NCT letter (English version) Vol. 8 September, 2022
ISSN 2758-285X

NCT letter（English version）

Vol. 8September, 2022

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NCT letter (English version) Vol. 8 September, 2022
ISSN 2758-285X

Contents● Preface
Request for Participation in the Joint Usage Research Project, Advanced Nuclear
Science Research Institute, Kyoto University
Minoru Suzuki
President of Japanese Society of Neutron Capture Therapy
Professor, Institute for Integrated Radiation and Nuclear Science, Kyoto University● Special Articles
・Medical physics research in BNCT
Hiroki Tanaka
Professor, Department of Particle Radiation Medical Physics
Institute for Integrated Radiation and Nuclear Science, Kyoto University
・After approval of antineoplastic agent "Steboronin® Bag for Intravenous
Infusion 9000 mg/300 mL"

Tomoyuki Asano
Chairman & CEO, Stella Pharma Corporation
・Initiatives for research on the expansion of BNCT indications for companion
animals
Minoru Suzuki
Professor, Institute for Integrated Radiation and Nuclear Science, Kyoto University● Academic meeting Reports
・Report on the 17th Japanese Congress on Neutron Capture Therapy
Jun Itami
President of 17th JNCTDirector, Radiation Therapy Center, Shin Matsudo Central General Hospital● Awardees
The Commendation for Science and Technology by the Minister of Education,
Culture, Sports, Science and Technology, Prizes for Science and Technology,
2021
Koji Ono
Professor, Kansai BNCT Joint Clinical Institute,
Osaka Medical and Pharmaceutical University● Awardees of BNCT related Conferences or Meetings
Best Presentation Awards of 17th Japanese Congress on Neutron Capture Therapy
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NCT letter (English version) Vol. 8 September, 2022
ISSN 2758-285X

・Translational research of the therapeutic application of boron neutron capture
therapy (BNCT) to primary central nervous system lymphoma (PCNSL)
Kohei Yoshimura, et al.
Department of Neurosurgery, Kansai BNCT Medical Center,
Osaka Medical and Pharmaceutical University
・Poly(vinyl alcohol) enhancing therapeutic effects of D-4-boronophenylalanine
Kakeru Konarita, et al.
Institute of Innovative Research, Tokyo Institute of Technology

・Refining the CBE factor of BPA in brain with malignant brain tumor
Keiji Nihei, et al.
Kansai BNCT Medical Center,
Osaka Medical and Pharmaceutical University
・Modeling of neutron production efficiency in an accelerator-based boron neutron
capture therapy system with a lithium target and evaluation of its accuracy inclinical use (in Japanese)
Satoshi Nakamura, et al.
Department of Medical Physics, National Cancer Center Hospital・Optimization of dose calculation algorithm for BNCT by a combination ofMonte Carlo and superposition method
Mai Nojiri, et al.
Department of Nuclear Engineering, Graduate School of Engineering,
Kyoto University
・Therapeutic effect of boron neutron capture therapy using a novel boron
compound targeting 18 kDa translocator protein (TSPO) on F98 rat model ofmalignant glioma
Hideki Kashiwagi, et al.
Department of Neurosurgery, Kansai BNCT Medical Center,
Osaka Medical and Pharmaceutical University
・Initial treatment experience of BNCT after insurance coverage
Mariko Sato, et al.
Department of Radiation Oncology, Southern Tohoku BNCT Research Center・Footprint and future prospects of human resource development activities by the
Human Resources Development Committee of the Japan Society for Neutron
Capture Therapy
Shin-ichiro Masunaga, et al.
Research Center for Boron Neutron Capture Therapy, Osaka Prefecture University● Introduction of the articles
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NCT letter (English version) Vol. 8 September, 2022
ISSN 2758-285X<Pharmaceutical Science >Title: Addressing the Biochemical Foundations of a Glucose-Based “Trojan Horse”Strategy to Boron Neutron Capture Therapy: From Chemical Synthesis to In Vitro
Assessment
Presented by Makoto Shirakawa
Department of Pharmaceutical Sciences, Fukuyama University<Physical Engineering >Title: 124Sb-Be photon-neutron source for BNCT: Is it possible?
Presented by Kenichi Tanaka
Division of Advanced Science and Engineering, Hiroshima University<Medicine>
Title: Accelerator-based BNCT for patients with recurrent glioblastoma: a multicenter
phase II study
Presented by Mariko Sato
Department of Radiation Oncology, Southern Tohoku BNCT Research Center<Biology>
Title:Evaluation of local, regional and abscopal effects of Boron Neutron Capture
Therapy (BNCT) combined with immunotherapy in an ectopic colon cancer model
Presented by Natsuko Kondo
Institute for Integrated Radiation and Nuclear Science, Kyoto University● Editorial Postscript
Mitsuko Masutani
Chief Editor of NCT letter
Graduate School of Biomedical Sciences, Nagasaki University

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NCT letter (English version) Vol. 8 September, 2022
ISSN 2758-285X● Preface
Request for Participation in the Joint Usage Research Project,
Advanced Nuclear Science Research Institute, Kyoto University
Minoru Suzuki
President, Japanese Society of Neutron Capture Therapy
Professor, Particle Radiation Oncology Research Center,
Institute for Integrated Radiation and Nuclear Science,
Kyoto University
Thanks to the efforts of Dr. Itsuro Kato, the former Editor-in-Chief of NCT letter, andDr. Mitsuko Masutani, his successor, as well as the cooperation of many doctors, we arepleased to publish NCT letter No. 8.
As mentioned in the preface of NCT letter No. 7, accelerator-based boron neutron
capture therapy (BNCT) for head and neck cancer has been started at two medical
institutions. Needless to say, the clinical study of BNCT using a research reactor is thecornerstone of the initiation of BNCT at these institutions. I have been involved in many
clinical studies at the Kyoto University Research Reactor (KUR) in the Institute forIntegrated Radiation and Nuclear Science, Kyoto University, in collaboration with
doctors from medical institutions. The curtain was pulled back on BNCT clinical studies
at KUR with the start of accelerator-based BNCT at medical institutions in FY2019, andthe future development of BNCT medicine was handed over from the research reactor
to medical institutions with accelerator-based BNCT irradiation systems.
I would like to discuss the role of KUR after the completion of clinical studies of
BNCT based on the current status of the Combined Research Center and from thestandpoint of conducting collaborative research with many researchers. The special
feature of BNCT research is that it requires neutrons as a proof of concept. The KUR
neutron source is the only one that can provide a sufficient number of neutrons for
BNCT research from the standpoint of the academia. Conversely, the start of BNCT
treatment at medical institutions will give rise not only to research on the developmentof new boron drugs but also to many other research subjects, such as bridge research toconnect the results of research from basic to clinical practice, and new research subjects
that will be fed back to basic research from the results of the BNCT clinical research at
medical institutions.

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NCT letter (English version) Vol. 8 September, 2022
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It is important to broaden the scope of BNCT research to allow a smooth transition to
BNCT research using accelerator-based neutron sources after the end of the KUR
Collaboration in Japan. The existence of more research subjects and BNCT researchers
will lead to the expansion of the use of not only the cyclotron accelerator-based BNCT
irradiation system at Institute for Integrated Radiation and Nuclear Science but also theaccelerator-based BNCT irradiation systems that are under demonstration studies atseveral sites in Japan. In this respect, I believe that the KUR, which only has 5 years
remaining, has an extremely important role to play. Above all, we strongly hope that the
number of young researchers entering BNCT research will increase. It is, after all,young researchers who can conduct many BNCT studies from unique viewpoints due totheir flexible imagination. The number of biological experiments conducted in FY2020
is expected to increase to 1,000 in FY2021. In FY2021, 180 experiments wereconducted from June to December (18 weeks of operation), and 10 biologicalexperiments were conducted on average per week of operation. Even if the number ofexperiments increases, we will cope with it by improving the efficiency of various
irradiation methods that we have been using.
In the Institute for Integrated Radiation and Nuclear Science (KURNS), there is theCenter for Particle Beam Oncology, of which I am the director, and to which faculty
members in the fields of particle beam oncology and particle beam medical physics
belong. One of the duties of the center's faculty members is to promote joint research. In
the last fiscal year and this fiscal year, due to the spread of the novel coronavirus, many
experiments have been conducted by the faculty members of the KURNS on behalf of
those who are unable to come to the center due to travel restrictions. The KURNS
faculty members are also responsible for observation of mice after irradiation, colony
fixation, mailing, etc. Please do not hesitate to contact us for consultation. The
remaining 5 years of the project, and since the current year's joint use is nearing its end,
the actual period of use is 4 years. In order for accelerator-based neutron sources toinherit the mantle of Japanese BNCT therapies, which are already world-leading in theirscope, it is extremely important for us to achieve many research results using theremaining lifespan of the KUR. Members of the society, if you are interested in BNCT
research but are unsure of how to approach performing the research itself, please visit
the website of the Particle Radiation Oncology Research Center. Contact information isavailable on the members' introduction page.
Thank you for your continued support and cooperation.

