NCT letter Vol. 5（English version）
March, 2019

NCT letter Issue 5 July 2018

Contents● Preface
Hiroyuki Nakamura
President of Japanese Society of Neutron Capture Therapy
Professor of the Institute of Innovative Research, Tokyo Institute of Technology● Special Articles
・As director of Kansai BNCT Medical Center, Osaka Medical College
Koji Ono
Director of Kansai BNCT Medical Center, Osaka Medical College

・Process of Including Japanese Particle Therapy into Insurance Coverage
Hideyuki Sakurai
Professor and Chairman
Department of Radiation Oncology, Faculty of Medicine, University of Tsukuba

・Ministry of Health, Labour and Welfare:Development of evaluation index of next-generation medical devices andregenerative products ―Development of the guideline on evaluating
BNCT―
Junichi Hiratsuka
WG Chairman of BNCT Evaluation Working Group (WG)
Professor, Department of Radiation Oncology, Kawasaki Medical School● Academic meeting Reports
・Report on the 14th Japanese Congress on Neutron Capture Therapy
President
Yoshihiro Takai
Director of the Southern Tohoku BNCT Research Center affiliated with Southern
Tohoku Research Institute for Neuroscience

・Report on the 9th Young Researchers BNCT Meeting (YBNCT9)
Yoshinori Sakurai

Chairman of the Organizing Committee

Associate Professor, Institute for Integrated Radiation and Nuclear Science, Kyoto
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NCT letter Issue 5 July 2018

University

・Notice on the 15th Japanese Congress on Neutron Capture Therapy
President
Masayori Ishikawa
Professor, Faculty of Health Sciences, Hokkaido University

・Notice on the 18th International Congress on Neutron Capture Therapy
President
Professor, PhD, National Tsing Hua University

Fong-In Chou

● Best Presentation Awards of 14th Japanese Congress on Neutron
Capture Therapy
・Accelerator-Based BNCT System at Nagoya University -Development ofa Sealed Li Target Sachiko Yoshihashi
Department of Energy Science and Engineering, Nagoya University

・Development of disulfide-bridged boron cluster maleimide (SSMID) andidentification of its conjugation site on albumin
Satomu Ishii, Shinichi Sato, Hiroyuki Nakamura
Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo
Institute of Technology

・The effective field size in depth allowed with the mucosal dose constraint
in head and neck BNCT
Katsumi Hirose1, Kazuhiro Arai1, Takaomi Harada1,
Tomoaki Motoyanagi1, Hidehiko Takeuchi 1, Ryohei Kato1,
Takahiro Kato1, Yoshihiro Takai1
1Southern Tohoku BNCT Research Center● Introduction of the articles

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NCT letter Issue 5 July 2018

1. <Physics >Title: Development of An Epi-thermal Neutron Field for Fundamental Researches
for BNCT with A DT Neutron Source
Authors:
Yuta Osawa,
Shoichi Imoto,
Sachie Kusaka,
Fuminobu Sato,
Masahiro Tanoshita and Isao Murata
The source: EPJ Web of Conferences 153, 04008, 2017https://doi.org/10.1051/epjconf/201715304008
Presented by Shingo Tamaki (Graduate School of Engineering, Osaka University)
2. <Physics >Title: BGO as a hybrid scintillator/Cherenkov radiator for cost effective
time-of-flight PET
Authors: S.E. Brunner and D.R. Schaart
The source: Physics in Medicine & Biology (2017) 62: 4421-4439
https://doi.org/10.1088/1361-6560/aa6a49
Presented by Tatsushi Shima and Ryoichi Seki (Research Center for Nuclear
Physics Osaka University)
3. <Pharmacology>
Title: Comparison of the pharmacokinetics between L-BPA and L-FBPA using thesame administration dose and protocol: a validation study for the theranostic
approach using [18F]-L-FBPA positron emission tomography in boron neutron capture
therapy
Authors: Tsubasa Watanabe, Yoshihide Hattori, Youichiro Ohta, Miki Ishimura,
Yosuke Nakagawa, Yu Sanada, Hiroki Tanaka, Satoshi Fukutani, Shin-ichiro
Masunaga, Masahiro Hiraoka, Koji Ono, Minoru Suzuki and Mitsunori Kirihata
The source: BMC Cancer (2016) 16:859
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100278/
Presented by Yoshihide Hattori (BNCT Research Center, Osaka prefecture
University)
4. <Biology>
Title: Abscopal effect of boron neutron capture therapy (BNCT): proof of principle inan experimental model of colon cancer
Authors: Verónica A. Trivillin, Emiliano C. C. Pozzi, Lucas L. Colombo, Silvia I.
Thorp, Marcela A. Garabalino, Andrea Monti Hughes, Sara J. González, Rubén O.
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NCT letter Issue 5 July 2018

Farías, Paula Curotto, Gustavo A. Santa Cruz, Daniel G. Carando, Amanda E.
Schwint
The sources: Radiation and Environmental Biophysics (2017) 56(4):365-375
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100278/
Presented by Yu Sanada (Particle Radiation Biology, Division of Radiation Life
Science, Kyoto University Institute for Integrated Radiation and Nuclear Science)● Editorial Postscript
Itsuro Kato
Chief Editor of NCT letter
Department of Oral and Maxillofacial Surgery II, Graduate School of Dentistry, Osaka
University

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NCT letter Issue 5 July 2018

