NCT letter Issue 7 August 2020

NCT letter Vol. 7（English version）
June, 2021

1

NCT letter Issue 7 August 2020

Contents● Preface
Minoru Suzuki
President of Japanese Society of Neutron Capture Therapy
Professor, Institute for Integrated Radiation and Nuclear Science, Kyoto University● Special Articles
・JSNCT Greetings from the inaugurated President
Minoru Suzuki
Professor, Institute for Integrated Radiation and Nuclear Science, Kyoto University

・Finishing phase II trial of accelerator-based BNCT on recurrent or locallyadvanced head and neck cancer and future development
Yoshihiro Takai
Director of the Southern Tohoku BNCT Research Center・Polyvinyl alcohol as the additive enhancing the therapeutic potential of pboronophenylalanine
Takahiro Nomoto
Assistant Professor, Institute of Innovative Research, Tokyo Institute of Technology● Progress Status of BNCT Project in Japan・The progress status of Tsukuba BNCT Project: iBNCT
Hiroaki Kumada
Associate Professor, Proton Medical Research Center, Faculty of Medicine, Universityof Tsukuba

・Progress of accelerator BNCT system in Nagoya University
Yoshiaki Kiyanagi
Designated Professor, Nagoya University Graduate School of Engineering
2

NCT letter Issue 7 August 2020

・Progress of accelerator BNCT system in Institute for Integrated Radiation
and Nuclear Science, Kyoto University
Minoru Suzuki
Professor, Institute for Integrated Radiation and Nuclear Science, Kyoto University● Academic meeting Reports
・Report on the 16th Congress on Japanese Society of Neutron Capture
Therapy

Natsuko Kondo

Assistant Professor, Institute for Integrated Radiation and Nuclear Science, Kyoto
University

・Notice on the 19th International Congress on Neutron Capture Therapy(ICNCT 19) at Granada
President of ICNCT
Ignacio Porras
Professor, Department of Nuclear Atomic and Molecular Physics, University of Granada

・Notice on the 17th Congress on Japanese Society of Neutron Capture
President of 17th CJSNCT
Jun Itami

Therapy

Professor, Institute for Integrated Radiation and Nuclear Science, Kyoto University● Awardees of BNCT related Conferences or Meetings
Best Presentation Awards of the 16th Congress on Japanese Society of
Neutron Capture Therapy
・Study on QA by phantom using 3D printing technology in BNCT
Akinori Sasaki, et al
Graduate school of Engineering, Kyoto University

・Evaluation of BNCT therapeutic efficacy by a novel boron compound(BAMP)
Makoto Shirakawa, et al
Department of Pharmaceutical Sciences, Fukuyama University
3

NCT letter Issue 7 August 2020

・Changes in the immune profile of tumor cells after BNCT
Mariko Sato, et al
Department of Radiation Oncology, Southern Tohoku BNCT Research Center

Travel Grants Award of 10th Young Researchers BNCT Meeting・ A study on development of remote-changeable Bonner sphere
spectrometer for characterization in BNCT irradiation field
Sadaaki Shiraishi, et al
Institute for Integrated Radiation and Nuclear Science, Kyoto University

・Evaluation of a treatment planning system used for BNCT at the Kansai
BNCT Medical Center
Naonori Ko
Kansai BNCT Medical Center, Osaka Medical College

・Development of gamma-ray dosimeter using radio-photoluminescenceglass dosimeter and gamma-ray filter in a neutron/gamma-ray mixed fieldfor BNCT
Tokiya Inoue
Division of Sustainable Energy and Environmental Engineering, Graduate School ofEngineering, Osaka University

MERIT Awards of European Society for Medical Oncology (ESMO)
2019
・Updated results of a phase II study evaluating accelerator-based boron
neutron capture therapy (AB-BNCT) with borofalan (10B) (SPM-011) inrecurrent squamous cell carcinoma (R-SCC-HN) and recurrent and locallyadvanced non-SCC (R/LA-nSCC-HN) of the head and neck
Katsumi Hirose
Southern Tohoku BNCT Research Center

4

NCT letter Issue 7 August 2020

● Introduction of the articles
1. <Pharmaceutical Science >Title: Target Delivery of Cell-Penetrating Peptide-Conjugated Dodecaborate for
Boron Neutron Capture Therapy (BNCT)
Authors: Ikuhiko Nakase, Miku Katayama, et al.
The source: Chem Commun (Camb), 55(93), 13955-13958 (2019).
Microsoft Word - Nakase-Katayama ChemComm Supplementary Information.docx (rsc.org)

Presented by Tooru Andoh (Laboratory of Frontier Pharmaceutical Technology,
Faculty of Pharmaceutical Sciences, Kobe Gakuin University)
2. <Physical Engineering >Title: A dual natural lithium formate/L-alanine EPR dosimeter for a mixed radiation
field in a BNCT irradiation facility
Authors: G. Alejandro, J. Longhino, et al.
The source: Journal of Physics D: Applied Physics (2020) 53:19
pdf (iop.org)

Presented by Nishiki Matsubayashi (Graduate School of Engineering, Kyoto
University)
3. <Medicine>
Title: Radiation and dual checkpoint blockade activate non-redundant immune
mechanisms in cancer
Authors: Christina Twyman-Saint Victor, Andrew J. Reck, et al.
The source: Nature 2015; 520:373-380.
https://www.nature.com/articles/nature14292.pdf
Presented by Tsubasa Watanabe (Program-specific Associate Professor, Institutefor Integrated Radiation and Nuclear Science, Kyoto University)● Editorial Postscript
Itsuro Kato
Chief Editor of NCT letter
Department of Oral and Maxillofacial Surgery II, Graduate School of Dentistry, Osaka
University

5

NCT letter Issue 7 August 2020

On the 7th volume of the NCT letter

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 NCT letter Editor-in-Chief Dr. Itsuro Kato and the cooperationof fellow doctors, we were able to publish this 7th volume of the NCT letter. I sincerely
express my gratitude towards everyone involved.
As members already may know, accelerator-driven BNCT has been receiving a lot of
attention since it began as health insurance treatment at two medical institutions in Juneof 2020. I hope that not only those attending this conference but also those who are not
in attendance can see this. This NCT letter, which reports both a current and prospective
view of BNCT medical practices and academic research, is progressively becoming amore important medium of communication for this information from this conference.
Volume 7 was also planned by Editor-in-Chief Dr. Kato and is rich with informationon the current state of BNCT research institutions, the announcement of the 16th congress,
paper introductions, etc. This letter will be a great lead for those who have an interest or
are currently engaged in BNCT research as it is filled with information on the current
affairs of fundamental BNCT research, medical practices, and a look at the future ofneutron radiation locations.
With the commencement of medical treatment for head and neck cancer using
accelerator-driven BNCT at medical institutions, the baton has been passed to these
institutions to continue the development of boron-agents and accelerator-driven BNCT.
The future results of BNCT research will be for patients to be able to receive acceleratordriven BNCT treatments in medical institutions. This "translational research", whichspans from the laboratory bench to the hospital bedside, will have a larger significancethan we have ever seen before. We are very much looking forward to hearing many great
clinical outcomes from these medical institutions. That being said, the bidirectional
exchange of research between the fundamental research and clinical practice is becoming
more and more important. Specifically, this includes both fundamental research
including the development of new boron agents, which will be critical for improving
clinical outcomes, and the clinical practice research that feeds back into that fundamental
research based on the results of human radiobiology. Up until now, in BNCT research,
6

NCT letter Issue 7 August 2020

from KUR being the common neutron source used in both fundamental research andclinical practice, we have already prepared the soil on which we can have thisbidirectional exchange of research between the fundamental research and clinical practice.
With medical institutions that use accelerator-driven BNCT facilities, integrated radiationand nuclear science that use BNCT neutron sources for research purposes, and the Aomori
Prefecture Quantum Science Center, we are highly anticipating many large flowers thatare the research result to bloom from this soil.
In the future, in order to continuously and steadily promote this bidirectional research,
it is important to expand the range of researchers and also have many younger researchers
to participate in fundamental BNCT research. I humbly ask all conference participants tointroduce this NCT letter to the students and young researchers around you. Furthermore,
I humbly ask all of you to contribute towards the development of the scientific field of
neutron capture therapy with both clinical practice research and foundational research as
the two wheels that help move us forward.