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NCT letter (English version) Vol. 8 September, 2022
ISSN 2758-285X● Special Articles
Medical physics research in BNCT

Hiroki Tanaka
Professor, Department of Particle Radiation Medical Physics
Center for Particle Radiation Oncology
Institute for Integrated Radiation and Nuclear Science,
Kyoto University
Medical physics research is critical to BNCT and has played a role in the proper"generation, control, detection, and evaluation" of neutrons. From the time clinicalresearch on BNCT began in the United States in 1951 until the 1990s, thermal neutron
beams, in which fission neutrons from research reactors were decelerated to the thermal
neutron energy region, were used for treatment. Since thermal neutrons cause anabsorption reaction with hydrogen, treatment was performed for surface malignant
melanoma or brain tumors in craniotomies.
In the 1990s, in research reactors around the world, there was a growing need toenable treatment at deeper depths, and it became possible to extract controlled
epithermal energy, which is more energetic than thermal neutrons. Since neutrons haveno electric charge, several materials with a nuclear reaction cross section with highscattering moderating ability and low absorption are used for the control of neutronenergy. This is applicable not only to reactor neutron sources but also to accelerator
neutron sources. In addition, accelerator neutron sources can produce neutrons in a wide
variety of ways, depending on the combination of charged particle energy and neutronproducing target. Neutron generation and control are closely related, and it is important
to design from the viewpoint of medical physics with clinical considerations.
Accelerator neutron source systems are described in detail in NCT letter No. 7.
Since generated and controlled neutrons have a wide energy range from 10-8 toseveral tens of MeV, proper detection of neutron energy spectra is necessary for clinicalapplications. It is difficult to measure 9 orders of magnitude of neutron energy at once
because the interaction between neutrons and materials is complex and the type ofinteraction differs for each energy. In addition, the neutron intensity in the irradiation
field of BNCT ranges from 106 to 109 (n/cm2 /s); thus, survey meters and other
instruments normally used in radiation protection are not applicable.
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Thermal neutrons are measured indirectly by measuring gamma rays emitted fromradionuclides produced by the capture reaction. We have followed the neutron detection
method used by the nuclear reactor neutron source. In contrast, a new detection method
is being developed using scintillators containing 10B and 6Li, which have highabsorption cross sections for thermal neutrons, to enable real-time measurements. Fastneutrons are also difficult to measure directly, and methods using activation of metal
foils sensitive to energies higher than a certain energy and Bonner spheres to detect
thermal neutrons by moderating them with a polyethylene sphere are being developed
for the BNCT irradiation field.
Measurement of epithermal neutrons used in therapy is more difficult, and we haveconfirmed the validity by measuring the thermal neutron flux distribution whenirradiated in a water phantom. Thermal to fast neutron detection requires a combined
evaluation with calculations such as Monte Carlo simulations.
Monte Carlo simulations are also used in treatment planning, where computed
tomography (CT) and magnetic resonance imaging (MRI) medical images are modeled
as voxels and neutron energy spectra are calculated for each voxel by performing
neutron transport calculations. Each energy is converted to a dose, and the equivalent Xray dose is evaluated considering the biological effects. The Monte Carlo simulation iscomputationally time-consuming; therefore, it is required to be completed in the sameamount of time as the treatment planning for X-ray therapy, and research to solve thisproblem is underway. It is expected that AI and machine learning, which areincorporated into the research of X-ray therapy, can also be applied to BNCT.
As described above, medical physics research at BNCT has been conducted with thetheme of appropriate "generation, control, detection, and evaluation" of neutrons. It isalso important to evaluate the cell-killing effect of BNCT because the effect depends onthe microscopic distribution of boron. With the development of computational science,
it has become possible to evaluate the boron distribution in the cellular dose and tosimulate the biological effects computationally. Furthermore, it has been proposed thatthe boron concentration during treatment can be measured by detecting prompt gamma
rays emitted by the reaction of thermal neutrons with 10B at BNCT, which is expected to
be a necessary technique for evaluating the treatment effect.
We believe it is important to link the above medical physics research to clinicalpractice. BNCT with insurance coverage for unresectable locally advanced or locallyrecurrent head and neck cancer has been started at medical institutions. Medical physics
research in clinical practice includes items related to optimization of dose distribution

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NCT letter (English version) Vol. 8 September, 2022
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and quality and accuracy control of equipment. It is expected that more and more
medical physics research will be performed in clinical practice in the future.
The Institute for Integrated Radiation and Nuclear Science, Kyoto University has twoneutron source facilities, a research reactor and an accelerator neutron source, both
unique in the world, and is promoting research and development of BNCT. The
Department of Particle Radiation Medical Physics, Particle Radiation Oncology Center(PBOCC) has succeeded to the BNCT medical physics research that has been conductedby Dr. Akira Maruhashi, and we hope to contribute to the spread and development of
BNCT by incorporating new knowledge.

After approval of antineoplastic agent "Steboronin®
Bag for Intravenous Infusion 9000 mg/300 mL"
Tomoyuki Asano
Chairman & CEO, Stella Pharma Corporation
Many patients with head and neck cancer wish to preservefunctions such as speech, swallowing, chewing, and breathing. Thus, it is hoped that
medical technology can enable us to shrink only the tumor in question, without
damaging surrounding normal cells, and thereby maintain the patient’s quality of life.
Therefore, in the treatment of head and neck cancer, efforts are made to minimize
functional disability after treatment as well as to cure the disease. From this perspective,
nonsurgical treatment is chosen when significant postoperative functional disability is
expected.
BNCT is expected to be a new radiotherapy for head and neck cancer that can also be
re-irradiated, since its principle allows high doses to be given to tumor cells withminimal effect on surrounding normal cells.
Based on the results of clinical trials conducted in Japan to meet these expectations,the drug received manufacturing and marketing approval in Japan in March 2020 for theindication of "unresectable locally advanced or locally recurrent head and neck cancer,"ahead of any other country in the world.
Below are the clinical results for the approved Steboronin®.
Phase II clinical study in Japan (JHN002 study)(1)9

NCT letter (English version) Vol. 8 September, 2022
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In 21 patients with (1) unresectable locally recurrent squamous cell carcinoma of thehead and neck following chemoradiation or radiation therapy or (2) unresectable nonsquamous cell carcinoma of the head and neck, 500 mg/kg of the drug was administeredintravenously at 200 mg/kg/h for the first 2 h and 100 mg/kg/h thereafter. Patients werealso irradiated with a single neutron dose of 12 Gy-Eq to the oral, pharyngeal, or laryngeal
mucosa for up to 60 min starting 2 h after the start of Borofalan (10B) administration. The
primary endpoint of response rate (the sum of complete and partial responses) by central
administration (RESIST v1.1) was 71.4% (90% confidence interval: 51.3–86.8%).
Regarding safety, brain abscess was observed in one patient (4.8%) as a serious adverse
event during the observation period of the JHN002 study (up to 90 days after BNCT); 16
patients (76.2%) had grade 3 or higher adverse events including the aforementioned
serious adverse events: increased amylase, lymphocytopenia in one patient (4.8%),
decreased lymphocyte count in one patient (4.8%), stomatitis in one case (4.8%), brain
abscess in one case (4.8%), and radiation skin damage in one case (4.8%).
In the JHN002 study, relatively common adverse events of BNCT included thirst,
parotitis, sialadenitis, nausea, stomatitis, vomiting, fatigue, conjunctivitis, increased
amylase, decreased appetite, dysgeusia, and alopecia. These events reported as adverse
reactions to BNCT were considered general radiation injury or irradiation site-dependent
events. Although "hematuria" was reported as an adverse reaction to BNCT in thedomestic Phase I study, its occurrence was considered to have decreased after the JHN002
study because fluid loading with infusion was recommended. Therefore, the package
insert “8. Important Basic Precautions” states “Crystalluria may occur; therefore, urinarydrainage should be encouraged by administering intravenous fluids as necessary after
completion of treatment. The following is a list of the important basic precautions.”
Based on the results of the above-mentioned clinical trials in Japan, BNCT using thisdrug is expected to have a tumor reduction effect not seen in existing therapies as a novel
treatment for patients with unresectable locally advanced or locally recurrent head andneck cancer, and is considered to meet the medical needs and provide a new treatment
option. The following are the [Use and Dosage ] and <Use and dosage precautions >specified in the package insert.
[Use and Dosage]
The usual adult dose of Borofalan (10B) is 200 mg/kg per hour intravenously for 2 h.
Neutron irradiation of the lesion site is then initiated, and Borofalan (10B) is given
intravenously at a rate of 100 mg/kg per hour during irradiation.

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ISSN 2758-285X<Use and dosage precautions>・The efficacy and safety of concomitant use with other antineoplastic agents have notbeen established.
・The neutron irradiation device manufactured by Sumitomo Heavy Industries, Ltd.,
shall be used to irradiate neutrons.
This drug was designated by the Ministry of Health, Labour and Welfare (MHLW) on
February 28, 2017, as a drug subject to the "Pioneer Review Designation System."This is proof that the Ministry of Health, Labour, and Welfare has recognized BNCT
as an innovative medical technology for life-threatening diseases for which there is noeffective treatment and as a medical industry that can keep Japan at the forefront of theworld.
We will never betray these expectations, and we will work hard to remain the best
globally.
【Reference】(1) Hirose K, et al. Boron neutron capture therapy using cyclotron-based epithermal neutron sourceand borofalan (10B) for recurrent or locally advanced head and neck cancer (JHN002)：An openlabel phase Ⅱ trial.