On the occasion of the publication of NCT letter
issue No.5
Hiroyuki Nakamura
President
Japanese Society of Neutron Capture Therapy(Professor of the Institute of Innovative Research, Tokyo Institute ofTechnology)
Thanks to the efforts of Dr. Itsuro Kato, who has taken up the post of chairperson ofNCT letter editorial committee this year, and through cooperation with our colleagues,
the fifth issue of NCT letter was published. I take this opportunity to express my sincere
gratitude.
Currently clinical trials using the world’s first accelerator-based neutron sources forbrain tumors and for head and neck cancer are underway. This therapy will soon be put
into practical use. Also, the boron neutron capture therapy (BNCT) system (February2017) and boron agents “SPM-011” for BNCT (April 2017) are designated by the
Ministry of Health, Labour, and Welfare (MHLW) for “prioritized review system forinnovative medicines” to enable a rapid review for approval under the Pharmaceuticals
and Medical Devices Law, accelerating the process. After these designations,“development of guidance for the approval process of brand-new medical products andregenerative medicine products” and “development of guidelines for further
development and practical use of medical devices” for BNCT have been underway sincelast year in collaboration with MHLW and the Ministry of Economy, Trade and Industry(METI). As a feature article illustrates, A 2017 WG report for BNCT review wascompiled under the leadership of Dr. Junichi Hiratsuka, professor of Kawasaki Medical
University and is now on the National Institute of Health Sciences website*. Our fellow
members are invited to see the report. Also in JSNCT, a reorganized working group has
been developing, since September 2017, a treatment guidebook for accelerator-based
BPA-BNCT under the leadership of Dr. Minoru Suzuki, professor of Institute forIntegrated Radiation and Nuclear Science, Kyoto University, in cooperation withJapanese Society for Radiation Oncology and Japanese Society of Nuclear Medicine.
As a feature article illustrates, in January 2018, BNCT Medical Center was
established, attached to Osaka Medical College, under its first director Dr. Koji Ono,
professor emeritus of Kyoto University. As seen above, medical bases for BNCT are
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NCT letter Issue 5 July 2018steadily being developed, showing a clearer path for “treatment within the reach ofpatients” along with the progress of clinical trials.
Based on these situations, JSNCT implements BNCT safely, and addresses, inaddition to the existing BNCT human resource development program, a well-planned
training of certified medical practitioners with appropriate expertise by developing “newJSNCT qualification criteria for certified medical practitioners” and by introducing thequalification test since last year, in the aim of further expanded use of the therapy. With
the progression of phase II accelerator-based BNCT clinical trials for brain tumor andfor head and neck cancer, we are now approaching a critical stage toward the review forearly approval of BNCT. We ask for your understanding and cooperation in order that
our fellow members unite to realize “treatment within the reach of patients” under an
all-Japan cooperative approach.
*URL:http://dmd.nihs.go.jp/jisedai/bnct_for_public/

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As director of Kansai BNCT Medical Center,
Osaka Medical College
Koji Ono
Director
Kansai BNCT Medical Center, Osaka Medical College
On January 1st, 2018, I was appointed to director of Kansai BNCT Medical Center,
Osaka Medical College. I would like to take this occasion to convey my greetings to our
fellow members of the Japanese Society of Neutron Capture Therapy
As you all know well, a basic idea of BNCT was proposed by an American physician
in 1936, four years after the discovery of neutron. In the 1950s, after World War II,
when nuclear reactors began to be used not only for manufacturing and research of
nuclear weapons but also for research of peaceful purposes, clinical studies started in
the US. But honestly speaking, these studies ended up in failure, because they had
problems with boron agents and neutron beam. It was Japanese researchers including
the late Dr. Hatanaka and the late Dr. Mishima who have changed the situation. Though
the results of Dr. Hatanaka’s clinical study on brain tumor with BSH was attractive,
experts on radiology and neurosurgery didn’t appreciate these achievements, as they
lacked sufficient scientific information due to limitations associated with thedevelopmental stage of the study. Thinking back now, it was insufficient in basic
research as well. Today’s development in BNCT was not triggered by BSH but by thearrival of BPA. It is clear that, without research on BPA-based BNCT led by Dr.
Mishima, actual BNCT wouldn’t exist. They organized a comprehensive group of
researchers in the fields of nuclear engineering, boron chemistry, radiobiology, radiation
oncology, nuclear medicine and medical physics, as well as clinical dermatology. The
first clinical treatment using BPA of a patient with melanoma was carried out in 1987,
when I first got involved in BNCT. Then fate led me to become a professor of Kyoto
University Research Reactor Institute in 1991, where I carried responsibility for
research on BNCT. Fortunately, I have successfully brought together many researchers
who would pursue their research on BNCT using Kyoto University Research Reactor,
especially from the Kansai region. Joint studies are primarily led by researchers inradiation oncology, of course, neurosurgery, head and neck oncology, dermatology andnuclear medicine. With them, we have carried out many world first clinical trials whichlead research on BNCT. In the Kansai region, following this active research, researchers
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NCT letter Issue 5 July 2018

have commonly recognized the need to establish a hub in order to link achievements inbasic research in research centers including Kyoto University (Research Reactor
Institute), Osaka University and Osaka Prefecture University to clinical therapy.
Responding to that demand, we decided to establish a clinical hub within our university.
Under such circumstances, our BNCT facility was named Kansai BNCT Medical Centeras a hub where relevant researchers can jointly carry out clinical practices.
Our Center is equipped with a cyclotron-based neutron irradiation system jointly
developed by Kyoto University and Sumitomo Heavy Industries, Ltd. Our facilities are
the third ones after No. 1 in Kyoto University Research Reactor Institute (renamed
Institute for Integrated Radiation and Nuclear Science, Kyoto University in April 2018)
and No.2 in Southern Tohoku BNCT Research Center, all of which are the only systems
in the world allowing full-scale BNCT clinical practices. Currently we are conducting
phase II BNCT clinical trials with boron agents manufactured by Stella Pharma
Corporation. These trials have been at the final stage, so we expect that it will obtainapproval within few years to make itself available for clinical practices. Also, ourCenter is equipped with a small cyclotron for the short-lived RI production. Along withPET facilities transferred from the university hospital, we will launch nuclear medicine
services in June when the Center will start operating. In BNCT, it is necessary to
determine beforehand for each patient how selectively boron agents accumulate intumor cells and how highly they concentrate. As such we will prepare for PET with
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F-labeled boron agents in the near future, but first we are implementing approved
18
F-FDG PET. Osaka Medical College belongs to the same incorporated educational
institution as Osaka University of Pharmaceutical Sciences. So we hope to collaborate
in basic research on boron agents.
Though in recent years, finally, BNCT has been widely known, there are only a small
number of medical practitioners / researchers who know perfectly from the basics toclinical practices. A large gap between expectation and reality exists. The Centre, which
maintains close coordination with the three universities / centers of research, also plays
a role in developing human resources. Therefore we think we have great responsibility
in bridging this gap.
Incomparably deeper and broader in its scientific and interdisciplinary natures than
traditional radiation therapy (including proton radiation therapy and carbon-ion
radiotherapy), BNCT has some characteristics enabling reaching extraordinarily highprecision depending on our future research efforts. It has unlimited potential. I would
ask you for your research efforts and cooperation with the Center.