7

NCT letter Issue 7 August 2020

JNCT Greetings from the inaugurated President

Minoru Suzuki
President, Japanese Society of Neutron Capture Therapy
Professor, Particle Radiation Oncology Research Center,
Institute for Integrated Radiation and Nuclear Science, Kyoto University
My name is Minoru Suzuki, Professor at Kyoto University Institute for Integrated
Radiation and Nuclear Science (KURNS) ・Particle Radiation Oncology ResearchCenter. On September 8th, 2019, I was the Chairperson of the 16th Congress on
Japanese Society of Neutron Capture Therapy held in Uji City, Kyoto, taking overthis major role from Professor Hiroyuki Nakamura of Tokyo Institute of Technology.
From my appointment as President to the time of my writing this message in July 2020,
the 17th Congress has been postponed for a year due to the unexpected pandemic COVID19. In June of 2020, insured BNCT treatment began for head and neck cancer by
accelerator-driven BNCT. A large number of participants and lively discussions based on
the BNCT clinical practice were to be expected at the 17 th Academic Conference which
was to be held in July, therefore it is a great pity that it has been postponed. In themeantime, since there will be an interval of almost 2 years between the Academic
Conference held in September 2019 to the next conference, I hope that many BNCT
academic researchers will be promoted by members of the academic society and lookforward to such presentations.
As representative for Japanese Society of Neutron Capture Therapy, I would like tofocus in particular on the following three points: education, qualification, andinternational cooperation. A committee has been set up in the academic society
concerning these 3 points, and I wish to promote these together with the committee
professors.
In the future, I hope to rely in great part on medical institution staffs regarding humanresources development related to BNCT clinical practice, including On the Job Training.
As the Academic Society, including postgraduate education, we look forward topromoting activities that will lead to the development of young researchers who will lead
8

NCT letter Issue 7 August 2020

BNCT academic research in the future. Thanks to the efforts of former chairman Miyatakeof Osaka Medical University, the BNCT certified physician system is in operation. With
the start of insured BNCT medical treatment and a reliable operation of the BNCT
certified physician system, I believe it is necessary to consider preparations from thispoint forward for certification system for medical physicists regarding BNCT in
anticipation of the spread of domestic medical institutions of the accelerator-driven
BNCT in the future. In regards to international cooperation, in addition to increasing thepresence of Japan which succeeded in putting the accelerator-driven BNCT to practicaluse for the first time in the world, as an academic society, I hope we can run a project todeepen exchanges between BNCT researchers around the world.
Due to COVID-19, methods for advancing our activities have changed significantlywith almost all academic conferences currently being held online. Currently, face-to-faceactivities are restricted, but I believe there is an aspect in which activities can be promotedeven further than ever by holding remote conferences and lectures. On the other hand, for
implementing accredited medical examination, given that it seems difficult to end
COVID-19 pandemic in 1 to 2 years, I think it has become crucial to consider a newembodiment. For next year’s academic conference, it will be necessary, consulting withthe chairperson, to rethink the format.
I became president of the society during an unforeseen emergency situation. I believe
all members of the society are devoting much precious time towards medical treatment
and the research environment coping with COVID-19. Based on the current situation, one
by one, I will review the academic society’s activities, especially those of each committee,
taking proper time to prepare, and steadily promote next year’s activities (Jan. to Dec.
2021) with the cooperation of the academic society members.
I would like to ask all members of the universities to pay sufficient attention inpreventing the spread of COVID-19, and would ask for your continued cooperation withJapanese Society of Neutron Capture Therapy.

9

NCT letter Issue 7 August 2020

Finishing phase II trial of accelerator-based BNCT on recurrent or
locally advanced head and neck cancer and future development
Yoshihiro Takai,
Director of the Southern Tohoku BNCT Research Center
Katsumi Hirose,
Clinic Director at the Southern Tohoku BNCT Research Center
At the Southern Tohoku Research Institute for Neuroscience (general incorporated
foundation), as part of the "Medical Welfare Devices and Pharmaceutical Industry BaseDevelopment Project" (The Ministry of Economy, Trade and Industry's 3rd
Supplementary Budget of 2013: Great East Japan Earthquake Reconstruction Project), a
policy meant to support the industrial rehabilitation of Fukushima Prefecture, we applied
to the "Subsidy for Internationally Advanced Medical Device Development Projects"
publicly offered by Fukushima, and were selected (June, 2012). Thereupon, we
introduced the Cyclotron-Based BNCT System (C-BENS). In September of 2014, weestablished the Southern Tohoku BNCT Research Center and in November of 2014 we
opened the facility as a non‐bed clinic. Two-thirds of the gross business expenses werecovered by the subsidy.
In 2016, we began a phase II trial for the recurrent malignant glioma and recurrent /locally advanced head and neck cancer. The first case of the clinical trial for the head andneck cancer was treated on July 7th and all 21 cases were registered and treated by
February 15th of 2018. 20 cases were from the Southern Tohoku Medical Clinic and 1
case was from the National Cancer Center Hospital. Treatments for all cases were carriedout at the Southern Tohoku BNCT Research Center. The objective response rate (ORR)
within 90 days, which was the primary endpoint for this clinical trial, was 71.4% for allcases, 75% for squamous cell carcinoma, and 69.2% for non-squamous cell carcinoma.
For squamous cell carcinoma, compared to the ORR of 20% for the CDDP+5FU groupin the EXTREME trial and 43% in trials using photoimmunotherapy, these results werevery promising. For more details regarding the results of this trial, please read the article
written by Dr. Hirose in this NCT Letter, "Winning the MERIT Award at European
Society for Medical Oncology (ESMO) 2019".
With the results of the phase II trial, we applied for approval of accelerator BNCT systemand boron compound (Borofaran) in October, 2019, under the Act on Securing Quality,
Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices.
Accelerator BNCT is designated as an item covered under the SAKIGAKE Designation
10

NCT letter Issue 7 August 2020

System, which has a 6-month long approval screening period. As already reported, in a
subcommittee of the Ministry of Health, Labor, and Welfare, manufacturing and sales
were approved for the Cyclotron-Based BNCT System on February 19th, 2020, and forboron compound (Borofalan) on the 26th. They will be officially approved in the middleof March. Once approval is received, we will apply to have them covered by insurance,
and are hopeful to see BNCT become acknowledged as a health insurance treatment by
the middle of 2020.
BNCT is a revolutionary form of radiation therapy that selectively targets tumor cells andcan treat cancer without affecting normal cells. By adding BNCT as a step for treating
cancer, it can be performed as a third curative treatment for recurrent head and neckcancer patients with no more treatment options, after surgery or curative
chemoradiotherapy (CRT). As stated above, BNCT has very high efficacy and does not
lower tolerance towards surgeries or CRT. Thus, if we reverse the order and perform
BNCT as a neoadjuvant therapy first, if a tumor still remains, it may allow for a safer andreduced surgery and perhaps CRT can be performed on a reduced-volume tumor. In thisway, BNCT has the potential to become a method of treatment that causes a paradigm
shift in the cancer treatment. As accelerator BNCT will start as a health insurance
treatment in the middle of this year, I truly believe that this treatment can bring good news
to the many patients battling against intractable cancer.

11

NCT letter Issue 7 August 2020

Polyvinyl alcohol as the additive enhancing thetherapeutic potential of p-boronophenylalanine
Takahiro Nomoto,
Assistant professor
Institute of Innovative Research, Tokyo Institute of Technology
Since the Asahi Shimbun reported on this research under the heading, “Scientists findliquid glue helps destroy cancer cells in mice”, it has been introduced by many media.
The use mentioned here is polyvinyl alcohol (PVA), and the method to "destroy cancer
cells" is BNCT. In this study, when PVA was added to p-boronophenylalanine (BPA), thetumor accumulation and retention of BPA was considerably improved, and theintratumoral boron concentration was maintained at the appreciably high level evenduring thermal neutron irradiation, resulting in a significant improvement in therapeutic
effect. [Science Advances 6, eaaz1722 (2020)]. Here, I introduce the results of animal
experiments and future prospects about the complex of PVA and BPA (PVA-BPA).
First, Figs. 1A–B show the tumor accumulation and retention of PVA-BPA in
subcutaneous tumor models. Fructose-BPA exhibited the apparently high tumor
accumulation immediately after administration, but the amount of boron in the tumor
gradually decreased. While PVA-BPA also showed a high tumor accumulation amount
immediately after administration like fructose-BPA, it maintained the high value even 6hours after administration. Although the blood retention was slightly higher than that offructose-BPA, the tumor/blood and tumor/normal tissue boron concentration ratios weresimilar to those of fructose-BPA. Improvement in tumor accumulation by utilizing theenhanced permeability and retention (EPR) effect (passive targeting) using
macromolecular medicine generally requires the increase of the blood retention,
compromising the tumor/blood boron concentration ratio. However, PVA-BPA can offer
the active targeting for LAT1 without requiring the longitudinal retention in the
bloodstream, which might contribute to the high tumor/blood ratio.

12

NCT letter Issue 7 August 2020

(A)

Fructose-BPA
PVA-BPA

8.0%Dose / g tumor

12.0

10.0

%Dose/g tumor

(C)

(B)

12.0

10.0
8.0

6.0

6.0

4.0

4.0

2.0

2.0

0.0

Fructose-BPA
PVA-BPA

(D)

0.0
0

3
Time (h)603Time (h)6Blood vessels PVA-BPA
Cells near blood vessels

Figure 1. Tumor accumulation and intratumoral distribution. (A–B) Tumor
accumulation within (A) subcutaneous pancreatic tumor models and (B) subcutaneouscolon cancer models. (C–D) Intratumor distribution of PVA-BPA in (C) a subcutaneous
pancreatic tumor and (D) a subcutaneous colon cancer.
PVA-BPA also exhibited efficient tumor permeability (Figs. 1C–D). Subcutaneous
pancreatic cancer models are known to have thick stroma around blood vessels thatprevent drugs from reaching tumor cells in a deep region. Although some of intravenously
injected PVA-BPA was trapped in the stroma, it also penetrated deep into the tumor.
Because the molecular weight of PVA was about 10,000, which is smaller in size than
general macromolecular drugs, PVA-BPA might be able to penetrate the thick stroma. In
the subcutaneous colorectal cancer model with less stroma, PVA-BPA was distributed
throughout the tumor. Since BNCT requires the distribution of boron throughout thetumor, such distribution is important in aiming for complete cure.
In line with these results, PVA-BPA showed remarkable therapeutic effects in both
subcutaneous pancreatic tumor and subcutaneous colon cancer models (Fig. 2). In
particular, in the subcutaneous colon cancer model, PVA-BPA accomplished the almost
complete cure, and we recently found that the similar therapeutic effect could be obtainedwith commercially available PVA.