Initiatives for research on the expansion of BNCT
indications for companion animals
Minoru Suzuki
Professor, Particle Radiation Oncology Research Center,
Institute for Integrated Radiation and Nuclear Science,
Kyoto University
The Center for Particle Radiation Oncology, Institute for Integrated Radiation and
Nuclear Science, Kyoto University has concluded a joint research agreement with the
Veterinary Clinical Center, Osaka Prefecture University, and has been working on the
expansion of the indications of BNCT for companion animals.
I would like to discuss the importance of research on extending BNCT indications forcompanion animals and the efforts of this research at the Institute for Integrated
Radiation and Nuclear Science. The importance of this research is based on the11

NCT letter (English version) Vol. 8 September, 2022
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principle of "One medicine, One health," which means that both "human medicine" and"animal veterinary medicine" are medicine in common, and the findings from thisresearch will be applied to human BNCT research. This is a bidirectional undertaking
that will benefit both fields. An example is my basic research on whole-organ BNCT. In
human BNCT for the liver and lungs, it is impossible to irradiate the entire organ
uniformly with neutrons. I have been conducting normal tissue studies of BNCT on theliver and lungs using mice and rats, and it is important to use companion animals suchas dogs and cats, which bridge the gap between humans and rodents. As for actual
veterinary medicine, I believe that bone and soft tissue sarcomas, head and neckcancers, and malignant brain tumors, for which clinical studies have been conducted inhumans as therapeutic targets at the Institute for Integrated Radiation and Nuclear
Science, may be candidates for BNCT. Conversely, if the size of dogs and cats is small,neutrons can be irradiated relatively uniformly to all target organs by whole-liver andwhole-lung irradiation, and patients with multiple lung metastatic tumors and multiple
liver metastatic tumors that are not eligible for radiation therapy in human treatment
may become eligible for BNCT treatment. In the field of veterinary medicine, BNCT
may provide a new treatment method for multiple metastatic tumors, and in the field of
human medicine, BNCT may enable long-term observation of the effects of BNCT on
normal liver and normal lung and may provide important knowledge on tumors in thehuman trunk.
As part of this research initiative at the Institute for Integrated Radiation and Nuclear
Science, research meetings have been held in FY 2019 and FY 2020. The FY 2020
meeting was held remotely on March 4, 2021 due to the coronavirus pandemic. Dr.
Amanda Schwint, who has conducted BNCT of companion animals from Argentina
using a research reactor, gave an educational lecture at this meeting. We are planning tohold another workshop in FY2021 as a specialized research group of RRI. In addition,"Basic Research for Expanding Adaptation of BNCT to Companion Animals" has been
adopted as a 3-year project research from FY2022, and several research themes havebeen applied for this project.
We would like to report many research results using the neutron source at KUR sothat as many veterinary researchers as possible can participate in this research.

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ISSN 2758-285X● Academic meeting Reports
Report on the 17th Annual Meeting of the Japanese Society for
Neutron Capture Therapy
Jun Itami
President of 17th JNCTDirector, Radiation Therapy Center,
Shin Matsudo Central General Hospital
The 17th Annual Meeting of the Japanese Society for Neutron Capture Therapy washeld on July 10–11, 2021, at the KKR Hotel Atami in Atami City, Japan, using a mix oflive and web-based presentations. In 2021, the situation was similar, but considering the
rapid development of accelerator-based BNCT in Japan, it was considered essential tohold an academic conference, even if it was via the web. We had planned to hold a live
conference in the gap between the emergency measures to prevent the epidemic, but amudslide occurred in Atami, where the conference was to be held, on July 3, 2021, andit was doubtful whether we could hold the conference in Atami considering the disaster.
However, when we contacted the city of Atami, we were told that the area around the
KKR Hotel Atami, the venue of the conference, was perfectly safe and that they would
be happy to host the conference. We would like to thank Dr. Hiroshi Igaki and Dr.
Tetsushi Nakamura of the Department of Radiotherapy, National Cancer Center
Hospital, and other doctors who worked day and night as the conference secretariat. I
would like to express my deepest gratitude to them.
The theme of the conference was "Neutron Capture Therapy from Japan to theWorld." The clinical practice of accelerator-based BNCT is now almost exclusively
performed in Japan. In the conventional reactor BNCT, the number of patients treated islimited and it is difficult to enroll a large number of patients in clinical trials. I am anewcomer to this society, but I have learned a lot from the reports of the wonderfulresearchers who have pioneered a new field and are full of spirit to go forward on an
unprecedented path at the annual meeting. It is truly "don't do the same thing as others."
However, once the topic shifts to clinical practice, it is necessary to increase the numberof patients and clear the question of whether BNCT is statistically significantly superior.
It is necessary to earn the number of patients with the same treatment by doing "thesame thing as others." It seems that the perspective that was a little lacking in the13

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conventional society is also important. To expand the indications for BNCT's insurance
medical treatment in the future, it is necessary to show the superiority of BNCT
statistically. Westerners appear to be quite good at this kind of thing, and Japanesepeople are relatively weak in this area. Indeed, I myself am completely unfamiliar with
this.
In Japan, the cyclotron-based BNCT accelerator and treatment planning systemdeveloped by Sumitomo Heavy Industries, Ltd., and Stella Pharma Corporation's
boronophenylalanine (BPA) is indicated for some head and neck cancers. In contrast,
the National Cancer Center Hospital is using CICS's linear accelerator-based BNCT
accelerator and Stella Pharma Corporation's BPA are used for malignant melanoma of
the skin and vascular sarcoma. If the current situation continues, each accelerator will
have to expand the range of indications for the same disease with separate trials. If
BNCT can be covered by insurance on a disease-by-disease basis, it will be possible totreat patients with both accelerators, which will be greatly beneficial.
Considering this, we invited Dr. Kiyoto Nakai, then Director of the Pharmaceutical
Safety Division, Pharmaceuticals and Consumer Health Bureau, MHLW, and Dr.
Kensuke Ishii, Director of the First Medical Device Review Division, Pharmaceuticals
and Medical Devices Agency, to give valuable presentations at this conference. The
meeting was very well attended. We, as an academic society, would like to clarify thebasic requirements for BNCT accelerators as soon as possible, and if these requirements
are met, regardless of the accelerator vendor, the regulatory approval should be obtained
as soon as possible. We now know that there is a way to be able to claim reimbursement
for BNCT-indicateddiseases. It is
important for us tomove forward byconcentrating thepower of our society
more and more.
In the generalabstracts, there werereports on clinicalresults of acceleratorbased BNCT,
development of new
BNCT drugs,
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improvement of administration methods, tolerable dose of normal tissues, real-timemeasurement method of thermal neutrons, etc. Many of the topics were discussed in
more depth than those at the international conference, and I felt deeply that this is atechnology that is still developing in Japan. We had a great time.
We hope that the conference members who came to the conference venue in Atami
enjoyed the hot spring while looking at the sea of Atami. Next year, Dr. Hiroaki
Kumada of Tsukuba University will hold the conference at Tsukuba International
Congress Center from October 29 to 30. We hope to see and talk with you all directly atthat time.
Thank you so much for this opportunity.

● Awardees

The Commendation for Science and Technology by the Minister of Education,
Culture, Sports, Science and Technology, Prizes for Science and Technology, 2021

2021 Commendation for Science and Technology by the Minister of
Education, Culture, Sports, Science and Technology
Science and Technology Prize
Koji Ono
Professor, Kansai BNCT Joint Clinical Institute,
Osaka Medical and Pharmaceutical University
In April last year, we received an award from the Minister of Education, Culture,
Sports, Science and Technology (MEXT) for the practical application of the world's
first accelerator-based BNCT system. We would have attended the award ceremony at
the MEXT, but due to the coronavirus disaster, the ceremony was held only with some
representatives of the Tokyo group, and we attended online. I am sure that all of you areaware that the achievements of the awardees are not only due to myself, Dr. Suzuki &Dr. Tanaka (Institute for Integrated Radiation and Nuclear Science, Kyoto University),Dr. Mitsumoto (Sumitomo Heavy Industries, Ltd.), and Dr. Asano (Stella Pharma
Corporation). In the field of accelerator irradiation systems, the contributions of Akira
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Maruhashi (Professor Emeritus of Kyoto University, Institute for Integrated Radiation
and Nuclear Science) and Takemi Sato (formerly of Sumitomo Heavy Industries, Ltd.)
have been extremely significant. The same is true of Mitsunori Kirihata (Professor
Emeritus of Osaka Prefecture University), who has contributed greatly to thedevelopment of boron-based drugs. Concurrently, many doctors and researchers who
were involved in clinical trials, which are indispensable for clinical application, are also
considered to have made great contributions. The collaboration of these many people
has resulted in an achievement worthy of commendation.
In retrospect, we conducted clinical research on BNCT using the Kyoto University
Reactor (KUR) and L-4-boronophylalanine (L-BPA) fructose complex solution formany years, but it was impossible to make BNCT an approved medicine as long as anuclear reactor was used as the neutron source. At the beginning of this century, we
made a world-leading leap forward in clinical research, and the momentum to make
BNCT an approved medical treatment grew among our collaborators. Therefore, wehave been developing an accelerator neutron source that can replace the research reactor
as an approved medical device, and a long-term stable BPA preparation that can replace
the fructose complex solution.
We designed an accelerator neutron source based on the results of medical physics
accumulated in the research using KUR and our past achievements in cyclotron
development. The cyclotron accelerates 1 mA protons to 30 MeV, and the target ismade of beryllium for heat and proton resistance, which enables us to obtain a stablebeam of epithermal neutrons with a flux density 1.5 times higher than that of the Kyoto
University reactor. The moderator system was optimized so that the most frequent
energy of the produced neutrons is 10 keV, which is higher than that of the Kyoto
University reactor.
Conventional L-BPA fructose complex solutions of boron drugs have instability due
to the Maillard reaction caused by the amino and carbonyl groups, which is a problem ifthey are to be used as drugs for which stable supply is essential. In this development,
the stability problem was solved by employing D-sorbitol as a dissolution aid, andcombined with our original boron-10 isotope enrichment technology, it became possible
to create a boron drug for BNCT with low systemic toxicity and high accumulation intumor tissues.