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NCT letter Issue 5 July 2018

Process for Japanese National Insurance
Coverage of Particle Therapy
Hideyuki Sakurai
Professor and Chairman
Department of Radiation Oncology, Faculty of Medicine, University ofTsukuba
Particle therapy, the clinical study of which had started in the late 1980s, has beenrecognized as an advanced medical treatment in 2000s. Just around the same time, its
numbers of facilities and patients have grown: there are approximately 4,500 cases ofparticle therapy a year at present (2,600 cases of proton therapy and 1,900 cases ofheavy ion therapy, which makes 2% of the total number of the patients in radiotherapy).
Currently, 12 facilities of proton therapy and 5 of heavy ion therapy are under operationin Japan. Although the implementation status and the treatment outcomes on particle
therapy, including prospective study, had been published as academic papers from eachfacility, there were only limited numbers of studies publicized as multi-institutional joint
research. Therefore, as for the insurance revision in FY 2016, Japanese Society for
Radiation Oncology, with assessment by external disease-specific committees,
conducted systematic reviews for childhood cancer, bone and soft tissue tumor, headand neck non-squamous carcinoma, liver cancer, and lung cancer as well as analyzed
the national treatment outcomes as a retrospective study. As a result, proton therapy forpediatric tumor and heavy ion therapy for unresectable bone and soft tissue tumor havebeen included in the insurance coverage as of medical fee revision in FY 2016.
After that, the clinical trials for the diseases and their conditions that should
particularly be focused on and evaluated, such as liver cell carcinoma and prostatecancer, have been performed as advanced medical treatment B. For advanced medical A,
the society consolidated the treatment plan for specific diseases, and all the treatment
facilities have uniformly been following the plan since FY 2016. By using thestandardized treatment plan for all the applicable patients in every facility nationwide
and by registering all the case data for analysis, the particle therapy has been carried out
in the system where it can be properly evaluated.
As for the revision in FY 2018, we appealed for inclusion of particle therapy on boneand soft tissue cancer and head & neck malignant tumor (excluding squamous
carcinoma in oral cavity, larynx, or pharynx) into the insurance coverage as sufficient
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NCT letter Issue 5 July 2018evidence of the effect was found, and it has been approved. We have also requested forinclusion of particle therapy for liver cancer, which was thought as a rare condition that
didn’t have any other radical treatment options to treat, yet it hasn’t been included in the
coverage at this revision. For prostate cancer, there is a variety of treatments that havereached maturity, and the methods that are safe and have high success rate on surgery
and on radiotherapy have been operated. In other word, it is the category difficult toprove the superiority of particle therapy among other methods of treatment. It, however,showed satisfactory records when the data was collected from multiple facilities in the
country. On the systematic review on particle therapy for prostate cancer, we found that
although there wasn’t any obvious evidence indicating its superiority among otheradvanced radiotherapies, a multitude of the treatment reports on particle therapy showed
at least equal to or better outcomes than that of other therapies. In addition, it is clearly
reducing radiation dosage affecting the surrounding area in fact. Meanwhile we wereconsidering that, upon the facts found in the systematic review, particle therapy forprostate cancer should be included in the insurance coverage as early as possible toprovide desirable quality of care, it has been approved at this revision in FY 2018.
Within a year and a half after the insurance revision in FY 2016, there have been 56
articles published on international journals (including 19 of multi-institutional studies),
15 articles contributed to ongoing publication, and 66 presentations in international
conferences regarding to clinical results (excluding of basic researches) of Japanesetreatment facilities for particle therapy. It can be said that it is the endeavor of thetreatment facilities that led to this achievement that particle therapy for those diseases
are now acknowledged under the insurance coverage.

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Ministry of Health, Labour and Welfare:Development of evaluation index of
next-generation medical devices and regenerative
products―Development of the guideline on
evaluating BNCT―
Junichi Hiratsuka
WG Chairman of BNCT Evaluation Working Group (WG)
Professor, Department of Radiation Oncology, Kawasaki Medical School
I was requested by editorial committee to write an article about the activity of “BNCT
Assessment WG” and I would like to take this opportunity to explain it here in this NCT
letter.
The objective of our activity is to develop an evaluation index to be used when
PMDA assessing an accelerator-based BNCT device.
To make the reactor-based BNCT a common (standard) treatment, developing theaccelerator-based BNCT device, which can be installed in medical institutions in urban
area, is imperative. Currently, a clinical trial using world’s first accelerator neutron
source for BNCT is conducted for brain tumors and head and neck cancer and it iscoming close to practical utilization. Furthermore, the Ministry of Health, Labour andWelfare designated neutron generator and boron carrier for the Sakigake Designation
Scheme in 2017 and this will accelerate the movement of introducing the accelerator
neutron source for BNCT into a clinical practice even more.
Considering this situation, it is an urgent issue to create an evaluation index forapproval process for the acceleration-based BNCT device, which will be entered in themarket in the future, even at the stage of development in order to accelerate the approval
process on medical devices by PMDA. In other words, the evaluation index, whichshould be check by PMDA when evaluating BNCT device, is needs to be developed
immediately.
In this WG, we established four task forces (TF) and investigated research anddevelopment, usage trends, and related standards on an accelerator for BNCT in andoutside of Japan. We also developed the evaluation index to measure its effectiveness,safety, quality appropriately and promptly based on scientific evidences.