13

NCT letter Issue 7 August 2020

B 200

Control (COLD)

10Control
Relative tumor volume

Relative tumor volume

A 12

Fru ctose-BPA

8

PVA-BPA64
20

Fructose-BPA 3 h
PVA-BPA 3 h

150
100
50
0

0

20

40

60

0

Day

10

20

30

Day

Figure 2. Antitumor activity. (A) Subcutaneous pancreatic tumor models. (B)Subcutaneous colon cancer models. Thermal neutrons were irradiated 3 h after
intravenous injection.
PVA has been studied for a long time as a biocompatible material and is widely used inclinical situations. In addition, a previous study reported that intravenously injected PVA
did not show apparent toxicity in humans at the similar dose to that used in our study,
indicating the potential of PVA for the practical application in BNCT. We are planning to
optimize the physical properties of PVA within a few years and carefully examine thepossible side effects on normal tissues. Also, PVA-BPA has been administered by bolus
injection in our animal experiments, but it should be administered by infusion for clinicalapplications. Since PVA-BPA is formed by the equilibrium reaction (boronate esters), wewould like to investigate how the injection methods affect the pharmacokinetics.

14

NCT letter Issue 7 August 2020

The progress status of Tsukuba BNCT Project: iBNCT
Hiroaki Kumada
Associate Professor, Proton Medical Research Center,
Faculty of Medicine, University of Tsukuba
University of Tsukuba established an industry‐government‐university project team(hereinafter referred to as iBNCT project) in 2011 under the partnership with academia
including High Energy Accelerator Research Organization, Japan Atomic Energy Agency,
manufacturers including Toshiba Energy Systems & Solutions Corporation and local
companies that deal with radiation facilities including NAT Corporation, and Ibaraki
Prefecture. The team is developing the demonstration device for an accelerator based
BNCT and implementing activities towards the realization of the relevant device.
[Development concept and characteristics of the device]
The development concept of the demonstration device of an accelerator based BNCT:“iBNCT001” is “enhancing the intensity of the neutron beam equivalent to the nuclear
reactor” and “lowering the radiation of the device”. Specific target figure at the time ofdesigning was set as “epithermal neutron flux at the beam hole location: 1.5x10 9 (n/cm2/s)
or more”, “dosage around the beam aperture of 1 minute after the irradiation is 100μSv/hor less”. With this target in mind, at the designing stage, we first selected the target
material. We adopted beryllium, from the perspective that at that time, the treatment
device made by preceding Sumitomo Heavy Industries, Ltd. was using beryllium and it
already had application achievements of the same material, and because it had higher
melting point than lithium, etc. Then we decided on the energy level of proton to beentered into beryllium. At this point, beryllium has the following physical characteristics.
(1) It does not activate by the reaction with the proton of 13.4 MeV or less. (2) The largest
energy level of neutron generated correlates with the energy of the proton that is entered.
(3) The lower the proton energy is, the lower the neutron generation efficiency will be.
Thus, from the perspective of “lowering the radiation”, we set the proton energy as 13
MeV or less. However, because of the characteristics of (3), if we lower the proton energy
15

NCT letter Issue 7 August 2020

too much, we cannot have sufficient neutron intensity. Therefore, in order to make thetwo concepts compatible, we set the condition of proton energy being “8 MeV”. Finally,
with the target of “generating neutrons of large intensity equivalent to the nuclear reactor”
in mind, we set “the average current of the accelerating proton as 5 mA or more”.
With these requirements in mind, as the accelerator of iBNCT001, we adopted the linear
accelerator (linac), which can accelerate the proton up to 8 MeV and can deal with theaverage electric current of 5 mA or more. Figure 1 shows the picture of the two
accelerating tubes (RFQ and DTL) of the iBNCT001 linac.

Figure 1 RFQ (right) and DTL (left) of iBNCT001
When producing the two accelerating tubes indicated in Figure 1, the generic technologyof the large intensity accelerator driven neutron source device for the large intensity
research, which already had long time of operation experience: J-PARC (Tokai village),
was applied. On the other hand, the requirement of proton beam current value, etc. for
iBNCT001 was higher than J-PARC, so concerning the ion source, cooling system, etc.,
the equipment dedicated to iBNCT001 was designed, developed and combined.
iBNCT001 was installed in the facility “Ibaraki Neutron Medical Research Center” which
is located at “Ibaraki Quantum Beam Research Center” (Tokai village) under the controlof Ibaraki Prefecture. Figure 2 shows the exterior appearance of the Ibaraki Neutron
Medical Research Center. In addition, Figure 3 shows how the irradiation room arrangedin the same facility looks like. In the facility, biological test facility is established next to
the irradiation room so that we can conduct nonclinical tests (cell irradiation, small animal
irradiation) etc. required from clinical studies.
16

NCT letter Issue 7 August 2020

Figure 2 Ibaraki Neutron Medical Research Center Figure 3 Inside the irradiation room

ビーム孔

患者用ベッド[Current status of the iBNCT project]
In 2016, iBNCT001 succeeded in neutron generation by the proton beam irradiation under
the condition of low proton beam current. After that, it increased the current value instages and at the time of 2019, it succeeded in generating the neutron under the conditionof the proton beam of the average current: 2.8 mA. This operation condition is the onethat can generate the epithermal neutron of approximately 1x109 (n/cm2/s) at the exit
location of the beam aperture. Moreover, under the operating condition of average
current: 1.4 mA, it conducted the long hour operation test multiple times and it confirmedthat it can generate the neutron stably and continuously. In addition, under this operating
condition, we conducted the neutron irradiation experiment against water phantom andconfirmed by the measurement that the thermal neutron having intensity required fortreatment in phantom can be generated. Furthermore, 5 minutes after this phantom
irradiation experiment, we went into the irradiation room and measured the residual
gamma-ray dose rate in the room. As a result, residual gamma-ray dose rate around thebeam aperture was about 40 μSv/h. From this result, we confirmed that this device allows
medical staff to come in the irradiation room and access the patient right after theirradiation or in case of emergency and confirmed that our development concept of thedevice “lowering the radiation” was realized. In addition, we conducted the cellirradiation test and preliminary test of irradiation experiment against mice in this facility
and confirmed that the series of nonclinical test can be conducted using the iBNCT001.

17

NCT letter Issue 7 August 2020

From now on, the iBNCT project will promptly conduct nonclinical test for iBNCT001,
and after that, based on this result, we plan to conduct clinical trial for real patients.

18

NCT letter Issue 7 August 2020

Progress of accelerator BNCT system in Nagoya University
Yoshiaki Kiyanagi
Designated Professor
Nagoya University Graduate School of Engineering
Nagoya University is developing an accelerator driven neutron source using anelectrostatic proton accelerator. This is mainly for BNCT research, and can also be used
for engineering and science applications. The accelerator is a Dynamitron accelerator
manufactured by IBA. The maximum acceleration energy of the proton beam is 2.8 MeV,
the maximum current is 15 mA, and the maximum power is 42 kW. Figure 1 is aphotograph of the accelerator and proton beam transport line of the first beamline when
set up [1]. As shown in Figure 2, three proton beamlines exist. The first beamline is used
for BNCT research, the main application, deflected by 20°. The second beamline is a
70°deflection beam used in science and engineering applications. In addition, there is astraight beamline for beam commissioning.