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We conducted physical characterization studies of the treatment system andpharmacological and toxicological studies of the boron drug prior to conducting clinical
trials, including the world's first accelerator-based BNCT phase I clinical trial forrecurrent malignant glioma in 2012 and a phase I clinical trial for inoperable locallyadvanced and recurrent head and neck cancer in 2014. We initiated a phase II clinical
trial in 2016. The response rate for head and neck cancer reached 71.4%, and thefrequency and severity of side effects were confirmed to be comparable to those ofexisting radiotherapy. In 2017, the Ministry of Health, Labour and Welfare designatedthe drug for the Pioneer Review Designation System, and an application for approval
will be submitted in 2019. In 2020 NeuCure® system and NeuCure® Dose Engine, a
BNCT dose calculation program, received manufacturing and marketing approval as
medical devices, and on March 25 of the same year, Steboronin® intravenous infusionbag, a boron drug for BNCT, also received manufacturingand marketing approval as a drug, and on May 20 of thesame year, the world's first BNCT drug is now on sale as adrug.
The BNCT treatment system NeuCure® has been
installed at the South Tohoku BNCT Research Center and
the Kansai BNCT Medical Center of Osaka Medical andPharmaceutical University, and the world's first insured
treatment of BNCT using Steboronin® started in June
2020.
These and other achievements wereachieved ahead of the world through purely
Fig. 1 Medals of commendation
domestic technology and collaboration
between industry, government, and academia,
and are expected to contribute to medical care not only in Japan but worldwide.
However, the PMDA has judged that the clinical trial results of BNCT for malignant
glioma, which has led the clinical research, have not yet been scientifically proven to beeffective, and are in the process of reanalyzing and reevaluating the data. From anotherscientific point of view, even though neutrons are used, BNCT is not yet fullyrecognized as one of radiotherapy. This is reflected in the fact that the relationshipbetween tumor dose and efficacy is not yet clear. The incorporation of FBPA-PET into
medical practice is indispensable to solve this problem, and the early initiation ofclinical trials of FBPA-PET is highly desirable. Optimization of neutron energy andenhancement of neutron intensity (flux density) are also important issues. Research on
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the effects of BNCT on normal tissues with tumors is also essential to expand theapplication of BNCT to new tumor types. It is clear that a further major breakthroughwill depend on the development of new boron drugs that far surpass BPA.
By reporting on the Minister's Commendation, I hope that JSNCT members would
continue their efforts in their respective fields for the further development of BNCT.

● Awardees of BNCT related Conferences or Meetings
The Best Presentation Award of the 17th annual Congress on Japanese Society of
Neutron Capture Therapy

Translational research of the therapeutic application of boron neutron
capture therapy (BNCT) to primary central nervous system lymphoma(PCNSL)
Kohei Yoshimura, et al.
Department of Neurosurgery,
Kansai BNCT Medical Center,
Osaka Medical and Pharmaceutical University
BNCT is a particle beam therapy that selectively destroys tumor cells using alphaparticles emitted by the nuclear reaction of non-radioactive boron atoms10B andneutrons (10B[n,alpha]7 Li). Primary central nervous system lymphoma (PCNSL) is amalignant brain tumor classified as World Health Organization grade IV. High-dose
methotrexate and whole brain radiation therapy are recommended for treatment. PCNSL
is highly responsive to initial therapy but relapses after successful treatment, andprognosis is poor with few treatment options for relapse. Therefore, there is a need todevelop novel therapies for PCNSL and potential therapies that can be used at relapse.
We performed a basic study of BNCT, which has already been clinically applied tomalignant glioma, a similar intracranial malignancy, to evaluate its potential as a newtreatment option for PCNSL, including recurrent cases, by taking advantage of its highcell selectivity.
In an in vitro study, boron accumulation after exposure to boronophenylalanine (BPA)
was evaluated using two types of human-derived lymphoma cells, Raji and RL, toassess the effect of BNCT with BPA on lymphoma cells. BPA was administered to18

NCT letter (English version) Vol. 8 September, 2022
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transplanted nude mice (mouse brain tumor model), and boron concentrations in eachorgan and tumor were measured. Neutron irradiation experiments were also performedon the mouse brain tumor model to evaluate the therapeutic effect of BNCT on themouse brain tumor model in terms of survival time.
Lymphoma cells demonstrated high boron uptake capacity. In vivo distribution
experiments using a mouse brain tumor model confirmed tumor-selective boron
accumulation. In the first neutron irradiation experiment in the mouse CNSL model, thesurvival time of the BNCT group was short because the equivalent dose to the oral
mucosa was high and the mucosal damage caused early death. The survival benefit of
BNCT was shown to be prolonged when neutron irradiation experiments with dose
reduction were designed and conducted. These results indicate that BNCT is effective inmalignant lymphoma. Based on the results of this study, we are now conducting
additional experiments to apply BNCT to PCNSL in clinical practice.
Finally, I would like to express my sincere appreciation to Dr. Shinji Kawabata for his
support for this presentation; Dr. Jun Itami, the conference director, who selected thispresentation for the Best Presentation Award; all the members of the conference
secretariat and the judges; and the authors of the NCT letter for their kind cooperation inthis project. I would like to thank Dr. Mitsuko Masutani for giving me the opportunity
to write this article.

The Best Presentation Award of the 17th annual Congress on Japanese Society of
Neutron Capture Therapy

Poly(vinyl alcohol) enhancing therapeutic effects of D-4boronophenylalanine
Kakeru Konarita, et al.
Institute of Innovative Research, Tokyo Institute of Technology
In 2020, our laboratory reported that the addition of polyvinyl alcohol (PVA) to Lboronophenylalanine (L- BPA) can improve BPA’s tumor accumulation and retention
capacities, thereby maintaining high intratumoral boron concentration during thermal
neutron irradiation and significantly enhancing the therapeutic effect of L- BPA[Science Advances 6, eaaz1722 (2020)]. In this study, we focused on the fact that Dboronophenylalanine (D-BPA), an enantiomer of L-BPA, has higher selectivity for

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LAT1 than L-BPA, and developed PVA-D- BPA, in which D-BPA is loaded on PVA,
and investigated its in vitro and in vivo behavior.
First, we evaluated the uptake and intracellular retention of sorbitol-L/D-BPA and
PVA-L/D-BPA in human pancreatic cancer cells. Sorbitol-D-BPA had a significantly
lower uptake efficiency than sorbitol-L-BPA. This may be due to the fact that D-BPA
was selectively taken up by LAT1, whereas L-BPA was also taken up by other LAT2
and ATB0,+ . However, D-BPA uptake was enhanced by the complex formation with
PVA. In addition, we found that D-BPA showed much longer intracellular retention
than L-BPA. This may be because LAT1 has an intracellular transport function that ispermissive for many neutral large amino acid compounds including D-BPA, and thisproperty does not work for D-BPA in extracellular transport.

Figure 1. (A) Accumulation of BPA in tumors in a mouse subcutaneous
pancreatic cancer model. (B) Tumor to muscle tissue ratio (T/N ratio) of
PVA-L/D-BPA.
Figure 2. Anti-tumor effect. (A) Subcutaneous pancreatic cancer model. (B)Subcutaneous colon cancer model. Thermal neutrons were irradiated 3 hafter intravenous injection.
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Tumor accumulation of these samples was then evaluated in a mouse subcutaneous
pancreatic cancer model (Figure 1). Sorbitol-D-BPA hardly accumulated, but D-BPA
significantly improved its tumor accumulation by forming a complex with PVA, andshowed higher boron concentration and long-term retention than PVA-L-BPA. In
addition, PVA-D-BPA accumulated less in muscle tissue than PVA-L-BPA, probably
due to its higher LAT1 specificity, and improved the T/N ratio. Moreover, PVA-D-BPA
showed superior BNCT effect on subcutaneous tumors (Figure 2).
D-BPA by itself has a lower uptake efficiency than L-BPA at first glance and is notexpected to have excellent tumor accumulation in vivo. However, D-BPA was shown to
exhibit its true value by forming a complex with PVA, suggesting that D-BPA may
even have a therapeutic potential greater than PVA-L-BPA for LAT1-targeted cancer
therapy. However, the mechanism by which the complex formation between BPA and
PVA increases BPA uptake remains unclear, and we intend to clarify this mechanism inmore detail in the future.
Finally, I would like to express my sincere gratitude to Dr. Jun Itami, the conference
chairman, Dr. Minoru Suzuki, the president of the society, for selecting this presentation
for the Best Presentation Award, and Dr. Mitsuko Masutani for giving me theopportunity to write this paper. We also thank Dr. Hiroyuki Nakamura for his great
advice and Dr. Yoshinori Sakurai, Dr. Hiroki Tanaka, and Dr. Takushi Takada for their
special support in neutron irradiation.