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Summaries of four TFs discussed lately are listed below.
Full content of the report can be found on the “National Institute of Health Sciences(Evaluation WG office) website.

TF1 Investigation Report(Research on development and usage trends in and outside of Japan and safety andperformance criteria in non-clinical studies)
Hiroaki Kumada (Leader: University of Tsukuba) Masayori Ishikawa (Hokkaido
University) Minoru Suzuki (Kyoto University) Hiroki Tanaka (Kyoto University)
Satoshi Nakamura (National Cancer Center Japan)
We reviewed criteria required in non-clinical studies for regulatory approval for theaccelerate-based BNCT device. BNCT using neutron radiation is categorized asradiation therapy. However, BNCT differs significantly from x-ray therapy or particle
radiotherapy as it uses boron agents and neutron radiation. Thus, it is necessary to takeits specificity into account when reviewing criteria for non-clinical studies. Also,
methods to generate neutron radiation varies from the previous nuclear reactor to theaccelerator method or the method using nuclear fusion reaction. In this review, therefore,
we first extracted the difference between the previous external radiation method and
BNCT and the specificity of BNCT and set the scope of this review. Because BNCT has
complex mechanism and uses various types of neutron sources, some parts such asmeasurement techniques are undeveloped. For that reason, we examined technicalissues and limitations and reviewed risk management. Considering these points,
following criteria are established for non-clinical studies for BNCT device.
1. Differences between the previous external radiation method and BNCT, specificity of
BNCT
2. Development status of BNCT device and scope
3. Current technical limitations and restrictions on BNCT
4. Risk management
5. Non-clinical studies proposal

TF2 Investigation Report(Safety and performance criteria in clinical studies)
Minoru Suzuki (Leader: Kyoto University), Hiroshi Igaki (National Cancer Center
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NCT letter Issue 5 July 2018

Japan), Shinji Kawabata (Osaka Medical College), Hideyuki Sakurai (University ofTsukuba)
BNCT system built from proton beam accelerator (including cyclotron) or target
materials, which are needed for neutron generation, need to be approved in accordancewith the law concerning quality, effectiveness, and securing safety (Pharmaceuticals andMedical Devices Law) for practical use. However, because the technology andtherapeutic principle of BNCT does not exist in the current clinical expertise, from thestand point of effectiveness and securing safety for humans, outcome of clinical studies(meeting practice standard for clinical studies for pharmaceuticals and medical devices(GCP: Good Clinical Practice)) needed to be clarified in an application for approval.
Because pharmaceuticals (boron agents) and medical devices (neutron generator andirradiation device) are used in BNCT, it is important to plan and design a clinical trialthat reflects performance of each items when implementing clinical trials. Also, setting
clinical criteria reflecting performance is necessary. In this report, matters which requirecautions when implementing clinical trials are established.

TF3 Investigation Report(Radiological safety)
Yoshitomo Uwamino (Leader: RIKEN), Mitsuru Uesaka (The University of Tokyo),Shunsuke Yonai (National Institutes for Quantum and Radiological Science andTechnology), Akiko Hachisuka (National Institute of Health Sciences)
Radiological safety related to following items are discussed and reported.
1. Safety of facilities
2. Safety of neutron generating target device
3. Radiation exposure of patients: normal tissues exposure
4. Radiation exposure of healthcare professionals
5. Radiation exposure of individuals who handles the accelerator and targets
6. Actions in response to additional measures for radiological protection

T4 Investigation Report(Fundamental information for development and usage status, safety andperformance of boron agents)
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Hiroyuki Nakamura (Tokyo Institute of Technology)
Following items are reported.
1. Development and usages status of boron agents for BNCT
2. Need for boron element
3. Boron agents for BNCT used in the clinical study.
4. Development status of boron agents for BNCTThe evaluation index is targeting the device which its technology development is
prominent and only shows the subjects that are considered important at this moment. It
is subject to revision due to further technological innovation or new findings and does
not have bindings on application for approval. When evaluating products targeted by theevaluation index, it is required to understand the characteristics of each product andrespond flexibly based on scientific rationality. I also would like to add that otherrelated guidelines inside and outside of the country should be used and as reference.

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NCT letter Issue 5 July 2018

The 14th Congress on Neutron Capture Therapy

Chairman Yoshihiro Takai
Director of the Southern Tohoku BNCT Research Center
affiliated with Southern Tohoku Research Institute for
Neuroscience
The 14th Congress on Neutron Capture Therapy was held on Friday 29th September
and Saturday 30th September 2017 at Koriyama View Hotel Annex located in Koriyama
City, Fukushima Prefecture. The 5th BNCT Workshop (hosted by the Human Resource
Development Committee of the Japanese Society of Neutron Capture Therapy andsupported by this Congress) was held on 28th September, the day before the Congress,
together with a facility tour of Southern Tohoku BNCT Research Center. Eighty-nine
participants observed the world’s first BNCT therapy facility annexed to a general
hospital.
Two hundred fifty-one participants (103 regular members, 129 non-members, 19
students) joined the Congressand hot discussions were madein the fields of physics,
pharmacy & chemistry, clinicalmedicine & technology, andbiology. Thank you for yourparticipation.
Symposium
The accelerator BNCT system which is installable in hospitals was introduced in
Kyoto University Research Reactor Institute and Southern Tohoku BNCT ResearchCenter. Phase II Clinical Study has been conducted for malignant brain tumor at both
institutions since January 2016 and for recurrent and advanced head and neck cancer atSouthern Tohoku BNCT Research Center since July 2016. Regulatory application is
expected to be made in the near future. Having proceeded to such stage of development,
it is important for Japan to transmit information on clinical techniques of the accelerator
BNCT in order to have it recognized as a clinical therapy and to have it used worldwide.
For this purpose, the theme of this Congress was decided as “Issues toward the15