Fig.１Accelerator and first beamline setup [1]

Fig.２ Beamline layout

A neutron moderator system for BNCT, Beam Shaping Assembly (BSA), is installed at
the tip of the accelerator. Figure 3 shows the BSA [2]. As a neutron generation target, Liwith high production efficiency in this energy region is used. It is well known that Li
produces 7Be, a radioactive substance due to the neutron generation reaction by protons.
To prevent Li and its products from diffusing into the accelerator vacuum lines as a resultof proton sputtering, we are developing a sealed Li target with a Ti thin film on the Li
surface. Due to the high accelerator power, cooling is one of the major challenges for low
19

NCT letter Issue 7 August 2020

melting point targets such as Li. For the copper cooling plate with rib structure watercooling channels, a heating test was conducted using a 30 keV electron beam from anultra-high heat load device (ACT2). As a result, it was confirmed that a high heat flux of
up to 20 MW/m2 could be removed [3], well above the heat flux required by our target.
About BSA, fluoride is effective element as an epi-thermal neutron moderator [4], andafter examining various fluorides, we chose MgF2, which is suitable for proton energies
less than about 10 MeV [1,4]. A nozzle was equipped at the exit of the neutron beam toallow the person being treated to sit comfortably. Figure 4 shows the energy spectrum
obtained by a Monte Carlo simulation for this BSA [2]. The beam characteristics, as
shown in Table 1, clear the conditions recommended in TECDOC-1223 [1].
The
neutronexperimentwasconducted when the proton beam
power was low. Since it is not easy to
directly measure the intensity of epithermal neutron flux from BSA, awater phantom was installed and thethermal neutron flux in it was
Fig.４Energy spectrum [2]measured. The size of the water Fig.３BSA structure [2]phantom was 20 cm cubic, asrecommended as the standard size in the Table１ Beam characteristics [1]physics field in Japan. The absolute
thermal neutron flux was measured by
the gold foil activation method, anddetailed spatial distribution wasmeasured by a fiber detector using
LiCaF [5]. Figure 5 shows the results ofa thermal neutron flux distribution along
the beam axis. As a result of the current 0.2
mA, it was found that 1 x 109 n/ cm2 canbe achieved as an epi-thermal neutron flux
when converted to 15 mA. Cell irradiationis also conducted as a performance test of
this device.
We continue commissioning toincrease the beam current, since stable

Fig.５ Beam axial thermal flux distribution

operation is at present possible at 3
20

NCT letter Issue 7 August 2020

mA. In the future, we plan to further
increase the current and develop atarget usable at high current situation.
[1] A. Uritani, et al., JPS Conf. Proc., 011002 (2018). doi:10.7566/JPSCP.22.011002[2] K. Sato, et al., JPS Conf. Proc., 011003 (2018). doi:10.7566/JPSCP.22.011003[3] S. Yoshihashi et al., submitted to Journal of Instrumentation.
[4] Y. Kiyanagi, Ther Radiol Oncol, 4 (2018). doi: 10.21037/tro.2018.10.05[5] A. Ishikawa, et al, Radiat. Meas. 133, 106270 (2020). doi:
10.1016/j.radmeas.2020.106270

21

NCT letter Issue 7 August 2020

Status of the Institute for Integrated
Radiation and Nuclear Science, Kyoto University
Minoru Suzuki
Professor, Particle Radiation Oncology Research Center,
Institute for Integrated Radiation and Nuclear Science, Kyoto University

The Kyoto University Research Reactor (hereinafter referred to as KUR) of the Institutefor Integrated Radiation and Nuclear Science, Kyoto University (hereinafter referred toas KURNS) has conducted more than 580 cases of BNCT treatment, which is the largest
number in the world. Since June 1, 2020, the health insurance treatment of pharyngeal
cancer using accelerator based BNCT at medical institutions started. In response to this,KURNS, which is not a medical institution, stopped accepting BNCT medical practice.
From FY2021, concerning the joint use research public invitation of KURNS, invitationfor BNCT clinical research (medical irradiation) topics will not be included.

The start of KUR activation in the FY2020 is postponed to October because we needed
to deal with COVID19 pandemic. Operation from Tuesday to Thursday is as usual but
since we do not accept medical irradiation, on Thursdays we accept full irradiation
experiments at 5 MW. The operation of irradiation experiments at 1 MW on Tuesdays andWednesdays is the same as last fiscal year.

Although we continue to be cautious enough to prevent the spread of COVID19, KURNS
will cooperate as much as possible to promote the joint use research so that the progressof the basic research using the KUR will not slow down. Operation pattern from FY2021
onward is not yet decided as of now, but we would like to work even harder to makeprogress in the basic research related to BNCT.
We are currently preparing for the application of the accelerator based BNCT irradiation
system used in the clinical trial installed at KURNS to the BNCT basic research. From
now on, we will keep you updated about our progress of preparation on the Particle
22

NCT letter Issue 7 August 2020

Radiation Oncology Research Center website.
KUR is currently the only source of neutron in academia that can be used for BNCT basic
research by the researchers at home and abroad. For the BNCT related research, neutron
irradiation is indispensable as Proof of Concept. In recent years, the number of applicationby the researchers of the joint use research topics that use the KUR of KURNS exceeded
90 cases. We are contriving ways to arrange the irradiation system and improving the jig
so that each research topic can have necessary number and time of irradiation allocatedfor conducting the research. We look forward to receiving participation of joint use
research from many researchers so that the report of the research results from the KUR at
KURNS concerning the BNCT basic research will continue to be state of the art in theworld.
Every year around September and October on the KURNS website, the invitation for thejoint use in the next fiscal year is announced. We would like to ask anyone who is thinkingof participating in the BNCT basic research for the first time, if you have anything unclear
or have any request, please contact us anytime from the contact form that you can find on
the KURNS website: https://bnct.rri.kyoto-u.ac.jp/access.

23

NCT letter Issue 7 August 2020

Report on the 16th Congress on Japanese Society of
Neutron Capture Therapy
Natsuko Kondo
Executive Committee Chairperson
Assistant Professor of Particle Radiation Oncology ResearchCenter, Institute for Integrated Radiation and Nuclear Science, Kyoto University
The 16th Congress on Japanese Society of Neutron Capture Therapy was held at Uji
Obaku Plaza in Kyoto University in Uji city in Kyoto prefecture on September 7th (Sat)and 8th (Sun) in 2019. (The chairperson of the congress was Minoru Suzuki, Professor ofParticle Radiation Oncology Research Center, Institute for Integrated Radiation and
Nuclear Science, Kyoto University.) The 7th BNCT Workshop (hosted by the Human
Resource Development Committee of the Japanese Society of
Neutron Capture Therapy and supported by this congress) was
held on September 8th (Sat), the second day of the congress.

Welcome from
Chairperson
Prof. Suzuki

Amid the lingering summer heat and concerns for the impact ontransportation due to Typhoon Faxai (Typhoon No.15)
approaching the area on the second day of the congress (8th), we
managed to successfully hold and finish the meeting. At thecongress, 235 participants (108 regular members, 92 nonmembers, and 35 students) joined to present the latest research

results and had lively discussions in the fields of physics, clinicalmedicine, pharmacy and chemistry, and biology. We would like to take this opportunity
to thank the participants very much for their active participation.
Using the experiences in many basic and clinical studies at reactor-based Boron Neutron
Capture Therapy (BNCT) research facilities, BNCT is transferring to be performed ataccelerator-based BCNT facilities attached to medical institutions. Several countries aredeveloping and installing the BCNT accelerators in or near hospitals, following Japan.
Therefore, we set the theme of this congress "Thinking about the Diversity in Neutron
Capture Radiation (NCR) Research" in the hope that the Institute for Integrated Radiation
and Nuclear Science, which has two neutron sources: nuclear reactor and accelerator, willcontinue to disseminate academic research information on BNCT from Japan to the world.
In the congress, there were extensive discussions about research of radiobiology, neutron
capture therapy using NCR, new drug development, and medical physics that supports all
24

NCT letter Issue 7 August 2020of the other research. The number of thepresentations was 76 in total: 2 educational
lectures, 4 symposium lectures, 47 general
presentations, and 23 poster sessions.
The Educational Lecture 1 with the theme of"Challenges for application of cancer
immunotherapy to radiation therapy anddevelopmentof
personalized
cancerPoster Display Session
immunotherapy" was delivered by Toshihiro Suzuki, from General Medical Education
and Research Center, Teikyo University. The Educational Lecture 2 with the theme of"Basic research on heavy ion beam induced damage to biomolecules in water using liquid
secondary ion mass spectrometry" was delivered by Hidetsugu Tsuchida, Associate
Professor of Quantum Science and Engineering Center, Graduate School of Engineering,
Kyoto University. At the symposium, four speakers presented "Status Report of theInternational Society for Neutron Capture Therapy (ISNCT)": (1) the current status andchallenges of ISNCT, (2) activity of the working group (WG) of BNCT in medical physics,(3) operating principles of ISNCT-Medicine WG, and (4) the future direction of the
Chemistry Technical Committee in ISNCT.
The speakers explained about ISNCT as anorganization strengthened to continuously conduct
planned and strategic operations, the current
challenges and progress reports in each field ofphysics, medicine, and chemistry, and its future
direction. Researchers gained comprehensive
understanding of the current challenges of BNCT
that ISNCT is working on.
The Congress dinner was successfully held withmore than 135 attendees at Restaurant Kihada and“Kagami biraki” at Congress dinnerHybrid Space in Obaku Plaza. We had a Japanese traditional ceremony "Kagami biraki"(opening a sake cask by breaking its lid with wooden mallets, performed at celebratory
events). The sake in the cask was Daiginjo KOTO, the product of Sasaki Shuzo in Fushimi,
Kyoto, and the attendees enjoyed tasting it.
Finally, I would like to express my appreciation to Prof. Hiroyuki Nakamura, thePresident of the Japanese Society of Neutron Capture Therapy, Prof. Masayori Ishikawa,25

NCT letter Issue 7 August 2020

the chairperson of the previous
Congress, and the members of
the Society for their fruitfuladvice and cooperation, and to
Junko Ikeda at the congresssecretariat, Kiyoshi Yamauchi
from Secand Co., Ltd., themanagement committee office,and the staffs of Institute forIntegrated Radiation andMembers of congress management commmittee

NuclearScience,
Kyoto
University for the management
and practical business for this congress. Let me also express sincere appreciation toward
14 companies which supported the management of this congress in the form ofadvertisements, setting up of booths, and sponsorship. For further details of this congress,
please refer to the "Information on Nuclear Technology in Medicine" Vol. 20 issued by
the Association for Nuclear Technology in Medicine.