The Best Presentation Award of the 17th annual Congress on Japanese Society of
Neutron Capture Therapy

Refining the CBE factor of BPA in the brain with malignant brain
tumorsKeiji Nihei, et al.
Director, Kansai BNCT Medical Center,
Osaka Medical and Pharmaceutical University
The biological effects of normal particle therapy can be describedby the product of the constant relative biological effectiveness (RBE) and the physicaldose. However, in BNCT, the microdistribution of boron changes depending on the
drug and the target tissue. Therefore, the biological effects of α particles and Li nuclei
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emitted by BNCR (boron-neutron capture reaction) cannot be calculated using a
constant RBE. Instead of RBE, compound biological effectiveness (CBE) is used in
BNCT. Currently, a value of approximately 1.35 is used worldwide for clinical studies
and trials of brain tumors as the value for normal brain tissue. However, this value iscalculated by physical dose based on the boron concentration in blood and is only avalue obtained under specific experimental conditions without considering the boron
concentration in normal brain. In 2016, co-author Ono reviewed several reports undervarious experimental conditions and found that CBE levels are significantly affected byboron concentration in normal brain tissue. Specifically, the value can be described by
the formula (CBE = 0.32 + 1.65 · N / B) with the term of N / B (normal brain / blood
blood) of boron concentration added (Journal of Radiation Research, Vol. 57, No. S1,
2016, pp. i83–i89). According to this formula, the CBE value of BPA for malignant
brain tumors was reconsidered.
The BPA concentration for malignant brain tumors was substituted by the brain
SUVmean obtained from FBPA-PET, and the blood BPA concentration was substitutedby the SUVmean obtained from the cardiac pool. Brain SUVmean was 1.21 ± 0.27 and1.65 ± 0.33 in the contralateral brain of the brain tumor and the ipsilateral brain
bordering the tumor, respectively. The blood SUVmean was 1.12 ± 0.17. These values
resulted in N(contralateral brain)/B(blood) = 1.07 ± 0.12 and N(ipsilateralbrain)/B(blood) = 1.46 ± 0.26. CBE was calculated based on N/B in the contralateralbrain (CBE=2.09) and N/B in the ipsilateral brain (CBE=2.73). In both ipsilateral andcontralateral brains, the CBE values were much higher than the conventional value(1.35).
The currently used CBE value of 1.35 is likely to be underestimated as thebioequivalent dose to the normal brain. SUV values in the ipsilateral brain in contact
with the tumor may be higher than in the contralateral brain due to partial destruction of
the blood-brain-barrier by the tumor in addition to the effect of FBPA accumulated ininfiltrating tumor cells. Furthermore, considering the dose effect of BPA in tumor cells
mixed with normal brain cells, the SUV values may be even higher than the CBE
estimated from the SUV values of the contralateral brain. More accurate calculation of
CBE values and dose assessment for the normal brain are mandatory in the future.
Finally, I would like to express my deepest gratitude to Dr. Jun Itami, the Congress
Director, who selected this presentation for the Best Presentation Award, to the judges,
and to the NCT letter committee for the opportunity to write this paper.

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The Best Presentation Award of the 17th annual Congress on Japanese Society of
Neutron Capture Therapy

Modeling of neutron production efficiency in an accelerator-based
boron neutron capture therapy system with a lithium
target and evaluation of its accuracy in clinical use (inJapanese)
Satoshi Nakamura, et al.
Department of Medical Physics, National Cancer Center HospitalAn accelerator-based boron neutron capture therapy (BNCT) system with a Li target(Cancer Intelligence Care Systems) has been installed at the National Cancer Center
Hospital. Previous studies have reported that the neutron output per unit number ofprotons of the accelerator-based BNCT system decreases dependent on the integrated
proton dose to the Li target1,2 . To use this system clinically, a default neutron fluencemust be delivered to the patient, and it is necessary to estimate the reduction in neutron
power that occurs during treatment before the patient is treated. Therefore, a theoreticalmodel for the neutron power reduction per unit proton fluence was developed, and its
accuracy and validity were verified based on measured data. Furthermore, assuming theclinical use of the accelerator-based BNCT system, we predicted the neutron output
after the irradiation of the assumed quantity of protons required for the BNCT treatmentusing the theoretical model and evaluated the accuracy of the model.
The acceptable output of radiotherapy equipment is within ±2% as recommended in
the QA system guideline for external radiation therapy by the Japanese Society ofRadiation Oncology, and the same accuracy should be achieved for the accelerator
BCNT system and neutron output.
The theoretical model constructed from the present results adequately reproduces themeasured values and has been validated.3 The results also satisfied the acceptable output
values recommended in the QA system guidelines for external radiotherapy when thesystem was assumed to be used clinically.
The data were obtained from a portion of a non-clinical study of the accelerator-based
BNCT system installed at the hospital. Based on those data, our hospital is conducting

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phase I clinical trials formalignant melanoma andangiosarcoma from 2019. We
will continue to exert every
effort to conduct research thatwill lead to the developmentof neutron capture therapy.
Finally, I would like toexpress my sincerest
gratitude to all who wereinvolved in thisFig. 1: The effect of proton irradiation on the Li target
as a function of the integrated proton fluence.
opportunity.
Comparison of measured neutron output andcalculated values by the model (Measured value:evaluated by the saturated radioactivity of gold).

1) Nakamura S et al., Dependence of neutrons generated by 7Li(p,n) reaction on Li
thickness under free-air condition in accelerator-based boron neutron capture therapy
system. Phys. Med. 58: 121-130 (2019)2) Nakamura S, et al., Characterization of the relationship between neutron production
and thermal load on a target material in an accelerator-based boron neutron capture
therapy system employing a solid-state Li target. PLoS One. 14(11): e0225587 (2019)3) Nakamura S, et al., Neutron flux evaluation model provided in the accelerator-based
boron neutron capture therapy system employing a solid-state lithium target. Sci. Rep.
11(1): 8090 (2021)

The Best Presentation Award of the 17th annual Congress on Japanese Society of
Neutron Capture Therapy

Optimization of dose calculation algorithm for BNCT by a
combination of Monte Carlo and superposition methods
Mai Nojiri, et al.
Department of Nuclear Engineering,
Graduate School of Engineering,
Kyoto University

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Recently, boron neutron capture therapy (BNCT) clinical treatment using an
accelerator-based neutron source has been provided for some cancers. Although theMonte Carlo (MC) method has been conventionally used as a dose calculation
algorithm for BNCT because of its high accuracy, it takes a few hours to obtain
distribution with high accuracy. Therefore, we are developing a hybrid algorithm
combining the superposition method and the MC method to accelerate the dose
calculation. In this algorithm, the neutron moderation process is calculated by the MC
method and the thermalization process is modeled as a kernel. For shortening the
calculation time, the thermalization process, which is time-consuming to calculate, isprepared as a kernel in advance, and the transport calculation by the MC method is
terminated when neutron energy reaches the lower limit (cutoff energy) to shift from themoderation process to the thermalization process. In this study, the calculation accuracyof the algorithm is experimentally verified, and the cutoff energy is optimized.
First, the content of the calculation using the hybrid algorithm is described as follows.
For the calculation of the kernel, a sufficiently large geometry filled with boric acidwater was used. The distribution of thermal neutron fluxes generated from a point
source with the same energy as the cutoff energy was derived in the geometry and usedas the kernel. Then, the flux distribution of neutrons that stop at the cutoff energy was
obtained by terminating the transport calculation by the MC method using the cut-off
function in the geometry that simulated the experiment as described below. The final
thermal neutron flux distribution was then derived by convolution-integration of the
distribution with the kernel.
Next, we describe a method for measuring thermal neutron flux using the gold
activation method. After a gold wire was placed on the central axis of a cubic phantom
filled with boric acid water, the phantom was irradiated by the epi-thermal neutron
beam in the heavy water neutron irradiation facility of the Kyoto University Research
Reactor. Thereafter, the radioactivity of the activated gold wire at each position wasmeasured by a gamma-ray detector, and the thermal neutron flux was obtained from thereaction rate of the gold wire.
Finally, we discuss the optimization of the cutoff energy. In this study, the cutoff
energies in the hybrid algorithm were set to 1, 2, 3, 4, 5, and 10 eV. The accuracy andtime were evaluated for each cutoff energy by comparing the thermal neutron
distribution obtained by the experiment with the calculations described above and bycomparing the calculation results with those by the full-energy MC method.
First, when the cutoff energy was set to 1 eV, the thermal neutron flux distribution
calculated by the hybrid algorithm was in good agreement with the experimental data at
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depths greater than 4 cm from the phantom surface. However, it overestimated theexperimental data in the shallower region, and the kernel should be improved. The
values calculated by the full-energy MC method were in good agreement with theexperimental values. In addition, when the cutoff energy was set to 2 eV, the same trendwith the reproduction shown when the cutoff energy was set to 1 eV. However, when
the cutoff energy was set to 3 eV or more, the difference from the values calculated by
the full-energy MC method became bigger. Furthermore, as the cutoff energy wasincreased, the calculation time per the same number of particles became shorter,
however, the difference became smaller. The convergence of the statistical uncertainty
was faster when the cutoff energy was set to 1 or 2 eV. These results suggested that 1 or
2 eV was the optimal cutoff energy.
In this study, the calculation accuracy of the hybrid algorithm was experimentally
verified. In addition, the accuracy and time of the hybrid algorithm were evaluated,while the cutoff energy was changed, to optimize the cutoff energy. As a result, we
confirmed that the calculation using the hybrid algorithm partially reproduces theexperimental results well, and the optimal cutoff energy was considered to be 1 or 2 eV.
In the future, we will develop the algorithm including the improvement of the kernel torealize more accurate and faster dose calculation.
Finally, I would like to express my sincere appreciation to Dr. Jun Itami, thePresident of the Congress; Dr. Minoru Suzuki, the President of the Society; all themembers of the Management Office of the 17th Annual Meeting of the Neutron Capture
Therapy Society; and the judges for selecting this presentation for the Best Presentation
Award, as well as to the following people for their kind cooperation in the NCT letter. I
would like to thank Dr. Mitsuko Masutani for giving me the opportunity to write thisarticle. I would also like to thank Dr. Hiroki Tanaka, Dr. Yoshinori Sakurai, Dr.
Takushi Takata, and Dr. Naonori Hu for their help in presenting this study.