NCT letter Issue 5 July 2018

realization of clinical practices using accelerator-based BNCT”. Various discussions
were made mainly at the symposium concerning issues that may be solved by analysesof a large amount of clinically obtained data, physico-technical issues including setup ofpatients and issues on nursing for BNCT. The future direction to be taken from the
aspect of clinical medicine has been indicated. Moreover, the issue on radiation
exposure by BNCT was raised and the low exposure dose of BNCT compared to theconventional therapies such as X-ray therapy was reported.
The numbers of the lecture themes were 57 intotal, consisting of 1 special lecture, 1
educational lecture, 2 symposium lectures (6lecturers, 1 discussant), 2 luncheon seminar
lectures, 36 general presentations and 15 poster
sessions.
Poster Session
Contribution of Japan in the BNCT research and new analysis of the CBE factor,
presented by the invited lecturers, were very meaningful for all researchers engaged in
BNCT. General presentations were made in 4 fields; physics, pharmacology &chemistry, clinical medicine & technology, and biology. Development of equipment,
new drugs, technological improvement at clinical sites and biological issues on theeffectiveness of BNCT were presented, each showing further progress compared to lastyear. These presentations, including questions and answers, ended in a great success.
Public program was jointly organized with the Association for Nuclear Technology in
Medicine. Two lectures and one special lecture were held. Dr. Katsumi Hirose of theSouthern Tohoku BNCT Research Center and Dr. Masao Murakami of the Proton
Therapy Center presented clear expositions of
BNCT and proton therapy. Mr. Shuntaro
Torigoe, a journalist, was invited for a special
lecture with the theme “Living with Cancer”.
310 citizens listened to the lecture with deep
concern and many questions were raised.
Party after the Congress
Finally, I would like to express my appreciation to Prof. Hiroyuki Nakamura, the16

NCT letter Issue 5 July 2018

President of the Japanese Society of Neutron Capture Therapy, Prof. Hironobu Yanagie,
the Chairman of the previous Congress and the members of the Society for their various
fruitful advice, and to the staff of the management secretariat for their valuable efforts
made for the management and practical business for this Congress.
For further details of this Congress, please refer to the “Information on Nuclear
Technology in Medicine” Vol. 18 issued by the Association for Nuclear Technology in
Medicine.

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Report on the 9th Young Researchers BNCT Meeting(YBNCT9)
Yoshinori Sakurai
Chairman of the Organizing Committee
Associate Professor, Institute for Integrated Radiation and
Nuclear Science, Kyoto University
The 9th Young Researchers BNCT Meeting (YBNCT9) was held for 3 days from
November 13th to 15th 2017 or for 7 days from November 11th to 17th including thetightly-scheduled “Dan-Gun (bullet) tour”. The Young Researchers BNCT Meeting(YBNCT) has been held every 2 years since 1999 between the International Congress
on Neutron Capture Therapy (ICNCT), mainly aiming at young researchers engaged invarious researches in relation with BNCT. The 9th Meeting was the first meeting held inJapan in 18 years of its history. It was operated in the “all-Japan” system with the Kyoto
University Research Reactor Institute(KURRI) (current name; Institute for Integrated
Radiation and Nuclear Science, Kyoto University) as a meeting steward.
On the 1st day, in November 11th, the observation tour of the Southern Tohoku
BNCT Research Center was held as the first stage of the “Dan-Gun tour” which was the
big attraction of this meeting. Although there were concerns that foreign participants
might feel that it was a vault to a challenging place, 17 participants joined the tour
which was as generally planned. We would like to express our appreciation to Dr.
Katsumi Hirose, Dr. Takaomi Harada and other staff of the Research Center.
On the 2nd day, in November 12th, the observation tour of the Kyoto University
Research Reactor Institute was held as the second stage of the “Dan-Gun tour” with 41
participants. At the same time a “Workshop on International Joint Research” was held
and active discussions were made on the international joint research using Kyoto
University Research Reactor (KUR). After the workshop, the participants moved to
Kyoto by a chartered bus with the staff of the Institute. That night, the members
deepened friendship at a Japanese bar restaurant near Kyoto Station.
On the 3rd to 5th day, from November 13th to 15th, the Meeting was held at the
Obaku Plaza on Uji Campus of Kyoto University. Since this Meeting is mainly foryoung researchers, the program was entirely composed of giving research presentations
with no special lecture. A total of 94 presentations were made comprising 53 oralpresentations and 41 poster presentations. It was a successful meeting beyond
expectation. A total of 161 participants from 16 countries joined the meeting during
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NCT letter Issue 5 July 2018