26

NCT letter Issue 7 August 2020

Guide for the 19th International Congress on Neutron
Capture Therapy at Granada, Spain
Ignacio Porras
Congress Chair of ICNCT-19, President of ISNCT
Professor, Ph.D., Granada University
Dear Colleagues,
We hope that you and your families are well during this difficult time.
We are all together in this crisis.
Many countries have been critically affected by COVID-19. We all have to deal withuncertainties in almost every aspect of our lives and it is clear that we will need time torecover. For this reason, and taking into account the high importance of ICNCT for ourcommunity, we have decided, with the approval of the Board of Councilors of the ISNCT,
to postpone the ICNCT 19, originally scheduled for September 2020.
The 19th International Congress on Neutron Capture Therapy (ICNCT 19) will beheld in Granada, Spain from 5th to 10th September, 2021*.
This postponement is a fully-equivalent replacement for the planned event originallyscheduled. It will appear in the website quite soon.
Registration fees for the conference will be unchanged for the new congress date.
Registration will remain open until 15th August 2021**.
Deadline for abstract submission will be open until 30th April, 2021***.
Specific information for participants who already made arrangements for September 2020is as follows:
Abstracts:
If you have already submitted abstract(s) for ICNCT you will be contacted soon by the
ICNCT 19 secretariat, who will offer the following three opportunities:
27

NCT letter Issue 7 August 2020

● You may keep the abstract as originally submitted;● You may modify the abstract;● You may withdraw the abstract.
Registration:
If you have already registered for the Congress you will be contacted soon by the ICNCT19 secretariat, who will offer the following two opportunities:● You may keep your registration in place (and in that case no action is required fromyour side);● You may withdraw your registration, with a full refund of the registration fee.
Our aim is to hold a conference that will help to maintain and strengthen the bonds
and collaborations in the BNCT community.
Therefore, we are already looking forward to welcoming you in Granada in
September, 2021!
Yours sincerely,
Javier Praena, ICNCT 19 Congress Chair.
Ignacio Porras, President of ISNCT*,**,***：each underlined date is update one.

28

NCT letter Issue 7 August 2020

Guide for the 17th Congress on Japanese Society of
Neutron Capture Therapy
Jun Itami
Head of the Department of Radiation Oncology
Cancer Center Hospitalat the National

This year, thanks to all of my fellow scholars, I have been given the opportunity to holdthe 17th Congress on Japanese Society of Neutron Capture Therapy in Atami over thetwo-day span of July 11th-12th. I am truly honored as a clinician specializing in radiation
oncology. This would not have been possible were it not for the efforts of the doctors wholaid the groundwork of boron-neutron capture therapy (BNCT) through nuclear reactors
and the doctors who exerted themselves to realize BNCT through particle accelerators.
The maintenance of theoretical systems like these and the development of BNCT facilities
capable of being established within hospitals are what have enabled even doctors
ordinarily performing radiation oncology practices to participate in BNCT. BNCT is truly
following the path from something unique to something progressively more common.
While it seems like ages ago now, when I was just a rookie doctor going into the medical
office, I met a prestigious, aging old man. He was the former teacher of my former teacher,Dr. Hirotake Kakehi, Professor Emeritus. He was a doctor with extensive knowledge suchthat he could identify meningitis from an abnormal accumulation in the cranium by image
reading through a bone scintigraphy. However, he wasn't just your average good-natured
old man. He created a new era of nuclear medicine. All of the nuclear medicine techniquesand equipment at the beginning of my career as a doctor were developed upon thefoundation laid by Dr. Kakehi.
In the beginning, there was a liver scintigram drawn onto paper represented by anaccumulation of dots from a dot printer. Then that became film, which later became
digitized images. The development of tracers thereafter were built upon the physicalscience foundations set by doctors like Dr. Kakehi and my former teacher Dr. Noboru
Arimizu, who did not even have computers to aid them. The particle accelerator BNCT
that we see today has reached a stage in development that has extensively grown,
stemming out of these foundations. We have come to understand that we can attain asufficient quantity of neutrons using particle accelerators in BNCT. In the future, we must
aim towards improving the efficiency of neutron generation out of neutron sources, the29

NCT letter Issue 7 August 2020

miniaturization of devices, and mobilization of gantries. Furthermore, we must develop
new boron agents using those neutron sources. It is also vital that we examine CBE foreach organ.
Karl Marx once said ”Daher stellt sich die Menschheit immer nur Aufgaben, die sie lösenkann”, meaning "Mankind inevitably sets itself only such tasks as it is able to solve."
Were it not for the ability to output a sufficient quantity of neutrons using particle
accelerators, we would not have been able to set these tasks for ourselves. These tasks
that have come before us are ones that we can solve.
The topic these days has been photoimmunotherapy. In photoimmunotherapy, it is clearthat it is necessary to irradiate antibodies that have bound with tumors using light and thatthe heterogeneity within this photoirradiation is connected to recurrence. The sameproblem is thought within BNCT, but compared to photoimmunotherapy, in BNCT, it isbelieved that the problem is more easily solvable using permeable neutrons.
10 years in the future, the things on which we now gingerly spend time might become
simple routine tasks. 20 years in the future, BNCT might become the initial treatment
towards large numbers of primary tumors. Apologies for all of the citations, but in thewords of Hegel, “die Eule der Minerva beginnt erst mit der einbrechenden Dämmerung
ihren Flug” (“the owl of Minerva spreads its wings only with the falling of the dusk”).
The Owl of Minerva that is BNCT may not take flight given its current stage. The
challenge we face over the next 10 to 20 years is to bring this Owl of Minerva into fruition.
I hope that this conference in Atami will leave an impact on the future of BNCT.
I am truly excited to welcome everyone in the Department of Radiation Oncology at the
National Cancer Center Hospital and everyone here in the beautiful city of Atami. Let's
all have a great and worthwhile time.

At the board meeting in April, 2020 held via Zoom, it was decided topostpone the 17th Congress on Japanese Society of Neutron Capture
Therapy ( Chairperson: Dr. Jun Itami) until July 2021.

30

NCT letter Issue 7 August 2020

The Best Presentation Award of the 16th Congress on Japanese Society of
Neutron Capture Therapy
Study on QA by phantom using 3D printing technology
in BNCT
1

Akinori Sasaki, 2Takushi Takata, 3Shinji Kawabata
4Shin-ichi Miyatake, 2Yoshinori Sakurai
2
Minoru Suzuki, 2Hiroki Tanaka
1) Graduate school of Engineering, Kyoto University,
2) Institute for Integrated Radiation and Nuclear Science, Kyoto University3)Osaka Medical College
Introduction:
In order to improve the quality of treatment in BNCT, it is desirable to evaluate thethermal neutron flux of each patient and to verify the dose before irradiation. In this study,
patient-specific water phantoms were created using 3D printing technology to enable
patient QA, and dose verification was performed. We report on the verification of thedose distribution based on the irradiation test before the treatment according to thetreatment plan.
Materials and methods:
A case of angiosarcoma was selected in this study. Surface data around the affected area
was created from CT data for treatment planning using the 3D surface rendering functionof OsiriX. This surface data was processed using 3D data processing software Meshmixer
and Autodesk Fusion 360, and a phantom of the affected area was created using a 3D
printer AGILISTA-3110 manufactured by Keyence. The structure of the phantom wasdesigned to allow water to be sealed inside the phantom.
The thermal neutron flux on the surface of the phantom was measured using the gold
activation foil method. Gold foil and gold wire with cadmium cover were placed on thephantom surface and irradiated with an epithermal neutron beam from the KUR heavy
water neutron irradiation facility. To increase the thermal neutron flux on the skin surface,a bolus was installed on the phantom surface. After the irradiation, the thermal neutron
flux distribution on the phantom surface was derived by measuring the amount of gold
activation, and the thermal neutron flux at the position of the gold foil was calculated by31

NCT letter Issue 7 August 2020

SERA and compared with the measured results.
Results:
As a result of the irradiation test, the thermal neutron flux distribution on the phantom
surface was obtained. By comparing the results of this phantom irradiation test with thetreatment plan, it was possible to evaluate the dose distribution on the surface of theaffected skin. In addition, by performing the irradiation test of the phantom of the affectedarea created from the CT data of the treatment plan, it was possible to confirm the dose
distribution in the area with a complicated shape by actual measurement, and to verify
the treatment planning. Furthermore, the effect of the bolus was confirmed.
Conclusions:
In this study, a phantom of the affected area was created from the CT data for treatment
planning, and an irradiation test simulating the actual treatment was performed for a caseof angiosarcoma in KUR. The results of the irradiation tests and the treatment plan by
SERA were compared and verified. It was confirmed that the proposed method in thisstudy can contribute to the improvement of the quality of treatment through patientspecific QA.
In the future, this method will be verified and refined. In addition, by using 3D printing
technology, it will be possible to create a bolus that can adhere to the complex skin surface
and form a uniform thermal neutron flux distribution. We will also develop such a bolus.

