning includes choosing a location and method for pressure sensor installation, delay time measurement of the system, and the final flow test. Additionally, we proposed a methodology for the determination of a threshold level of generating an on/off gate for the beam to the respiratory waveform, which is important for clinical application. Regarding the location and method for installation of the pressure sensor, the actual person's abdomen, back of the body position, and supine/prone positioning were checked. By comparing the motion between the pressure sensor output and the reference LED sensor motion, the chest rear surface was shown to be unsuitable for the sensor installation, due to noise in the signal caused by the cardiac beat. Regarding delay time measurement of the system, measurements were performed for the following four steps: (a). Actual motion to wave signal generation; (b). Wave signal to gate signal generation; (c). Gate signal to beam on/off signal generation; (d). Beam on/off signal to the beam irradiation. The total delay time measured was 46 ms (beam on)/33 ms (beam off); these were within the prescribed tolerance time (

Purpose The QA team of the Japan carbon‐ion radiation oncology study group (J‐CROS) was organized in 2015 to enhance confidence in the accuracy of clinical dosimetry and ensure that the facility QA procedures are adequate. The team conducted onsite dosimetry audits in all the carbon‐ion radiation therapy centers in Japan. Materials and Methods A special phantom was fabricated for the onsite dosimetry audit. Target volumes such as the GTV, CTV, and PTV were contoured to the obtained CT images, and two plans with different isocenter depths were created. The dose at the isocenter was measured by an ionization chamber, in the onsite audit and compared with the calculated dose. Results For all the centers, the average of the percentage ratio between the measured and calculated doses (measured/calculated) was 0.5% (−2.7% to +2.6%) and the standard deviation, 1.7%. In all the centers, the beams were within the set tolerance level of 3%. Conclusions The audit demonstrated that the dose at a single point in the water phantom was within tolerance, but it is a big step to say that all doses are correct. In addition, this external dosimetry audit encouraged centers to improve the quality of their dosimetry systems.

量研・ 関西研では 、超電導シンクロトロンとレーザー駆動炭素インジェクターを組み合わせた重粒子線治療装置の量子メスの開発を進めている。この開発では、 TNSA 法 により、4MeV/ 核子の炭素を発生させ入射することを目標としているが、レーザー駆動加速イオンの特徴であるピコ秒領域の極短パルス大電流という炭素ビームが「ビーム輸送系を介して超伝導 シンクロトロン のアクセプタンスに入射できるのか」という点については十分な検討がされていない。そこで、ビーム診断系および輸送系コンポーネント（磁石、静電レンズ）通過時 に生じる磁場および電場（空間電荷効果以外の外力）による 非線形性の増大に関して計算できるように整備した。今回はそれらの 結果と、量子メス実験用プラットホームでペッパーポット式のエミッタンスモニタで求めた数十keV級低エネルギーのイオンビームのエミッタンス量の結果を比較検討したので報告する。, 日本物理学会第76回年次大会

「電子・イオンビームハンドブック」第４版の分担執筆者として、18.4章 重粒子線によるガン治療を執筆した。

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−1 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 σ 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.

著者人数: 22名, 形態: カラー図版あり, Number of authors: 22, Physical characteristics: Original contains color illustrations, Accepted: 2020-03-13, 資料番号: PA2010004000