these three days. It is assumed to be the record number of participants among theprevious meetings. Almost half of them were from overseas. I would like to thank Ms.
Reiko Matsuoka for her help in the reception.
We lined up a number of awards to encourage young researchers this time. 16 young
researchers were awarded; 5 for the Kent Riley Award which was newly established in
the last meeting, 5 for the Best Presentation Award and 6 for the Best Poster
Presentation Award. Moreover, apart from the awards, 7 young researchers were offered
travel grants. We extend our gratitude to the Kyoto University Foundation, the JapaneseSociety of Neutron Capture Therapy and other enterprises for their support for theseawards and travel grants.
On the 6th day, in November 16th, the observation tour of the National Cancer Center
Japan was held as the third stage of the “Dan-Gun tour”. We needed to conduct the tour
smoothly since we only had time allowed for the tour at lunch break from 12:00 to
13:00, therefore, two graduate students from the Graduate School ofEngineering, Kyoto University were sent as tour conductors for the third and fourthstages of the “Dan-Gun tour”. 45 participants, which was the largest number ofparticipants among the stages of the “Dan-Gun tour”, joined this observation tour. We
extend our gratitude to Dr. Hiroshi Igaki, Dr. Satoshi Nakamura and the staff of theCenter.
On the 7th day, in November 17th, the observation tour of the Ibaraki Quantum BeamResearch Center was held as the fourth stage of the “Dan-Gun tour”. 34 participantsjoined the tour. We extend our gratitude to Prof. Hiroaki Kumada and Prof. Teruhito
Aihara of Tsukuba University and the staff of the Center. We also appreciate Mr.
Naonori Ko and Mr. Keita Okazaki, the graduate students of Kyoto University, for theirsupport as tour conductors. I remember I realized the completion of the YBNCT9 when
Prof. Kumada reported me that the tour had ended.
We got cooperation from many people for holding the YBNCT9 and would like toreiterate our gratitude to the staff of the YBNCT9 Organizing Committee. We extend
our appreciation especially to Ms. Maki Nakatani of BNCT Promotion Office in Kyoto
University Research Reactor Institute, for her dedication to the general clerical work,venue establishment and reception work for the Meeting. Finally, we would like toexpress our sincere gratitude to all participants, especially to participants from overseas.
For those who fully participated the scheduled events, the whole travel distance during
the seven days in Japan were about 1,500 km at the shortest, starting and ending at
Narita; Narita→Koriyama→Kumatori→Uji→Tokyo→Tsukuba→Narita. Thank you allfor your participation.
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“Bullet tour” 2nd stage-Kyoto Univ.
Research Reactor Institute

Deepening friendship at Kyoto

Group photo of the MeetingAward ceremony

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NCT letter Issue 5 July 2018

Notice on the 15th Congress on Neutron Capture
Therapy

President Masayori Ishikawa
Professor, Faculty of Health Sciences, Hokkaido University“The 15th Congress on Neutron Capture Therapy” will be held at the Hokkaido
University Conference Hall on September 1st (Sat) and 2nd (Sun) 2018. This is the 15th
Congress since the foundation of the research meeting and it is my great honor to beappointed a chairman of the Congress when its scale is growing gradually and steadily.
All the staff of the Organizing Committee is proceeding with the preparations to makethe Congress fruitful and successful, with reference to the previous congresses.
Boron Neutron Capture Therapy (BNCT) is now making a transition from irradiation
based on research reactor to irradiation using accelerator-based neutron source and that
may enable much more facilities to provide BNCT. The quality of the therapy has been
secured by choosing the best therapy through trial and error for each case, however, toenable equivalent therapy to be provided by the facilities which are assumed to increasein the future, it is essential to share the consensus on the base technology and toestablish the process of quality management/quality assurance of BNCT.
For that purpose, the 15th Congress will be held with the theme “Establishing theBase Technology to Improve the Quality of the Therapy”. BNCT is generally
categorized into three fields; medicine & biology, physics & engineering and chemistry& pharmacology. The established technologies and technologies that still need to be
discussed are mixed in each field. In the field of medicine & biology, careful discussion
is necessary on prescribed dose and normal tissue tolerance dose in association withexpanding the applicable diseases and devising the irradiation methods. In the field ofphysics & engineering, the appearance of irradiation facilities using accelerator-based
neutron source raises the need to establish technologies for defining and controlling
precise neutron irradiation levels. In the field of chemistry & pharmacology,
establishment of methods for quantitative rating of drug accumulation in tumors are thecritical issue, as well as the new drug development. In the 15th Congress, the program isorganized to enable enough time for discussions, including symposiums to discuss theabove mentioned issues, luncheon seminars to introduce new technologies and general
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NCT letter Issue 5 July 2018lectures in oral and postal forms. We expect active discussions by all participants. The
6th BNCT Workshop is also scheduled at the same venue on the day before the 15th
Congress.
The Congress will take place in Hokkaido University surrounded by rich nature.
Taking a walk in the campus may give you a refreshing feeling. We hope you enjoy thecool climate of Sapporo in the season when it may still be hot outside Hokkaido.
Sapporo is also rich in foodstuffs, so have a nice time with delicious foods during yourstay. We welcome you all and hope the Congress would be fruitful and successful.
Website URL: http://jsnct15.unim.jp

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The Best Presentation Award of the 14 th annual meeting of Japansociety for Neutron Capture Therapy
Accelerator-Based BNCT System
University- Development of a Sealed Li Target -atNagoyaSachiko Yoshihashi
Department of Energy Science and Engineering, Nagoya University
1. Introduction
An accelerator-based neutron source for BNCT is currently under development with a
combination of a DC accelerator and a compact sealed lithium (Li)target in Nagoya
University. Proton beam of 2.8 MeV and 15 mA (42 kW) ejected from a Dynamitron
accelerator will be injected to the Li target. Low energy proton beam incident of Li
target is one of the most suitable reactions for accelerator-based BNCT system, becausea sufficient flux and good quality of epi-thermal neuron beam can be obtained by using
a compact beam shaping assembly (BSA), and also the radiation exposure of medical
staffs can be reduced by lowering the activation of accelerator facility. However,metallic Li has several difficulties in chemical properties (low melting point, highchemical activity, and Be-7 production) as target materials. For resolving those issues,
we are developing a compact sealed Li target.
2. The progress of accelerator and beamline
In August 2017, we completed the installation of the beamline and confirmed the proton
beam with an energy of 2.8 MeV and a current of 2 mA can be transmitted to the target
position. Beam profile was obtained using a beam profile monitor installed on thebeamline and the stability of the proton beam was confirmed.
3. Development of sealed Li target
A thin Li layer (0.14 mm) is set on the embossed structure of a tantalum plate andcovered by thin titanium (Ti) alloy foil to confine liquid Li and radioisotopes (Be-7 ortritium) in the target. A proton beam of 42 kW will irradiate the Li through the Ti foil
(irradiation area: 80 x 80 mm2). A new cooling system with a strong turbulent flow inthe water channels induced by the V-shaped staggered rib structure was developed toremove the high heat load from the target. Heat removal experiments were performed
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NCT letter Issue 5 July 2018by utilizing an electron beam in the Active Cooling Test Stand 2 (ACT2) at National
Institute for Fusion Science (NIFS). In the experiments, we had confirmed the new
cooling system could remove the high heat load of 42 kW, efficiently. Based on the
result of the heat removal test, we had estimated the surface temperature of the Ti is
about 160 degree C, when the heat load of the proton beam is 6.6 MW/m2. In theestimation, we assumed a good heat transfer rate between the Ti foil, the Li metal andthe target base plate, based on a mockup test about the wettability between those metals.
4. Conclusion
In the next step, we will confirm the endurance of the sealed Li target of the proton
beam and prepare for the In-vitro test.

