Figure 1.1 PHITS geometry for PTB irradiations with: broad beam, upper panel; mono energetic beams, lower panel. Pictures of the setups and of the

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1 Figure 1.1 PHITS geometry for PTB irradiations with: broad beam, upper panel; mono energetic beams, lower panel. Pictures of the setups and of the PMMA ring holder with 7 containers are also shown.

Relative Dose Fluence (1/cm 2 -source) 1.00E-05 1.00E-06 Container #1 Container #2 Container #3 1.00E-07 1.00E-08 1.00E-09 1.

00E-01 2.00E-01 1.00E-01 0.00E+00 proton deuteron C O electron Figure 1.

2 Relative Dose Fluence (1/cm 2 -source) 1.00E E-06 Container #1 Container #2 Container #3 1.00E E E E E E E-01 proton photon C O electron Container 1 Container 2 Container E E E E E E+00 proton deuteron C O electron Figure 1.2 Simulation results (PHITS) for the fluence (upper panel) and relative doses (lower panel) inside the containers placed at three different distances from the neutron source of 1.2 MeV.

3 Figure 1.3: MC simulation geometry of a 3-field proton treatment plan on of a prostate within the stylized phantom. Primary protons are shown in light blue, while neutrons are shown in yellow.

4 Figure 2.1: Trend of calculated RBE for DNA cluster damage as a function of neutron energy, compared with ICRP 103 and US NRC w r s (details in Baiocco et al, to be published). 40x 100x 200x Figure 3.1. Images of primary thyroid gland spheres at increasing magnification.

5 Figure 3.2. Surviving Fraction (SF) as a function of dose for thyroid gland stem cells. Best fit curves are obtained: with the Linear Quadratic model for SF as a function of radiation dose D: SF = exp (-αdβd 2 ), with α and β free fit parameters for neutron irradiations; with a modified LQ model (Joiner et al., 1988) for X-ray irradiations. The dotted line is the fit to X-rays survival data with a LQ model, given for reference.

6 Figure 3.3. Extra yield (over the 0 Gy value) of foci as a function of dose scored in thyroid gland stem cells 30 minutes after irradiation. Best fit curves obtained with a linear dose-response model are also shown.

7 Fig. 3.4 Surviving fraction as a function of dose for mammary gland cells. Best fit curves obtained with the LQ model as in figure 3.2 are also shown.

8 Figure 3.5. Extra yield (over the 0 Gy value) of foci, as a function of dose, scored in mammary gland cells 24 hours after irradiation. Best fit curves obtained with a linear dose-response model are also shown.

9 Figure 3.6. Fold difference in expression of tumour suppressors (RB1, p27, p53) relative to GAPDH 72 hours following 1.2 MeV monoenergetic neutrons (left), MeV monoenergetic neutrons (middle) and scattered secondary neutrons (right); * p 0.05, ** p 0.01; mean ± SEM

10 p27 expression 220 kv X-rays HDR 0 Gy MammaCA N/A 0 Gy MammaCA N/A 0 Gy MammaCA 5% 0.1 Gy MammaCA N/A 0.1 Gy MammaCA N/A 0.1 Gy MammaCA N/A 0.25 Gy MammaCA 15% 0.5 Gy MammaCA 10% 1 Gy Fibrosarcoma 5% 220 kv X-rays LDR 0 Gy MammaCA N/A 0 Gy Fibrosarcoma N/A 0 Gy MammaCA 70% ~5 MeV neutrons with BED, HDR 0 Gy MammaCA 30% 0 Gy MammaCA 20% 0.1 Gy MammaCA 5% 0.5 Gy MammaCA N/A ~5 MeV neutrons with BED, LDR 0 Gy MammaCA N/A 0 Gy MammaCA 40% 0 Gy MammaCA 30% 1.2 MeV monoenergetic neutrons 1 MammaCA 20% secondary scattered neutrons (KVI) 0 Gy MammaCA 5% 0 Gy nerve sheath tumour N/A 0 Gy MammaCA 10% 0 Gy MammaCA 50% 0.1 Gy nerve sheath tumour N/A 0.1 Gy Fibrosarcoma N/A 0.1 Gy nerve sheath tumour N/A mean [%] 22.5 ±SD [%] 19.7 Table 3.1. Expression of p27 in histological analysed tumours

11 Figure 3.7. Predicted RBE values for DSB cluster induction for the different experimental setups as a function of neutron energies (average neutron energies for the broad beam and the KVI setups are respectively 5 and 17 MeV), compared to different experimental RBE values from Surviving Fraction (SF) vs. extra yield of residual foci correlations in mammary gland cells: RBEs are obtained as SF ratios at fixed ΔY (RBE from Sf in the legend) or as residual damage ratio at fixed SF (RBE from ΔY in the legend).

12 Figure 4.1. Modeled neutron dose in Gy/proton on the proton pencil beam axis as the solid lines shown together with Monte Carlo simulated data for the proton energies 138 MeV (diamonds), 160 MeV (triangles) and 177 MeV (squares). Figure 4.2. Modeled relative lateral neutron dose as the solid lines shown together with Monte Carlo simulated data for the proton energy 177 MeV in a proximal and in b distal to the Bragg Peak.

13 Figure 4.3. Proton dose distribution for a pediatric ependymoma planned with 160 MeV protons in a. The corresponding neutron dose distributions in mgy per fraction are shown in b-d.

Figure 4.3. Plot of excess absolute carcinoma risk for cancer of the salivary glands per 10,000 persons per year as a function of point dose in the organ.

Figure 4.4. Plot of excess absolute carcinoma risk for cancer of the female breast per 10,000 persons per year as a function of point dose in the organ.

14 Figure 4.3. Plot of excess absolute carcinoma risk for cancer of the salivary glands per 10,000 persons per year as a function of point dose in the organ. The 3 curves correspond to different assumptions of the amount of repopulation/repair. The fits are presented for age at exposure of 30 years and attained age of 70 years. Figure 4.4. Plot of excess absolute carcinoma risk for cancer of the female breast per 10,000 persons per year as a function of point dose in the organ. Fully modelled dose-response relationship is depicted by the solid line and the symbols represent the epidemiological data of Travis et al (2003). The fits are presented for age at exposure of 30 years and attained age of 70 years.

15 Newborn male 1-year male 5-year male 10-year male 15-year male 15-year female Adult male Adult female Figure 4.5. The NCI-UF family of anthropomorphic phantoms (courtesy Dr. Choonsik Lee).

The ANDANTE project: a multidisciplinary approach to neutron RBE

The ANDANTE project: a multidisciplinary approach to neutron RBE Andrea Ottolenghi, Klaus Trott, Giorgio Baiocco, Vere Smyth Università degli Studi di Pavia, Italy On behalf of the ANDANTE project MELODI