The Best Presentation Award of the 17th annual Congress on Japanese Society of
Neutron Capture Therapy

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NCT letter (English version) Vol. 8 September, 2022
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Therapeutic effect of boron neutron capture therapy using a novel
boron compound targeting 18 kDa translocator protein (TSPO) on F98
rat model of malignant glioma
Hideki Kashiwagi, et al.
Department of Neurosurgery,
Kansai BNCT Medical Center,
Osaka Medical and Pharmaceutical University
Background: Malignant gliomas are intractable diseases that easily recur from residual
tumors even after complete surgical treatment and postoperative radiation chemotherapy
because of their invasive growth into the normal brain. Therefore, postoperative therapy
must be highly biologically targeted, as it must be able to select tumor cells that haveinvaded the normal brain. The efficacy of BNCT in the treatment of malignant gliomas
has been demonstrated, but complete cure has not yet been achieved, and thedevelopment of new boron compounds with different biological targeting properties
from BPA is desired. Recently, it has been demonstrated that TSPO-targeted tracer ishighly concentrated in malignant gliomas in positron emission tomography (PET) scanstargeting 18-kDa TSPO, and that recurrence of malignant gliomas is detected earlier
than in contrast-enhanced MRI scans. We have been conducting basic research on
TSPO-targeted BNCT using the F98 rat glioma model and reported the results obtained
thus far.
Methods: In vitro, we confirmed TSPO expression in F98, 9L, and C6 rat glioma cells.
BPA, BSH, and TSPO-targeted boron compounds were used to evaluate boron
accumulation in tumor cells in several malignant tumor cell lines. In F98 rat glioma
cells, after each boron compound exposure, neutron irradiation and the estimatedbiological effect coefficients were calculated.
In vivo, TSPO expression in tumors of the F98 rat brain tumor model was evaluated. In
the biodistribution evaluation, the intravenous administration (IV) of the TSPO target
boron compound did not give a sufficient intratumoral boron concentration. Therefore,
we chose convection-enhanced delivery (CED) administration, which is a local dosing
method. BPA was evaluated using IV.
In neutron irradiation experiments using the F98 rat glioma model, the following groups
were used: untreated control group, neutron irradiated control group, TSPO-targetedboron compound (CED) control group, BPA (IV) BNCT group, TSPO-targeted boron
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compound (CED) BNCT group, TSPO-targeted boron compound (CED)-BPA (IV)
BNCT group, TSPO-targeted boron compound (CED) BNCT group, and TSPO-targetedboron compound (CED)/BPA (IV) BNCT group, and the treatment efficacy wasevaluated by survival.
Result: Three rat glioma cells were found to express TSPO; in F98 rat glioma cells,boron accumulation in TSPO-targeted boron compound exposure was higher than thatin BPA or BSH exposure, and the estimated biological effect coefficient after neutron
irradiation was the highest among boron compounds.
In the F98 rat glioma model, TSPO was highly expressed in tumors 16-fold incontralateral normal brain tissue. Biodistribution evaluation showed that the TSPOtargeted boron compound (CED) group yielded more than twice the intratumor boron
concentration of the BPA (IV) group.
In neutron irradiation experiments using the F98 rat brain tumor model, both BNCTtreated groups showed a significant survival advantage over untreated controls; theTSPO-targeted boron compound (CED) BNCT group showed no significant survival
advantage over the BPA (IV) BNCT group; however, the BPA (IV) and TSPO-targetedboron compound (CED) BNCT group obtained a significant prolongation of survival
compared to the BPA (IV) BNCT group.
Conclusion: TSPO-targeted PET for malignant gliomas has already developed several
TSPO-targeted tracers to estimate patients suitable for BNCT; malignant gliomas withhigh expression of TSPO may be expected to take up TSPO-targeted boron compounds,
and TSPO-targeted boron compounds (CEDs) and BPA (IV) in combination with BPA(IV) are promising agents for BNCT for malignant gliomas, adding a cell-killing effectto cells that are inadequately treated by BNCT with BPA alone.

The Best Presentation Award of the 17th annual Congress on Japanese Society of
Neutron Capture Therapy

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Initial treatment experience of BNCT after insurance
coverage
Mariko Sato, et al.
Department of Radiation Oncology,
Southern Tohoku BNCT Research Center
Insurance reimbursement for BNCT for unresectable advanced or locally recurrent
head and neck cancer began in June 2020. We have performed 78 cases of BNCT in our
hospital in the following 1 year, and we present three cases as our initial experience.
All patients were treated using the clinical pathway and were hospitalized for 1 week
after irradiation to deal with acute adverse events. All treatments were performed withsitting immobilization and a maximum mucosal dose of 12 Gy-Eq prescription.
[Case 1] A female in her 80s, with left maxillary gingival cancer recurrence, SCC,
rT4aN0M0
The patient was referred to our department because of recurrence of right maxillary
gingival carcinoma after 70 Gy combined dynamic radiotherapy and postoperative left
maxillary gingival carcinoma after 24 Gy combined dynamic radiotherapy. Four hours
after irradiation, oral pain was noted and analgesics were started; however, the patient
was discharged on day 7 in good general condition. After discharge, oral mucositis (Gr.
3), epistaxis (Gr. 1), and alopecia appeared. The left maxillary tumor decreased in sizeon day 3, and MRI 1 month after irradiation showed that the mass had disappeared, andthe patient was considered to be CR. CR was maintained at the visit 9 months after
irradiation (Figure below).

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ISSN 2758-285X[Case 2] A female in her 50s, recurrent cancer of the right external auditory canal, SCC,
rT0N3bM0
The patient was referred to our department after chemoradiotherapy (80 Gy) andpostoperative recurrence, and MRI showed a soft shadow with contrast effect in theright interpharyngeal space and PET showed FDG accumulation with SUVmax 11.0.
BNCT was performed and GTV dose was 41.7 max, 26.8 min, and 33.6 Gy-Eq on
average. Right neck pain (Gr. 2) was noted 5 h after irradiation, including nausea (Gr. 3)
and decreased appetite (Gr. 3) from day 1, which were treated symptomatically. Her
symptoms gradually improved and she was discharged on day 7. After discharge, oral
mucositis (Gr. 2), decreased taste (Gr. 1), and alopecia appeared. Three months after
irradiation, SUVmax decreased to 2.8 on PET, and soft-tissue shadows disappeared on
MRI; hence, the patient was considered CR. However, a PET scan 6 months after
irradiation showed reappearance of FDG accumulation with an SUVmax of 6.9 at thesame site, and a diagnosis of recurrence was made.
[Case 3] A male in his 70s, recurrent tongue cancer, SCC, rT1N2aM0
The patient was referred to our department because of local recurrence of the tongueand left cervical lymph node after radiotherapy (70 Gy). The GTV dose was max 40.1,
min 20.8, mean 29.8 Gy-Eq. Nausea (Gr. 2) from day 1 and fatigue (Gr. 1) anddecreased appetite (Gr. 2) from day 2 were observed. On day 6, he developed fever andCT showed aspiration pneumonia; thus, antibiotics were initiated. On MRI at 3 months,
the metastatic lymph node had shrunk and was considered to be CR; 6 months later, thepatient was still in CR.
All of the above cases were recurrent cases, but responded well to BNCT. While somepatients showed rapid tumor shrinkage and maintained CR in a short period of timeafter irradiation, others developed recurrence after CR, requiring careful follow-up. In
the acute phase, adverse events such as pain, nausea, decreased appetite, and mucositis
were observed, and attention should also be paid to aspiration pneumonia, especially inelderly patients. However, most patients can be discharged from the hospital within 1
week after irradiation with symptomatic treatment.