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NCT letter Issue 5 July 2018

The Best Presentation Award of the 14 th annual meeting of Japansociety for Neutron Capture Therapy
Title Development of disulfide-bridged boron cluster
maleimide (SSMID) and identification of its
conjugation site on albumin
Satomu Ishii, Shinichi Sato, Hiroyuki Nakamura
Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo
Institute of Technology
For the treatment of cancer where p-boronophenylalanine (BPA) does not accumulate
and is not effective for BNCT, development of methods for selectively and efficiently
delivering boron to various types of cancer based on the different uptake mechanism
from BPA is required. We focused on serum albumin which is known to selectively
accumulate in tumors using the enhanced permeability and retention (EPR) effect as aboron delivery carrier and has developed maleimide-functionalized closo-dodecaborate(MID) as a reagent for binding boron cluster to albumin. Boron cluster-conjugatedalbumin can be readily prepared using MID. When MID-conjugated albumin was
administered to tumor bearing mice, high efficiency boron delivery to tumor tissues wasachieved 12 hours after drug administration in the 30 mg [B] / kg administration group.1
It is generally known that the maleimide group selectively binds only with free cysteine
residues under physiological conditions. Although albumin has only one free cysteine
residue, Cys34, western blotting and inductively coupled plasma (ICP) analysis
revealed that multiple MID molecules bind to one molecule of albumin. These results
suggested that MID may bind to amino acid residues other than Cys34. Therefore,
MS/MS analysis was attempted in order to identify the modified site of MID. However,
due to the negative charge of the boron ion cluster, it was difficult to identify themodified site.
For the purpose of identifying the modified site of MID in this study, a compound
named SSMID, having a disulfide bond in the linker structure of MID, was newly
synthesized. By reducing the disulfide bond in SSMID-conjugated albumin, thenegatively charged cluster was cleaved and an ionizable peptide derived from the
SSMIDbindingsite
wereobtained.
MS/MS
analysisbyliquidchromatography-matrix-assisted laser desorption/ionization mass spectrometry(LC-MALDI) revealed that SSMID binds to at least three amino acid residues besides
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the free cysteine residue (Cys 34). From the information on identified binding sites, it
was revealed that MID binds to drug binding sites in albumin, promoting the formationof bonds with amino acid residues in proximity to drug binding sites.
Finally, we would like to thank Prof. Yoshihiro Takai, the chairperson of the 14th Japan
BNCT conference, the secretariats and the referee of this best presentation award. We
also would like to thank Dr. Itsuro Kato who gave us the opportunity to publish ourfindings in NCT Letter.
【reference】
1．S. Kikuchi, D. Kanoh, S. Sato, Y. Sakurai, M. Suzuki, H. Nakamura, J. Control.
Release 2016, 237, 160–167.

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The Best Presentation Award of the 14th annual meeting of Japan society
for Neutron Capture Therapy
The effective field size in depth allowed with themucosal dose constraint in head and neck BNCT
Katsumi Hirose1, Kazuhiro Arai1, Takaomi Harada1,
Tomoaki Motoyanagi1, Hidehiko Takeuchi 1, Ryohei Kato1,
Takahiro Kato1, Yoshihiro Takai1
1Southern Tohoku BNCT Research CenterIn boron neutron capture therapy, thermal neutron flux peaks at a depth of about 2 cm
and then decreases according to the depth of the tissues. Therefore, the field withtreatable level of neutron flux is limiting. Especially in the head and neck cancer,
treatment time and prescribed dose are often passively determined depending on thetolerable dose of the oral and pharyngeal mucosa. However, the anatomical structure of
mucosa is very complicated and there is a risk that delineation of mucosa will be
performed with less reproducibility. As a result, the validity of adopting mucosal dose asa prescribe dose is missing. However, there is no consensus of methodology fordelineating mucosa, and furthermore, the detailed way of delineation has not beenpresented in reported clinical trials. Therefore, in this study, we investigated the impactof tumor localization on treatable field size of BNCT based on dose prescription
passively defined by mucosal tolerable dose in the patients with a head and neck cancer.
Fourteen patients with newly diagnosed/recurrent head and neck cancer who
received prior radiotherapy were enrolled. Treatment plan for sitting-positioned BNCT
with CT datasets taken at past treatment plan were re-performed assuming treatment for
tumor recurrence. Using treatment planning system SERA, delineation of organs
including oral and pharyngeal mucosa was performed on past treatment plan CT
integrated with MRI GdT1-weighted images or STIR images. Patients were fixed withposition optimized with neutron beam setting. Prescribed dose for tumor was calculated
as the maximal dose of mucosa was given 12 Gy-Eq with adoption of a fixed T/B ratioof boron as 3.5 and a blood boron concentration as 25 ppm. Tumor dose distribution on
the beam axis was decided and the region with ≥20 Gy-Eq as tumor dose was regarded
as treatable field, and depth and width of the field size were evaluated.
The results of evaluation of the treatable field size were depicted in Figure 1.
Oral cavity cancers had short treatment time and resulting tendency with field size
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narrowing. On the other hand, tumors located apart from oral cavity, such as orbital,
parotid gland, maxillary, and nasal cavity cancer had comparative wide treatable fieldsize.
In this investigation, tolerance dose of mucosa was set as 12 Gy-Eq. It shouldbe elucidated how to define the delineation of mucosa in past clinical studies of BNCT
and the true tolerable dose for mucosa should be re-evaluated based on a newly
standardized delineation method of mucosa from the past clinical studies.