Finally, I would like to express my sincere gratitude to Dr. Minoru Suzuki, the conference
director, Dr. Hiroyuki Nakamura, the secretariat of the 16th Neutron Capture Therapy
Conference, and the judges for selecting this presentation as the Best Presentation Award.
I would also like to express my sincere gratitude to Dr. Itsuro Kato for giving me theopportunity to write in NCT Letter.

32

NCT letter Issue 7 August 2020

The Best Presentation Award of the 16th annual Congress on JapaneseSociety of Neutron Capture Therapy
Evaluation of BNCT therapeutic efficacy by a novel
boron compound (BAMP)
Makoto Shirakawa 1,2, Kei Nakai 2, Takumi Omoto 1,
Maki Shigeto 1, Fumiyo Yoshida 2, Ryota Takeuchi 3,
Minoru Suzuki 4, Hitoshi Hori 3,5, Akira Matsumura 2
1

Department of Pharmaceutical Sciences, Fukuyama University
Department of Neurosurgery, Faculty of Medicine, University of Tsukuba
3
Morita Pharmaceutical Ind., Ltd.
4
Institute for Integrated Radiation and Nuclear Science, Kyoto University
5
Niigata University of Pharmacy and Applied Life Sciences2

To perform BNCT most effectively, it is desirable that the boron drug is selective andaccumulates in a large amount in the tumor. It is a well-known fact that the required boron
concentration is more than 25 ppm per tumor tissue, and in addition, the formulation musthave low toxicity, water solubility, and low distribution in normal tissues.
As methods to accumulate boron, there remains an ever-increasing interest andchallenge to use ligands such as antibodies, proteins, and peptides. These methods areused to increase biological selectivity of boron compounds. However, the necessity ofsignificant biological selectivity is unsolved for boron drugs, because BNCT can achieve
physical selectivity depending on the site and extent of neutron irradiation.
Therefore, when developing a novel boron compound, the authors chose the idea ofsafety, solubility in water and the possibility of high dose administration, rather than theidea of increasing its biological selectivity.
The novel compound (named BAMP) is designed, with polyethylene glycol (PEG) and
BSH whose safety has already been established in clinical studies. Since no organic
solvents are used for the synthesis, and both compounds are highly water-soluble, BAMP
is expected to high safety and water solubility.
In addition, we confirmed the pharmacokinetics and anti-tumor effect of BAMP. From
the results, we found that BAMP remained in the tumor for a long time, and significantly

33

NCT letter Issue 7 August 2020

inhibited tumor growth by neutron irradiation at the research reactor of the Institute forIntegrated Radiation and Nuclear Science, Kyoto University.
As the next step, we are optimizing the dosage, administration time, and also the lengthof PEG chain.
Finally, I would like to acknowledge Prof. Minoru Suzuki and Dr. Itsuro Kato for givingme the opportunity to introduce this study. I would also like to thank Prof. Yoshinori
Sakurai, Dr. Hiroki Tanaka, and Dr. Takushi Takata for their kind support about neutron
irradiation.

34

NCT letter Issue 7 August 2020

The Best Presentation Award of the 16th Congress on Japanese Society of
Neutron Capture Therapy
Changes in the immune profile of tumor cells after
BNCT
Mariko Sato, Katsumi Hirose, Yoshihiro Takai
Department of Radiation Oncology, Southern Tohoku BNCT
Research Center
Several anticancer drugs and radiation therapy have been shown to produce immunogenic
cell death (ICD), a cancer cell death that induces an antitumor immune response. In ICD,
calreticulin and high mobility group box-1 (HMGB1), called damage-associatedmolecular patterns (DAMPs), act as mediators of antitumor immunity. It has beenreported that radiation therapy induces the expression of calreticulin and the release of
HMGB1. We hypothesized that BNCT may induce the activation of anti-tumor immunity
in a shorter time and more potently than conventional radiotherapy, and evaluated thechanges in calreticulin expression and HMGB1 secretion by BNCT. Furthermore, there
are several reports of favorable treatment outcomes (1) and abscopal effects (2, 3) inradiotherapy combined with immune checkpoint inhibitors. We investigated the effect of
BNCT on programmed death-ligand 1 (PD-L1) expression.
Human tongue cancer SAS cells and human glioblastoma A172 cells were used in thisstudy. Cells were collected into a suspension and incubated with/without 10B-boronophenylalanine (BPA). Thereafter, the cell suspensions were irradiated with neutrons.
Irradiation was performed using the accelerator neutron generator system (20 MeV
cyclotron with Be target, Pb+D2O moderator) in Aomori prefecture Quantum Science
Center, and the proton charge was 60 mC. Irradiated cells were evenly seeded in 6 wellplates. The medium and cells were collected separately at 24, 48, 72 and 96 hours after
neutron irradiation (NR). HMGB1 concentration of the medium was measured by ELISA.
The expression of calreticulin and PD-L1 were measured by flowcytometry using PEconjugated anti-calreticulin antibodies and FITC-conjugated anti-human CD274
antibodies.

35

NCT letter Issue 7 August 2020

BNCT significantly increased the concentration of HMGB1 and continued to increase in
SAS cells. The expression of calreticulin was increased by BNCT in SAS and A172 cells.
The mean fluorescence intensity (MFI) increased approximately 2-fold in SAS cells and1.5-fold in A172 cells compared to the control. PD-L1 positive cells markedly increasedby BNCT in both cells and continued to increase.
We revealed that BNCT dramatically promotes HMGB1 secretion and calreticulin
expression. Moreover, since PD-L1 expression was promoted by BNCT, it was suggested
that an environment where the combined use of BNCT and PD-L1 inhibitors can beeffective for tumor control effect of BNCT may be induced.
【References】
1. S J Antonia et al. Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell
Lung Cancer. N Engl J Med. 2017; 377(20): 1919-1929
2. C Britschgi et al. Report of an abscopal effect induced by stereotactic bodyradiotherapy and nivolumab in a patient with metastatic non-small cell lung cancer. Rad
Oncol. 2018; 13(1): 102.
3. C A Baker et al. Concurrent radiotherapy and ipilimumab immunotherapy for patientswith melanoma. Cancer Immunol Res. 2013; 1(2): 92-98.

36

NCT letter Issue 7 August 2020

Travel Grants Award of the 10th Young Researchers BNCT Meeting
A study on development of remote-changeable Bonner
sphere spectrometer for characterization in BNCT
irradiation field

Shiraishi Sadaaki1), Takushi Takata2), Hiroki Tanaka
2)and Yoshinori Sakurai2)
1) Graduate School of Engineering, Kyoto University,
2) Institute for Integrated Radiation and Nuclear Science, Kyoto University
Introduction:
At the Kyoto University Reactor (KUR), the multi-foil activation method is used toevaluate the energy spectrum of the neutron irradiation field for BNCT. However, there
are few types of activation foils that can be used to evaluate the epi-thermal neutron region,
especially the keV region. Then, a Bonner sphere spectrometer is also used. There aresome problems with a general Bonner sphere spectrometer such as (1) It is necessary toenter the irradiation chamber to replace the moderator. (2) Responses are obtained foreach moderator thickness, but not all response data are effectively utilized in the final
spectral evaluation. (3) In the epi-thermal neutron region, the energy resolution is poor
due to the flat response function regardless of the thickness of the moderator. In order tosolve these problems, a new-type Bonner sphere spectrometer by the name of “Remotechangeable Bonner sphere spectrometer” has been developing. An optimization study was
performed for this new-type spectrometer mainly by simulation.
Methods:
The Bonner sphere was optimized assuming the following configurations and conditions
with reference to the previous studies.
- A five-layer concentric spherical acrylic shell is used as a container for the Bonner
spheres.
- Pure water and 0.15-weight-percent boric acid water for boron-10 (45 g/L solubility at
20 degree Centigrade) are used as liquid moderators.
- The moderator injection part is 10 mm or 20 mm with the same thickness in each layer.

37

NCT letter Issue 7 August 2020

- Each acrylic wall is 1 mm, 2 mm, 3 mm, 4 mm or 5 mm, and all walls have the same
thickness.
- A LiCaF scintillation detector is used for online measurement.
The simulation was performed for thirty-three different injection patterns for themoderators in each of 10 types of multi-layer concentric spheres with different acrylic
wall thickness (5 types) and moderator injection layer thickness (2 types) using Monte
Carlo calculation code "PHITS”. Widely different response functions were selected using
the obtained response function matrix, and the combinations for the moderator injection
patterns was optimized.
Results:
From the optimization study, it was resulted that the
thickness of the acrylic wall was 3 mm, the thickness ofthe moderator injection layer was 10 mm, and fivecombinations for the injection patterns were sufficient.
Figure 1 shows an example of the optimized
combinations for the moderator injection patterns.

Acrylic thickness : 3mm

Liquid moderator injection part : 10mm

Blue area → Pure water
Yellow area → Boron acid water

Fig. 1 An optimized combinations.