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Neutron Capture Therapy

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NCT letter (English version) Vol. 8 September, 2022
ISSN 2758-285X

Footprint and future prospects of human resource
development activities by the Human Resources
Development Committee of the Japan Society for
Neutron Capture Therapy
Shin-ichiro Masunaga, et al.
Research Center for Boron Neutron Capture Therapy,
Osaka Prefecture University
Thank you very much for selecting us for the Best Presentation Award at the 17th
Annual Meeting of the Japanese Society for Neutron Capture Therapy. We haveupdated the contents of the abstracts presented at the conference.
The aim of this project is to provide human resources in medical physics for thecomprehensive development of basic research, clinical research, and medical
advancement of BNCT, targeting all creative researchers who are interested inparticipating in BNCT as staff, not only those with physics and engineering
backgrounds but also those with medical and pharmaceutical backgrounds. The BNCT
version of the Medical Physicists WG was established, consisting of committee
members. The WG has the following objectives: (1) organize seminars at the time of theannual meeting for specialized and interested researchers, (2) conduct social awarenessraising activities on BNCT, (3) discuss the special nature of BNCT work and the ideal
educational organization, (4) discuss the knowledge that NCT medical physicists(tentative name) and NCT medical physicists (tentative name) should acquire anddevelop their applied skills for optimizing NCT, and (5) discuss the role of NCT as a
medical physics professional and discuss the role of NCT as a medical science
profession. The activities of the committee included the development of guidelines. In
particular, with regard to human resource development, it was decided to develop
appropriate human resources by establishing an educational organization related to
NCT, to realize the sound development of NCT and contribute to the health and welfareof the public, and to establish the status of staff involved in the NCT (especially medical
physics-related staff) who are not stipulated by laws and regulations.
Thereafter, at the 9th-JSNCT (Japanese Society for Neutron Capture Therapy) and15th-ICNCT (International Conference on Neutron Capture Therapy) Society Executive
Committee Meeting (Tsukuba) in September 2012, it was decided that a workshop washeld at the next JSNCT Annual Conference and that a joint committee for "BNCT
Human Resource Development Study Group (tentative name)" with the Atomic Energy

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Society of Japan was organized. A proposal was made and approved to work towards
the establishment of a new committee.
Based on this approval, the following events were held: the1st BNCT Medical
Physics Workshop (September 8, 2013, two lectures [both physics], pre-registration of
47 people, on-site registration of three people, 10th-JSNCT-Okayama); the 2nd BNCT
Medical Physics Workshop (July 4, 2014, three lectures (biology, nuclear medicine,
pharmacy), pre-registration of 79 people, on-site registration of 32 people, 11thJSNCT-Osaka); and the 3rd BNCT Medical Physics Workshop (September 3, 2015,
three lectures (pharmacy, clinical, physics), pre-registration of 67 people, on-site
registration of 23 people, 12th- JSNCT-Kobe).
The BNCT version of the Medical Physicists WG has been performing practicalwork related to human resource development for BNCT, such as holding workshops atacademic conferences and sponsoring the BNCT workshop organized by the BNCT
Research Group at the Kyoto University Research Reactor Institute. The usefulness ofthese activities was evaluated, and this WG was re-established as the "BNCT Human
Resource Development Committee" (chaired by S. Masunaga) with nine new members
and 15 members in total at the annual meeting of the Japanese Society for Neutron
Capture Therapy in 2015. The main tasks of this committee are to train BNCT
specialists (BNCT physicians and BNCT physicists or engineers) to ensure the future
development of BNCT and to promote social awareness of BNCT as one of establishedmedical treatment modalities.
Thereafter, the following events were held by the "BNCT Human Resources
Development Committee": the 4th BNCT Workshop (August 5, 2016, three lectures(clinical, biology, pharmacy), pre-registration of 48 people, on-site registration of 24
people, 13th- JSNCT-Tokyo), the 5th BNCT Workshop (September 28, 2017, visited
South Tohoku BNCT Research Center, two lectures (About South Tohoku BNCT
Research Center, Accelerator BNCT), registration for participation of 89 people, 14thJSNCT-Koriyama, Fukushima), the 6th BNCT Workshop (August 31, 2018, two
lectures (both physics), pre-registration of 23 people, on-site registration of eightpeople, 15th- JSNCT-Sapporo, Hokkaido), the 7th BNCT Workshop (September 8,
2019, two lectures (physics, clinical), pre-registration of 16 people, on-site registrationof 10 people, 16th- JSNCT-Uji, Kyoto), the 8th BNCT Workshop (December 23-24,
2020, held online by Zoom, co-sponsored by the BNCT Promotion Council Human
Resources Development WG, with 36 participants, Kumatori, Osaka), and the 9th
BNCT Workshop (July 11, 2021, held online, 17th-JSNCT-Atami, symposium in theacademic conference in Shizuoka, with 78 participants).
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In order for Japan to lead the world in NCT, JSNCT will take the lead in the near
future; however, from the viewpoint of human resource development, it is necessary foreach research institute and medical center to conduct lectures and practical training
under the leadership of each facility that has its own neutron source. It is consideredessential. Furthermore, in the future, it would be desirable to implement human resource
development that organically links specialized NCT basic education and NCT clinicalpractice education, and to have an organization named "NCT Human Resource
Development Center" that coordinates the promotion of NCT and comprehensively
takes charge of tasks such as coordination among these centers and organization oftraining course.
Finally, I would like to thank the members of the Human Resource Development
Committee of the Japanese Society for Neutron Capture Therapy for their great support
and cooperation in conducting the activities of the committee, especially Dr. Takada
Takushi and Dr. Maruhashi Akira, who were members of the committee and co-authorsof the paper, and Dr. K. Kato, who was a member of the committee. We would like toexpress our deep appreciation to Dr. Hiroyuki Nakamura, the former President of theJapanese Society for Neutron Capture Therapy, and Dr. Minoru Suzuki, the present
President of the society. We also thank Dr. Jun Itami, the President of the 17th Annual
Meeting of the Japanese Society for Neutron Capture Therapy, who selected ourpresentation for the Best Presentation Award, and all the other related authors who took
their time to review the presentation. I would like to express my sincere gratitude to Dr.
Mitsuko Masutani, who is Chairman of the NCT letter editorial committee, for givingme the opportunity to write this article.

● Introduction of the articles<Pharmaceutical Science >Presented by Makoto Shirakawa
Department of Pharmaceutical Sciences, Fukuyama University
Title: Addressing the Biochemical Foundations of a Glucose-Based“Trojan Horse”-Strategy to Boron Neutron Capture Therapy:
From Chemical Synthesis to In Vitro Assessment
Authors：Jelena Matović, Juulia Järvinen, Helena C. Bland, Iris K. Sokka, Surachet
Imlimthan, Ruth Mateu Ferrando, Kristiina M. Huttunen, Juri Timonen, Sirpa
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Peräniemi, Olli Aitio, Anu J. Airaksinen, Mirkka Sarparanta, Mikael P. Johansson,
Jarkko Rautio, and Filip S. Ekholm
The source: Molecular Pharmaceutics, 17, 3885−3899 (2020)
https://doi.org/10.1021/acs.molpharmaceut.0c00630
Comments:
In 2020, NeuCure™, a medical device for BNCT and the boron drug Steboronin®
received marketing authorization for head and neck cancer and will enter the phase of
indication expansion. In BNCT, intracellular boron delivery via LAT-1, represented by
BPA, is often the focus, but tumor LAT-1 is not always highly expressed in some cells.
The CAL27 cell line used in this study has minimal BPA uptake (or sequestration), andstrategies other than LAT-1 are required to achieve a therapeutic effect with BNCT.
Some other carcinomas are known to be hepatoma (FLC-4 cell line) and breast cancer(MDA-MB-231-luc cell line) (T. Andoh, et. al, Appl. Radiat. Isot., 2020
Nov;165:109257., P. Wongthai., et. al, Cancer Sci. 2015 Mar; 106(3): 279-286.) As we
aim to expand the indications for BNCT in the future, boron delivery studies usingtransporters other than LAT-1 are of great significance, and this report targeting GLUT1
is expected to contribute to the advancement of BNCT. Jelena Matovic et al. also
reported a comparison of o-carbaborane binding sites in Glucoconjugate (Mol.
Pharmaceutics, 2021, 18, 285-304). We will wait for further in vivo studies such as thetherapeutic effects of neutron irradiation in animal models of carcinoma.
With your permission, my research group also reported glucoconjugate of sugar (Dglucose, D-galactose) and BSH at the annual meeting of the Glycoscience Society ofJapan in 2018. We have delayed the in vitro and in vivo evaluations due to our hecticschedule, but we are planning to reexamine the usefulness of the in vitro and in vivo
evaluations with reference to these reports.