Finally, I would like to express my gratitude to Dr. Itsuro Kato for giving me
an opportunity to introduce my presentation at this Newsletter.

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Article-introduction of the topic

1. <Physics >Title: Development of An Epi-thermal Neutron Field for
Fundamental Researches for BNCT with A DT Neutron Source
Authors:
Yuta Osawa,
Shoichi Imoto,
Sachie Kusaka,
Fuminobu Sato, Masahiro Tanoshita and Isao Murata
The source: EPJ Web of Conferences 153, 04008, 2017
http://www.epj-conferences.org/articles/epjconf/pdf/2017/22/e
pjconf_icrs2017_04008.pdf
Presented by Shingo Tamaki (Graduate School of Engineering, Osaka University)

2. <Physics >Title: BGO as a hybrid scintillator/Cherenkov radiator for costeffective time-of-flight PET
Authors: S.E. Brunner and D.R. Schaart
The source: Physics in Medicine & Biology (2017) 62:
4421-4439
http://iopscience.iop.org/article/10.1088/1361-6560/aa6a49/pdf
Presented by Tatsushi Shima and Ryoichi Seki (ResearchCenter for Nuclear Physics Osaka University)

3. <Pharmacology>
Title: Comparison of the pharmacokinetics between L-BPA and L-FBPA using thesame administration dose and protocol: a validation study for the theranostic
approach using [18F]-L-FBPA positron emission tomography in boron neutron capture
therapy
Authors: Tsubasa Watanabe, Yoshihide Hattori, Youichiro Ohta, Miki Ishimura,
Yosuke Nakagawa, Yu Sanada, Hiroki Tanaka, Satoshi Fukutani,
Shin-ichiro Masunaga, Masahiro Hiraoka, Koji Ono, Minoru
Suzuki and Mitsunori Kirihata
The source: BMC Cancer (2016) 16:859
https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/218
460/1/s12885-016-2913-x.pdf
Presented by Yoshihide Hattori (BNCT Research Center,
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Osaka prefecture University)

4. <Biology>
Title: Abscopal effect of boron neutron capture therapy (BNCT):
proof of principle in an experimental model of colon cancer
Authors: Verónica A. Trivillin, Emiliano C. C. Pozzi, Lucas L.
Colombo, Silvia I. Thorp, Marcela A. Garabalino, Andrea Monti
Hughes, Sara J. González, Rubén O. Farías, Paula Curotto,
Gustavo A. Santa Cruz, Daniel G. Carando, Amanda E. Schwint
The sources: Radiation and Environmental Biophysics (2017)
56(4):365-375
https://link.springer.com/content/pdf/10.1007%2Fs00411-017-0704-7.pdf
Presented by Yu Sanada (Particle Radiation Biology, Division of Radiation Life
Science, Kyoto University Institute for Integrated Radiation and Nuclear Science)

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Editor’s Postscript

On the Publication of NCT letter Vol. 5

Chief Editor of NCT letter
Itsuro Kato
The 2nd Department of Maxillofacial Surgery, Graduate School of
Dentistry, Osaka University

I would like to take this opportunity to wish every success to all of the members of
the Japanese Society of Neutron Capture Therapy. I took over the role of the chief editor
from Dr. Teruyoshi Kageji at the board meeting of the Society held on September 30th,
2017. The members I worked with for the NCT letter were Prof. Mitsuko Masutani of
the Department of Frontier Life Sciences, Nagasaki University Graduate School of
Biomedical Sciences and Dr. Teruyoshi Kageji of the Department of Neurosurgery,
Tokushima Prefectural Kaifu Hospital as editors and Prof. Hideki Matsui of the
Department of Physiology, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences as an advisor. The NCT letter Vol. 5 waspublished, seeking advice from Prof. Hiroyuki Nakamura, the president of this Society,although behind schedule.
As described in the feature article written by Dr. Hideyuki Sakurai, particle
radiotherapy is now covered by insurance also for malignant head and neck tumors(excluding oral and laryngopharyngeal squamous cell carcinoma). As a result, proton
beam therapy currently has little difference with IMRT in therapy cost, giving patients
free choice of therapy.
On the other hand, in the field of “immunotherapy”, long-term surviving cases were
determined in the clinical trial for treatment of advanced cancer in various areas using
immune checkpoint inhibitors, therefore, malignant melanoma, non-small cell lungcancer, head and neck cancer and gastric cancer have been included in the insurance
coverage in succession. On the contrary, the “immune cell therapy” of which medical
expenses have not been covered by insurance and thus is a high-cost therapy is showing
signs of decay.
As to the current situation of BNCT, Phase II study has completed using accelerator
BNCT for recurrent head and neck cancer and brain tumor at the Institute for Integrated
Radiation and Nuclear Science, Kyoto University and the Southern Tohoku Hospital.
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Hereafter, the treatment results in Phase III study will be the “key” point. In the future,
proton beam therapy and immune checkpoint inhibitors are expected to be therapies
comparable to BNCT, depending on the area.

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