Future plan:
Based on the optimization, a prototype spectrometer is to be built with experiments
planned of the BNCT irradiation field at KUR to confirm its effectiveness.
Impressions of attending the conference:
This is the second time I have attended the Young Researcher's BNCT Meeting,following the previous one held in Uji, Kyoto, and the second time since the International
Congress on Neutron Capture Therapy held in Taiwan in 2018. This is the second time I
have participated in an international conference, so I could calmly give a presentation andlisten to presentations by foreign researchers. In addition, at the social gathering, I could
have direct discussions with foreign researchers. I would like to continue to actively
participate in international conferences.
Lastly, I would like to thank Prof. Takushi Takada, Prof. Hiroki Tanaka and Prof.
Yoshinori Sakurai for their instruction. I also would like to thank Dr. Hanna Koivunoro(Meeting Chair) for selecting my presentation to Travel Grants Award, and Prof. Itsuro
Kato for giving me the opportunity to write this article.

38

NCT letter Issue 7 August 2020

Travel Grants Award of the 10th Young Researchers BNCT Meeting
Evaluation of a treatment planning system used for
BNCT at the Kansai BNCT medical center
Naonori Ko
1) Kansai BNCT Medical Center, Osaka Medical College
2) Institute for Integrated Radiation and Nuclear Science, Particle Radiation Oncology
Research Center, Kyoto University
The 10th Young Researchers’ BNCT meeting was held in Finland, Helsinki from2019/9/26 ~ 2019/9/29. This was my first attendance at an international conference after
graduating from university. As many of you are aware, it is difficult to obtain researchfunds early in your career to attend international conferences. I was fortunate enough toreceive a travel grant to attend this conference.
The title of my presentation was evaluation of a treatment planning system used for BNCTat the Kansai BNCT Medical Center. At the Kansai BNCT Medical Center, a phase II
clinical trial of grade 2 and 3 meningioma has begun, and the center is aiming to provide
BNCT medical care in the year 2020. The center is fitted with a cyclotron-based
epithermal neutron source (C-BENS), providing high flux of epithermal neutrons to treat
tumors located several centimeters below the surface of the skin. The treatment planningsystem used during the clinical trial was the Simulation Environment for Radiotherapy
Applications (SERA). Evaluation of a TPS is crucial to understand the limitations of thesystem to allow a better understanding on the treatment outcome. This study aims toevaluate SERA TPS by comparing the results against measured data.
The SERA simulation showed a good agreement with measured values (difference of lessthan 2%), with the exception near the buildup region (i.e. up to 2 cm depth) and at depths
greater than 5 cm. From a clinical perspective, the surface dose (i.e. dose delivered to theskin region) is extremely important and an accurate determination is desirable. Given thecalculation voxel size used in SERA is a 10 mm cube, the uncertainty in the flux and dose
simulation around the buildup region is high. A more robust Monte Carlo system, such as
Particle and Heavy Ion Transport code System (PHITS), will be used to evaluate thethermal neutron flux and dose distribution at these regions.
39

NCT letter Issue 7 August 2020

The author would like to thank Hanna Koivunoro and the organising committee membersof the 10th YBNCT for kindly supporting my travel.

Figure 1a) Thermal neutron flux along the central axis for the 10 cm diameter collimator. b) Off-axis thermal neutron
flux at a depth of 2.5 cm for a 12 cm diameter collimator.

Figure 2 (Top) South Harbour, Helsinki. (Bottom left) Author and graduate engineering students
at Kyoto University, (Bottom right) Entrance hall of the conference venue.

40

NCT letter Issue 7 August 2020

Travel Grants Award of the 10th Young Researchers BNCT Meeting
Development of Gamma-ray Dosimeter Using RadioPhotoluminescence Glass Dosimeter and Gamma-ray
Filter in A Neutron/Gamma-ray Mixed Field for
BNCTTokiya Inoue
Division of Sustainable Energy and Environmental Engineering, Graduate School ofEngineering, Osaka University

1. Introduction
Boron neutron capture therapy (BNCT) is a radiation therapy that requires an accurate
understanding of the patient's dose. However, since the irradiation field is a mixed fieldof neutrons and gamma-rays, it is difficult to accurately measure the patient's dose.
Therefore, we have proposed a method to measure the gamma-ray exposure dose in themixed field using RadioPhoto-Luminescence Glass Dosimeters (RPLGD) that is
generally used as a personal dosimeter. In this study, two dosimeters are used and covered
with different shielding filters appropriately designed so that the difference in their
gamma ray responses becomes equal to the air kerma coefficient. We named this methodthe "shielding filter method". Currently, we are studying a method of controlling the
response of one RPLGD by giving a distribution to the thickness of the shielding filter.
By setting the response of one RPLGD to be equal to the air kerma coefficient, it canmeasure dose in a wide-energy gamma-ray field. This time, we describe the result ofirradiation experiments with one RPLGD with a shielding filter made by iron.
2. Materials and methods
The response 𝒇𝐴 [µGy/h/(cm-2∙sec-1)] of the RPLGD covered with a shielding filter canbe expressed as 𝒇𝐴 = 𝑹 ∙ 𝒕 using the response function matrix 𝑹[µGy/h/(cm-2∙sec-1)] of
the RPLGD with the filter material and the filter
thickness ratio 𝒕 . The filter shape was designed by
2cm
solving 𝜶 = 𝑹 ∙ 𝒕 for 𝒕 using Baysian estimation
method so that this response 𝒇𝐴 is equal to the air
kerma coefficient 𝜶 [µGy/h/(cm-2 ∙ sec-1)]. 𝑹 is
41

NCT letter Issue 7 August 2020

calculated absorbed dose of RPLGD when covered with a shielding material of eachthickness using the particle and heavy ion general-purpose Monte Carlo code PHITS(Particle and Heavy Ion Transport code System) [1]. This time, we adopted iron as theshielding material. As shown in Fig. 1, the design results were 0 mm: 20%, 2 mm: 20%,
4 mm: 25%, 10 mm: 35% with respect to the reading area (6 mm in height) of RPLGD(GD-301). Irradiation experiments with this filter were conducted with standard radiation
sources (133Ba, 137Cs, 60Co) and in a nuclear fuel storage room (~2 tons of naturaluranium) in OKTAVIAN facility of Osaka University, Japan.
Figure 1 Photo of thedesigned filter.
3. Result
Figures 2 and 3 show the results of irradiation experiments with standard radiation
sources and in front of the nuclear fuel storage room, respectively. From Fig. 2, it can beseen that in the case of 137Cs and 60Co, the agreement of experiment and calculation is
acceptable, however, in the case of 133Ba, the measured dose is slightly smaller than thecalculated value. In addition, the irradiation result in front of the nuclear fuel storageshows that the experimental value is slightly larger.

Fig.2 Experimental result.
Experimental result.
(Standard γ-ray sources)

Fig. 3(Nuclearfuel storage room)
4. Discussion and conclusion
For the discrepancy observed in the result of 133Ba we expect that it is due to adifference between the actual response in the low energy region of RPLGD (read with
FGD-1000) and the estimation by PHITS (calculated absorbed dose). It is generally said
that the actual response in the low energy region shows lower than Monte Carlosimulation, which seems to be consistent with the experimental result.
42

NCT letter Issue 7 August 2020

As for the reason why the measured dose shows slightly larger in front of the nuclear
fuel storage room, we expect it is that the filter is designed under the condition that the
gamma-rays are incident in parallel from the side. In other words, for accurate dosimetry
we should consider strictly photons entering the RPLGD from various directions whenirradiated with a volumetric source such as the case in front of the nuclear fuel storage
room.
5. Future work
The R matrix will be modified by making clear the response difference between PHITS
response and the actual one. In addition, we think that the effect of random photon
incidence can be reduced by making the filter thinner. And for that, we plan to design a
new filter that employs multiple materials to reduce the thickness.
Acknowledgement
Finally, I would like to express my sincere gratitude to Dr. Isao Murata for hiscooperation in making the presentation at this conference and Dr. Itsuro Kato for givingme the opportunity to write a paper in this NCT Letter.
【Reference】[1] Y. Iwamoto et al., “Benchmark study of the recent version of the PHITS code”，J.
Nucl. Sci. Technol., 54[5], pp. 617-635(2017).

43

NCT letter Issue 7 August 2020

Receiving ESMO 2019 Merit Award of ESMO
Updated results of a phase II study evaluating
accelerator-based boron neutron capture therapy(AB-BNCT) with borofalan(10B) (SPM-011) inrecurrent squamous cell carcinoma (R-SCC-HN) andrecurrent and locally advanced non-SCC (R/LAnSCC-HN) of the head and neck
Katsumi Hirose
Southern TOHOKU BNCT Research CenterI have attended European Society for Medical Oncology (ESMO) Congress held inBarcelona from Sep. 27th to Oct. 1st in 2019 and have presented the results of the phase Ⅱ
study of accelerator-based boron neutron capture therapy (BNCT) for recurrent andlocally advanced head and neck cancer.
It was the first time for me to attend an ESMO, and I was impressed by the scale andquality of the lectures. It incorporated a lot of useful tips on established standard
treatments that would help clinical oncologists with tomorrow's practice, and that wasdifferent from ASCO (American Society of Clinical Oncology), which lays greatemphasis on advanced and important clinical trials that can change the future standardsof the therapies. There were many people who stopped at my poster presentation, andasked me questions or gave their opinions frankly such as "What is boron neutron capture
therapy?" "What is that?" or "I didn't know there was such a treatment." Those comments
made me realize that BCNT was still not well known and left me feeling deflated. Evenso, when I had discussions with those participants, they formed positive expectations forthis treatment with the desired outcomes, and many said that they hoped that theapplication of the treatment would be extended to treat various types of cancers. Although
I was unable to take part in the Young Researchers BNCT Meeting held in Finland during
the same period, the experience in ESMO reminded me of the importance ofdisseminating information at these international conferences of clinical oncology.
The presentation was titled "Updated results of a phase Ⅱ study evaluating acceleratorbased boron neutron capture therapy (AB-BNCT) with borofalan (10B) (SPM-011) inrecurrent squamous cell carcinoma (R-SCC-HN) and recurrent and locally advanced nonSCC (R/LA-nSCC-HN) of the head and neck." I showed the updated results of the phase44

