Global Conference on Neuroscience and Neurology August 24 2019 Chicago, Hiroshi Horiike Fukui University of Technology Osaka University

1. Progresses in Liquid Li based
neutron source for BNCT
Hiroshi Horiike
Fukui University of Technology
Osaka University
Global Conference on Neuroscience and Neurology
August 24 2019 Chicago

2. Contents
• Introduction BNCT
• Lithium as the beam target
• Physical Experiments
• Performance and Prospects
• Summary

3. What is BNCT (Boron Neutron Capture Therapy)
3
BNCT is a kind of particle beam therapy that selectively destroys cancer cells with using
reaction between a slow neutron and a boron accumulated in a cancer cell.
<Source: Association For Nuclear Technology in Medicine website>
Cancer
cell
5G
y
20Gy
exposure
Nutrient with boron is
swallowed by active
cancer cells.
Boron
Compound
s
Cancer
cell
Normal
cell
Energetic ions work as a
heavy ion therapy.
Cancer cells with many
boron are selectively
destroyed.
10B + n → He + Li + 2.31MeV + γ ray
where
Eα=1.47MeV, ELi=0.84MeV, Eγ=478 keV
Ion’s ranges < 5 – 7mm < cell diameter
Accumulation, T/N ratio measurable by PET

4. Status of CSePT
4
Operation
Chemo-
therapy
Radiation
Photon
beam
Gamma
beam
X-Ray
Particle
beam
Proton
beam
Heavy
particle
beam
Neutron
beam
(BNCT)
Beryllium
method
Solid Lithium
Method
Liquid Lithium
Method CSePT
Immuno-
therapy
Nuclear
reactor
method
Cyber Knife
IMRT
Next
Generation!
BNCT : Boron Neutron Capture Therapy
CSePT ： Cell Selective Particle Therapy

5. Cases of nuclear reactor-based BNCT
5
Country Facility CASE Period
Japan Kyoto Univ. Research Reactor (KUR) 510 ~2014.5.22
Finland Finland Research Reactor (FiR-1) 318 1991~2012
Japan Japan Research Reactor (JRR-4） 107* 1999~2007, 2009~
U.S.A. Brookhaven 99 1951-61, 1994~99
Sweden R2-0 Research Reactor 52 2001~05
U.S.A. MIT Reactor 42 1959~61, 1994~99
Taiwan Tsing Hua Open-pool Reactor (THOR) 34 2010~
Netherlands Petten Reactor (HFR Petten) 22 1997~
Argentina Research Reactor 7 2003~
Italy Research Reactor 2 2002~
Czechia LVR-15 2 2000~
<As of November 2014>
*53 of them were carried out by the Kyoto University group and cooperative researchers
during the shutdown period of Kyoto University nuclear reactor.
<Source: “Conference for promotion of practical use and formation of base of BNCT” Osaka Prefecture, 2014>

6. BNCT using nuclear reactors has attained excellent treatment results for many years.
However,
there is a big problem, that is,
the use of nuclear reactors.
● Limited machine time for patients
● Shut down of available nuclear reactors
Many patients and medical professionals were eager to re-operate.
Increasing requirement about nuclear reactor-free BNCT
Ion beam irradiation onto beryllium or lithium target generate high energy
neutrons.
These neutrons could be used with suitable moderation in energy
Accelerator-based BNCT further reduced patients' exposure from nuclear reactor BNCT.
Towards accelerator-based BNCT
6

7. Structure of accelerator-based BNCT
7
Proton accelerator
Cut double helix in the cell
Ion source Proton beam
Target
Neutron moderation unit
Neutron
Boron
Helium nucleus
Lithium nucleus
Cancer
cell
Irradiate cancer cell with neutrons
obtained by the accelerator
Reacts with boron atoms
ingested in cancer cell
Nuclear reaction
The range of energetic ions
from reaction is shorter than
the cell diam.

8. What is CSePT
8
Next-generation type of BNCT by liquid lithium method
Proton
accelerator
Ion source Proton beam
Target
Neutron
Moderation
unit
Liquid lithium loop
Neutron
Liquid lithium
flowing target
● Low exposure
● Stable operation
● No target
replace
Neutrons from the lithium
target are low in energy,
so that the (n, g) reactions
are much less.

9. Dose Components for Tumors
and Tissues
1H(n,n)p
14N(n,p)14C
mucosa < 12 Gy
This Dose is
minimized with
Lithium
Malignant Cells
Normal Cells
Depends on T/N ratio
H.Kumada, K.Takada Therapeutic Radiology and Oncology 2018; 2:50

10. covalent binding = 1eV
Neutron = 0.1eV
Thermal neutrons do not produce harmful
effect in human body
CARBON
HYDROGE
N

11. covalent binding = 1eV
Neutron = 0.1eV
High energy neutrons recoil protons which
produce harmful effects
CARBON
HYDROGE
N

12. FBPA-PET
Jun Hatazawa
Professor Osaka University Faculty of Medicine

13. COOH
NH2
CH
CH2
HO
HO
10
B
F
18
Boron-10 Carrier and PET Imaging Tracer
18F fluoro-borono-phenylalanine
COOH
NH2
CH
CH2
HO
HO
10
B
10B borono-phenylalanine
BNCT
PET
measurement
18F
e+
e-