<Physical Engineering >Presented by Kenichi Tanaka
Division of Advanced Science and Engineering,
Hiroshima University
Title：124Sb-Be photon-neutron source for BNCT: Is it possible?
Authors：Mohadeseh Golshanian, Ali Rajabi, Yaser Kasesaz
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The source: Nuclear Instruments and Methods in Physics Research A836 (2016) 182185
Comments:
The paper was about BNCT in a moderator-free beam forming section using 124SbBe, which can selectively produce neutrons in the 21-24 keV range, which is close to
the extra-thermal region, or is treated as the extra-thermal region in some facilities. I
had also considered the same point of view (Appl. Rad. Isot. 164 (2020)109227) before
and after the paper, but the γ rays from 124Sb require tens of cm of shielding foradequate quality. Therefore, although the beam forming part within 1 m is good, 1016
Bq order and 124Sb with large radioactivity are required. Because its half-life is about 60
days, procuring 124Sb will be a practical issue.
Neutron sources using isotopes have the advantage of being stable in time and aresmall in size and have a high degree of freedom in operation. In terms of licensing, italso has the advantage of an accelerator that it is easy to install in a hospital near thecity. In addition, the only thing that needs to be controlled is the positional relationshipbetween the source and the target, which has the advantage of a simple and trouble-freestructure. It is meaningful for the BNCT industry to sort out the conditions for using
isotopes-nuclear reactions as the third neutron source. This paper showed an approachto reduce the neutron loss by suppression of the generated neutron energy and reductionof moderator size.

<Medicine>
Presented by Mariko Sato
Department of Radiation Oncology,
Southern Tohoku BNCT Research Center
Title: Accelerator-based BNCT for patients with recurrent
glioblastoma: a multicenter phase II study
Authors： Shinji Kawabata, Minoru Suzuki, Katsumi Hirose, Hiroki Tanaka, Takahiro
Kato, Hiromi Goto, Yoshitaka Narita, Shin-Ichi Miyatake
The source: Neuro-Oncology Advances, Volume 3, Issue 1, January-December 2021,
vdab067, https://doi.org/10.1093/noajnl/vdab067

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Comments:.
Malignant gliomas, especially glioblastomas, have very poor prognosis and arecharacterized by high invasiveness and rapid proliferation. BNCT is expected to be a
new treatment option for glioblastoma because of its cell-selective nature and single
high-dose irradiation.
The 1-year overall survival (OS) and median OS shown in this study were bothsignificantly higher than the results of the JO22506 trial. Conversely, the 6-monthprogression-free survival (PFS) of 5.3% and mPFS of 0.9 months compare unfavorablywith the 33.9% and 3.3 months in JO22506, indicating a reversal. This can be expected
because many pseudo progressions after re-irradiation by BNCT were included in the
PD evaluation, and the limitation of the RANO criteria for efficacy evaluation isconsidered to be truly apparent.
Radiation brain necrosis occurs frequently after radiation therapy with TMZ, which isthe standard of care for malignant gliomas, with a reported frequency of 30% or more
(Alba A. Brandes et al. J Clin Oncol. 26:2192-2197, 2008). The RANO criteria (WenPY et al. J Clin Oncol. 28:1963-1972, 2010) are based on post-treatment outcomes. It
was developed to distinguish between pseudo-progression and recurrence, with PD
defined as the appearance of a new contrast-enhanced lesion outside the high-dose or
80% isodose range within 12 weeks after chemoradiotherapy. However, the RANO
criteria may not be appropriate for determining the efficacy of re-irradiation, and in the
future, at least a superimposition of the BNCT dose distribution chart and the dose
distribution chart of the previous treatment should be performed to determine theefficacy of re-irradiation. The accumulation of data on the evaluation using cumulative
doses after matching the data will be necessary.
It is also noteworthy that KPS was preserved after BNCT, which may indicate thebenefit of cell-selective BNCT. Although the majority of patients in this study had KPS> 80% at enrollment, only two of the 13 patients with evaluable KPS at 12 months after
BNCT had KPS < 50% (original article, Figure 3). The ability to maintain ADLs for a
relatively long period of time, even though many patients are receiving BEV due to PD,
represents a very significant treatment option for malignant gliomas.
This study shows that BNCT can be performed safely and effectively, especially inpatients with KPS > 80%, first recurrence, and relatively small tumor volume. It will be
important to establish a medical system that allows careful imaging follow-up after
standard treatment and prompt selection of BNCT when recurrence is diagnosed. With
very limited treatment options available, insurance reimbursement for BNCT for
malignant gliomas is anticipated.
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NCT letter (English version) Vol. 8 September, 2022
ISSN 2758-285X<Biology>
Presented by Natsuko Kondo
Institute for Integrated Radiation and Nuclear Science, Kyoto
University
Title: Evaluation of local, regional and abscopal effects of Boron
Neutron Capture Therapy (BNCT) combined withimmunotherapy in an ectopic colon cancer model
Authors：Trivillin VA, Langle YV, Palmieri MA, Pozzi ECC, Thorp SI, Benitez
Frydryk DN, Garabalino MA, Monti Hughes A, Curotto PM, Colombo LL,
Santa Cruz IS, Ramos PS, Itoiz ME, Argüelles C, Eiján AM, Schwint AE.
The source: Br J Radiol 2021; 94: 20210593.
Comments:
It has been reported that an abscopal effect occurs when immune checkpoint inhibitors
are combined with X-ray therapy, and we have heard that various clinical studies arebeing conducted. BCG is known as a local immunomodulator, but local and abscopal
effects have been reported when BCG is combined with low LET radiation. The direct
effect of DNA damage is stronger. The abscopal effect is thought to be caused by theactivation of immune signaling by damaged double-stranded DNA. In this paper, acolon cancer transplantation model was used, but translational studies that can beapplied to clinical practice, such as those with other cancer types or in combination with
BPA-BNCT with other immunotherapeutic drugs, are increasingly needed.

● Editorial Postscript
Mitsuko Masutani
Chief Editor of NCT letter
Professor, Graduate School of Biomedical Sciences, Nagasaki
University

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I would like to take this opportunity to congratulate all the members of the JapaneseSociety for Neutron Capture Therapy (JSCT). Under the guidance of the former editorin-chief, Dr. Itsuro Kato (Osaka University), Dr. Teruki Kageji (Tokushima Prefectural
Kaifu Hospital), and Dr. Minoru Suzuki (Kyoto University), and with the cooperation of
all the authors, the newly joined editorial board members, Dr. Toru Ando (Kobe Gakuin
University), Dr. Isao Murata (Osaka University), Dr. Kazuhiro Nakamura (Osaka
University), and Dr. Kazuhiro Kato (Osaka University), have been working hard to
improve the quality of our work. We also thank Dr. Kazuyo Igawa (Okayama
University), Dr. Katsumi Hirose (Minami-Tohoku BNCT Center), Dr. Tsubasa
Watanabe (Kyoto University), Dr. Shoji Imamichi (Nagasaki University), Dr. Shinji
Kawabata (Osaka Medical and Pharmaceutical University), Dr. Hiroki Tanaka (Kyoto
University), Dr. Koki Matsumoto (University of Tsukuba), Dr. Takahiro Nomoto(Tokyo Institute of Technology), Dr. Tetsushi Nakamura (National Cancer Center), Dr.
Tetsushi Nakamura (National Cancer Center), and Dr. Tetsuo Kurokawa (Osaka
University). We would like to thank Dr. Hiroshi Igaki (National Cancer Center) and Dr.
Teruhito Aihara (Osaka Medical and Pharmaceutical University) for their efforts inpublishing NCT letter No. 8.
The preface of this issue, "Prologue to the NCT letter No.8", is written by Dr. Minoru
Suzuki, President of NCT, which is about the participation of the Institute for Integrated
Radiation and Nuclear Science, Kyoto University in the joint research.
In the special feature article, Dr. Hiroki Tanaka of the Research Institute for
Composite Nuclear Science, Kyoto University, gave an overview of medical physics
research in BNCT; Dr. Tomoyuki Asano of Stella Pharma Corporation. talked about the
BPA preparation Steboronin®, which was approved in 2020, and Dr. Kazuhiro
Nakagawa of the University of Tokyo talked about the companionship of Dr. Minoru
Suzuki who has written an article on the BNCT indication expansion research foranimals.
The 17th Annual Meeting of the Japanese Society for Neutron Capture Therapy(JSNCT), which was postponed for 1 year due to the coronavirus pandemic, was heldwith the efforts of all concerned, and Dr. Jun Itami, the chairman of the organizing
committee, wrote a report on the meeting.
Dr. Koji Ono, the winner of the Commendation for Science and Technology by the
Minister of Education, Culture, Sports, Science and Technology, and the 10 winners of
the Best Presentation Award at the 17th Annual Meeting of the Japanese Society for
Neutron Capture Therapy have contributed to this issue. In the paper introduction, Dr.
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Makoto Shirakawa, Dr. Kenichi Tanaka, Dr. Mariko Sato, and Dr. Natsuko Kondo
explained recent noteworthy papers in an easy-to-understand manner.
The bulletin board contains information about the operation and activities of theJapanese Society for Neutron Capture Therapy (JSNCT), as well as updates to thewebsite.
The NCT letter editorial committee looks forward to the future activities of all themembers of the society and has started to prepare the next issue of the NCT letter,hoping to transmit your activities in real time as much as possible. We would like tofeature a wide range of articles on BNCT, including new projects and desired
submissions to the journal. We would be very grateful if you could send your frankopinions and information to the NCT letter editorial committee members.
Thank you very much for your cooperation.

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