NCT letter Issue 7 August 2020

Ⅱ study I presented at ASCO this year. Eight patients with local and locoregionallyrecurrent squamous cell carcinoma of head and neck and thirteen patients with locallyadvanced non-squamous cell carcinoma of head and neck were continuously administeredwith 500 mg/kg borofalan (10B) (generic name of 10B-BPA). After two hours, neutron wasirradiated until the maximum dose of the oral mucosa, nasopharyngeal, oropharyngeal,
and hypopharyngeal mucosa and laryngeal mucosa reached 12 Gy-Eq. The primary
endpoint was the objective response rate of 90 days, and the antitumor efficacy and safety
were evaluated as the secondary endpoint. The objective response rate for all the patientswere 71.4%, and CR/PR (complete response/partial response) of patients with squamouscell carcinoma (R-SCC-HN) and patients with non-squamous cell carcinoma (R/LAnSCC-HN) were 50.0%/25.0% and 7.7%/61.5% respectively. With a median follow up of
21.3 months (range, 9.2–30.6), 1-year progression-free survival (PFS) by investigator
review were 70.6%. For adverse event, nausea, dysgeusia, acute parotitis were observed
frequently.
I have received Merit Award from ESMO for this poster display session. This
achievement is not at all the result of myself or of a facility, but the result of the efforts
made by the researchers of this society who have led the world’s BNCT research. As an
extension of their assiduous work, I would be very happy if our clinical ingenuity helped
bring about this successful outcome.

45

NCT letter Issue 7 August 2020

Introduction of the articles
1. <Pharmaceutical Science >Tooru AndohAssistant Professor
Laboratory of Frontier Pharmaceutical Technology, Faculty of
Pharmaceutical Sciences, Kobe Gakuin University

Title: Intracellular Target Delivery of CellPenetrating Peptide-Conjugated Dodecaborate for Boron Neutron
Capture Therapy (BNCT)
Authors: Ikuhiko Nakase, Miku Katayama, Yoshihide Hattori, Miki Ishimura,Shunsuke Inaura, Daisuke Fujiwara, Tomoka Takatani-Nakase, Ikuo Fujii, Shiroh
Futaki, Mitsunori Kirihata

The source: Chem Commun (Camb) 2019; 55(93), 13955-13958.
Microsoft Word - Nakase-Katayama ChemComm Supplementary Information.docx (rsc.org)

2. <Physical Engineering >Nishiki Matsubayashi
Graduate school of Engineering, Kyoto University

Title: A dual natural lithium formate/L-alanine EPR
dosimeter for a mixed radiation field in a BNCT
irradiation facility
Authors: G. Alejandro, J. Longhino, N. R. Alvarez, E.Pawlak, A. Butera
The source: Journal of Physics D: Applied Physics 2020; 53:19
A dual natural lithium formate/L-alanine EPR dosimeter for a mixed radiation field ina boron neutron capture therapy irradiation facility - IOPscience46

NCT letter Issue 7 August 2020

3. <Medicine>
Tsubasa Watanabe
Program-specific Associate Professor
Institute for Integrated Radiation and Nuclear Science, Kyoto
University

Title: Radiation and dual checkpoint blockade
activate non-redundant immune mechanisms in cancer
Authors: Christina Twyman-Saint Victor, Andrew J. Reck, Amit Maity, Ramesh
Rengan, Kristen E. Pauken, Erietta Stelekati, Joseph L. Benci, Bihui Xu, Hannah Dada,
Pamela M. Odorizzi, Ramin S. Herati, Kathleen D. Mansfield, Dana Patsch, Ravi K.
Amaravadi, Lynn M. Schuchter, Hemant Ishwaran, Rosemarie Mick, Daniel A. .
Pryma, Xiaowei Xu, Michael D. Feldman, Tara C. Gangadhar, Stephen M. Hahn, E.
John Wherry, Robert H. Vonderheide, Andy J. Minn.
The source: Nature 2015; 520:373-380.
https://www.nature.com/articles/nature14292.pdf<Review of the paper>
In recent years, X-ray irradiation to tumors has been shown to evoke a variety of tumor
immunostimulatory effects, which is thought to be a new aspect of the anti-tumor
effects of radiotherapy. The primary purpose of this paper was to investigate the effectof radiation and immune checkpoint inhibitors (ICBs) such as an anti-PD1 antibody(P1) and anti-CTLA4 antibody (C4). Mechanistic analysis has revealed that irradiation
has an immunostimulatory effect that does not overlap with other immunotherapies.
First, the combined effect of RT+P1+C4 was demonstrated in an abscopal mouse model(tumors were implanted on both sides, and only one side was irradiated) (Figure 1, d),(https://www.nature.com/articles/nature14292/figures/1 ), and this was due to anincrease in functional CD8+ T cells. (Figure 1, d)(https://www.nature.com/articles/nature14292/figures/1 ), indicating that the increase infunctional CD8+ T cells was a contributing factor why RT + ICBs combination had
better effects on tumor control. Next, they examined the clonality of T cells infiltratingtumor tissue in the C4 alone group compared to the RT+C4 combination group andfound that the clonal frequency of T cells increased and the diversity of T cell receptors
increased with irradiation (Figure 3, c, d)47

NCT letter Issue 7 August 2020

( https://www.nature.com/articles/nature14292/figures/3 ). Surprisingly, irradiation
increased significantly the repertoire of T-cell receptors and thus their reactivity. They
showed that RT has non-redundant synergistic effects on anti-tumor immune reactions(Extended Data Figure 6, e) (https://www.nature.com/articles/nature14292/figures/10 ).
<Comments>
This is an exciting paper focusing on the immunostimulatory effects of radiation withdetailed analyses.
In clinical practice, the tumor cure rate of X-ray irradiation and immunotherapy
combination is still not satisfactory. In the future, it will be necessary to develop atreatment strategy that combines not only radiation and C4/P1/anti-PD-L1 antibody but
also other immunomodulators. In recent years, we conducted a mouse study using an
indoleamine 2,3-deoxygenase inhibitor, one of the immunomodulators, as combination
therapy of RT + P1 + α, and obtained a positive effect and analyzed the mechanism(Watanabe et al. Clinical Cancer Res 2020).
In reading this paper, along with BNCT standpoint of view, the following point should
be noted. The combination of C4+P1 has a high incidence of adverse events, and theregimen including the combination of C4+P1 should not be recommended for all patientsroutinely, and this is also the case with BNCT. Regarding BNCT, we need to knowwhether BNCT + immunotherapies is better than BNCT alone first, and the mechanisms
underneath it.

48

NCT letter Issue 7 August 2020

Editor’s Postscript
On the Publication of NCT letter Vol.
7Chief 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 themembers of the Japanese Society of Neutron Capture Therapy (JSNCT). We could
publish the NCT letter No. 7 supported by the all of contributors. I worked with Prof.
Mitsuko Masutani (Nagasaki University) and Prof. Teruyoshi Kageji (Tokushima
Prefectural Kaifu Hospital). Prof. Minoru Suzuki, a new president of this Society also
gave us suggestions.
Prof. Suzuki wrote “JNCT Greetings from the inaugurated President ” with enthusiastic
thought at the beginning of NCT letter No. 7. BNCT System NeuCure® by Sumitomo
Heavy Industry for an unresectable, locally advanced, and recurrent carcinoma of thehead and neck region under the national health insurance system on 1st June in 2020.
The related articles have been written by Prof. Takai and Prof. Hirose in the Special
article, and that of the Awardees of BNCT related Conferences or Meetings, respectively.
Prof. Nomoto of Tokyo Institute of Technology, wrote on the hot topic about “liquid glue”,
PVA-BPA which is additively enhancing the therapeutic potential of BPA. His animalmodel experiments demonstrated its usefulness and possibility in BNCT.
About the progress of each BNCT facility was reported by Prof. Kumada (Tsukuba
University), Prof. Kiyanagi (Nagoya University) and Prof. Suzuki (Kyoto University).
I asked Associate Prof. Watanabe (Kyoto University) to introduce articles which
demonstrate the relationship between radiation therapy and host immunity, from various
viewpoints. I will recommend the young members to read “Introduction of the articles”
I expect and wish every success to all of the members of JSNCT and I will try to send
all activity of JSNCT members to foreign countries as much as possible at real time,through linking HPs of ISNCT and TCNCT to that of JSNCT.
I would like to take up the media news, the transfer of the members, a new plan, an
article about BNCT including the contribution to this letter desired widely. I would liketo think about with you a new role of our committee in New Era of “with corona virus”
I’m very happy if you could frankly give me your opinion. Thank you for yourcooperation.
49