14. 18F-BPA PET in normal volunteers
0-4.5min 6.5-11.5 13.1-17.5 19.6-24.1 26.1-30.6 32.7-37.2 39.2-43.7
Shimosegawa E, et al. Ann Nucl Med (2016) DOI 10.1007/s12149-016-1121-8
COOH
NH2
CH
CH2
HO
HO
10
B
F
18

15. T2WI T1WI(CE+)
PET/CT
PET
FBPA PET
(60min after injection) Beshr R, et al. Ann Nucl Med 2018 Dec; 32(19): 702-708
FBPA PET in Radiation Necrosis
FBPA PET
10

16. 10
FBPA PET in Radiation Necrosis
Beshr R, et al. Ann Nucl Med 2018 Dec; 32(19): 702-708
FBPA PET
(60min after injection)
T1WI(CE+)
PET/CT FBPA PET

17. Lithium for intense neutron source
• Lithium has excellent properties for intense neutron source
• Low vapor pressure enables forced circulation in vacuum space
• High cooling capacity for beam heat deposition
• Liquid lithium target technology has developed in Nuclear
Fusion research called
‘International Fusion
Materials Irradiation
Facility:IFMIF’
• Down sizing this will
lead to BNCT system
17

18. Liquid Metal Lithium Loop
The Li facility for IFMIF was constructed by a
transfer of engineering experiences of LI and
personnel, from Osaka to Oarai center in
Japan Atomic Energy Agency.
For the BNCT application, much smaller
facility is sufficient. A very stable neutron
generation can be attained with using a
liquid metal system.
Osaka University Loop
ELTL
(Oarai,
JAEA)
Up grade
BNCT
target
P-beam
Li Flow
50mm
~2mm
n g
15m/s

19. Liquid Metal Lithium Free Surface Flow
15cm
7cm

20. Experiments on neutronics
Li neutron production test in Birmingham University
Ampere
1mA 1mA 30mA
Design Value：30mA 2.5MeV
Neutron Flux:109/sec・cm2
2012
Tohoku Univ.
Source term exp.
2013
Birmingham Univ
1. Produced neutron properties and accompanying gamma rays and high
energy components of neutrons were studied in detail.
2. Calibration of numerical code system, and verification of irradiation
performances up to 30mA.
Moderator assembly exp.
2017

21. Experiments
2013 June at Birmingham University
 Dynamitron Accelerator
Beam species ： Hydrogen
Energy ：2.25,2.65,2.95(MeV)
Current on average ：450 mA
 Neutrons Generated
Energy：700keV at maximum
Yield ：～4.5×1011 n/sec
 Measurements
Neutron：Gold foil（198Au)
Gamma：Glass dosimeter
Foils and glass chips were placed inside
and under the moderator, and inside of
phantom.
 Target : Li
Isao Murata, “Mock-up Experiment
at Birmingham University for
BNCT Project of Osaka University
- Outline of the Experiment-
ICNCT-16 Helsinki 2014
Accelerator
Moderator
Assembly

22. Neutron Flux Measurement with Gold Foil
Epithermal neutron profile
Collimator radius(100 mm)
 Neutron flux is collimated well and low beyond collimated radius.
→ Suppression of the total body dose for a patient
Shingo Tamaki, “Mock-up Experiment at Birmingham University for BNCT Project of Osaka
University - Neutron Flux Measurement with Gold Foil –” ICNCT-16 Ps2P01 Helsinki 2014
 A peak of the gamma at the center is partly attributable to neutron doses, which has
verified by numerical analysis and by new differential measurement of g-ray.
→ A glass dosimeter is tested to have sensitivity to neutrons.
Sachiko Yoshihashi, “Mock-up Experiment at Birmingham University for BNCT Project of Osaka
University - Gamma-ray Dose Measurement with Glass Dosimeter – “ICNCT-16 (Ps2 P03) Helsinki
2014
1.E+04
2.E+06
4.E+06
6.E+06
0 200 400 600 800
Neutron
Flux
[neutrons/cm
2
/sec]
Distance from the center [mm]
2.65 MeV w/o phantom
0
5
10
15
20
25
30
35
40
45
0 200 400 600 800 1000
Gamma-ray
dose
[mGy]
Distance from the center [mm]
Experiment
Calculation
Gamma ray profile

23. Estimated completion of CSePT
23
Moderator/Collimater
Operating
room Accelerato
r
Treatment
room
Liquid lithium loop

24. Estimated Real Machine Performance

25. Summary
• Intense neutron sources have developed for Fusion program
which is called IFMIF-EVEDA under treaty of JA and EU
• For BNCT, low energy P-Li reaction system will be very suited
with using a small and stable liquid Li circulation system.
• An accelerator of 30mA at 2.5MV will be fabricated from Fusion
Technology too.
• The moderator system was tested in Birmingham University at
2.65MeV 0.5mA beams.
• Neutron intensity by energy is found to be satisfactory as
designed, and gamma-ray dose be suppressed very low.
• The total whole body dose for a patient aligned perpendicular to
the beam line will be as low as 0.26 Sv/treatment for an example.
• This performance enables us to employ this treatment with no
concern of radiation hazards.