1. Deterministic Parsing model of CBE factor for Intra-cellular 10 B Distribution in Boron Neutron Capture Therapy Shintaro ISHIYAMA ※ a and Yoshio IMAHORI b ※ a Quantum Beam Science Center, Japan Atomic Energy Agency, Tokai-mura, Naka-gun Ibaragi 319-1195 Japan b Cancer Intelligent Care System Ltd, Ariake 3-5-7 Kouto-Ku, Tokyo Japan 1

2. No.Tissue N B-max (μg/g) CBE factor 11）11） Tumor723.8 2 2) Normal skin tissue28.82.5 3 3) Normal brain tissue201.34 4 4) Normal oral mucosal tissue21.54.87 5 5) Normal liver tissue244.25 6 6) Normal lung tissue242.3 7 7) Normal heart tissue241.35 1 ） Fukuda et al,. 1994, 2 ） Kiger et al., 2008, 3 ） Suzuki et al., 2000, 4-7 ） Morris et al., 1997 with BPA experiments of mice Physical Dose Rate of BNCT D= （ 6.78×N×RN+6.93×N B ×CBE ） ×Φ×10 -14 +γ N ： Nitrogen density, RN: 14 N(n,p) 14 C, N B : Boron density, CBE ： 10 B(n,α) 7 Li BPA : Boronophenylalanine CBE=Compound Biological Effectiveness B OH 18 F CO 2 HH2NH2N 2

3. No relation was found between N B-max and CBE factor ! 3 123 45 60 0 20 40 60 80 CBE factor N B-max (μg/g) Tumor Liver Skin Lung Heart Brain Oral Normal tissues 10 BPA B OH 18 F CO 2 HH2NH2N ?

4. 4 Ⅰ. How to express the CBE factor model for tissues/tumor ? Presentation Ⅱ. How to define CBE factor for Human Brain Tumor by CBE factor model ?

5. BB Atomic distance :2r r0≦rr0≦r r 0 >r BNCT Atomic distance :2r B B r0r0 α range: r 0 (8 ～ 9μm ） α range: r 0 (8 ～ 9μm ） What is CBE in BNCT ? nnnnnnn n n n γ ray Single hit events Duplicative volume : V d Duplicative volume : V d 5 CBE factor γ ray 1 CBE Cell (Beam oriented) (Boron distribution oriented) 10 B(n,α) 7 Li Selective concentration in nucleus is dominant

6. CBE ∝ F ・ V dnol F: Proximity of boron atoms How can be defined the CBE factor model with V d ? V dnol =V d /V 0 V 0 =4/3πr 0 3 B B B B B B B B B B B B B B B B B B BB r0r0 VdVd 6 r V0V0 Volume of spherical cap

7. (1) Duplicative volume model 1 r0r0 V dnol (2) Space filling model Cell 2r 0 2r 1 2r 2 N0N0 N 1 (>N 0 ) N 2 (>N 1 ) Boron 0 0 How can be expressed V dnol ? n: Dimension number(=1,2,3) N th : Eigen-value of N 7 Volume of spherical cap

8. How can be expressed for CBE factor ? From model (1) From model (2) Deterministic Parsing model of CBE factor Where constants: CBE 0, F and n(=1,2,3) Eigen-value: N th, Saturation density: N max where 8 0 ＜ N th /N max ＜ 1

9. Data set (N imax, CBE i ) i=1,2,3 ・・・ n Initial data (CBE 0, F, n(=1,2,3) 0 ) Eigen-value: N ith Data set:(N ith /N imax, CBE i ) (CBE 0, F ） i Least square method YES NO Determination (CBE 0, F, n, N thi ) Correlation (CBE, N max /N th ） r>0.999? n=1,2,3 (CBE 0, F ） i +Δ Iteration 9

10. Simulation results of the CBE factors obtained for normal and tumor tissues by deterministic parsing model Results of simulation Where constants: CBE 0, F and n(=1,2,3) Eigen-value of N: N th Maximum uptake of Boron: N max 10

11. No relation was found between N B-max and CBE factor ! 11 123 45 60 0 20 40 60 80 CBE factor N B-max (μg/g) Tumor Liver Skin Lung Heart Brain Oral Normal tissues 10 BPA B OH 18 F CO 2 HH2NH2N ?

12. 1 Deterministic Parsing Model for the CBE factor with N th /N max 12 0.10.01 0 1 2 3 4 5 6 N th /N max （＝ FD) CBE factor 10 BPA Tumor Oral mucosal Liver Skin Lung Heart Brain CBE 0 = 0.5 F = 8 n = 3 CBE factor model CBE ∝ 1-N th/ N max

13. No. Tissue N max (μg/g) N th (μg/g) CBE factor CBE (Calc.) N th /N max 1Tumor728.713.83.810.121 2Normal skin tissue28.87.202.52.500.25 3Normal brain tissue209.301.341.350.465 4 Normal oral mucosal tissue 21.51.274.87 0.059 5Normal liver tissue242.214.25 0.092 6Normal lung tissue246.672.32.310.278 7Normal heart tissue2411.141.35 0.464 ※ 13 (Calc.)

14. What is the distribution factor DF in CBE factor model ? 14 DF=N th /N max Cell model BPA DF 1 Cell nucleus Endoplasm N max 1-DF

15. What is the CBE 0 ? B B B B BB B B B B B B B B BB B B B B B B B BB BB B B B BB B B B B B B B B B B B B BB BB B B B BB B B B B B BB B B B B B B B N = N th N > N th N < N th r< r 0 r=r 0 r> r 0 15

16. What is the Proximity of boron atoms F (=8)? B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B Mode 2 (F=2) Mode 4 (F=4) Mode 6 (F=6) Mode 8 (F=8) Octahedron B B B B B B B B B B B B B B B B B B TetrahedronHexahedronDihedral 16

17. What is the Space filing factor n ? r/r 0 DF(=N th /N max ) n=3 (Stereo) n=2 (Planar) n=1 (Liner) 00.51.0 0.01 0.1 1 B B B B B B B B B B B B B B B B B B 17

18. 18 Classification of normal tissues/tumor Oral Liver Skin Lung Tumor Brain 0 0.2 0.4 0 4 8 12 DF(=N th /N max ) N th (Calc.), μg/g Normal tissue Heart Group I Group II Group III Group IV 4 3 2 1 CBE factor BPA

19. How to define CBE factor for Human Brain Tumor by CBE factor model ? 19 DF=N th /N max Patients with Glioma AII(8) AIII(11) GBM(13) Total 33 Imahori, Ueda et al., J Nucl Med (1998)

20. 1,8000 20 Definition of DF for the case of tumor and normal tissues 5 10 15 20 25 30 35 40 4,000 8,0001,20001,6000 0 Tissue 10 B content,N (μg/g) Dose of BPA （ mg/kg ） Blood Brain Spinal cord Morris MG et al. (1997) N th DF=1-0.17 (=0.83) (0.8) (0.93) N max Normal tissue DF=1-N th /N max Tumor DF=N th /N max 5050

21. 21 Imahori Y., et al., J Nucl Med (1998) Gjedde-Patlak plotting model(1983) C p (t) C e (t) C n (t) K1K1 k2k2 k3k3 Endoplasm Cell nucleus B in blood K1 k3k3 k2 Dynamic PET TumorNormal K1<k2<k3 K1>k2>k3

22. 22 0.01 0.1 1 0 1 2 3 4 5 CBE factor model Oral （ N ） Liver （ N ） Tumor Skin （ N ） Lung （ N ） Brain （ N ） Heart （ N ） Human brain tumor N:Normal tissue DF(=Nt h /N max ) CBE factor GBM(L) AIII(L) AII(L) Control Grade GBM AIII AII Imahori Y., et al., J Nucl Med (1998)

23. 23 BNCT effectiveness 0 GBMAIIAIII 1 2 3 4 5 CBE factor GBM(DL) AIII(DL) AII(DL) Control Grade Control BNCT effectiveness on tumor grade B in blood ?

24. 24 CBE transition process on the grade of glioma Damage on toughness of membrane in cell and nucleus K1K1 k3k3 k2k2 K1K1 k2k2 k3k3 K1K1 k2k2 k3k3 NormalAIIAIII GBM CBE C p (t) K1K1 k2k2 k3k3 Endoplasm Cell nucleus K1 k2 k3 Positive object Negative K1↑ oriented k3↓ BPA G-P model Imahori Y., et al., J Nucl Med (1998)

25. Conclusion 25 (1) The CBE factor is well expressed by the following equation, DF=N th/ N max, N th : Threshold of boron concentration N max : Boron concentration at saturation point Constant: CBE 0, F, n (2) Calculated CBE factor indicates the BNCT effectiveness on the grade of brain tumor CBE 0 =0.5, F=8,n=3 for BPA

26. 26 Thanks you all for attentive listening BNCT for health and happiness of all patients in the world