Impact of proton therapy on the DNA damage induction and repair in hematopoietic stem and progenitor cells.

Proton therapy is of great interest to pediatric cancer patients because of its optimal depth dose distribution. In view of healthy tissue damage and the increased risk of secondary cancers, we investigated DNA damage induction and repair of radiosensitive hematopoietic stem and progenitor cells (HSPCs) exposed to therapeutic proton and photon irradiation due to their role in radiation-induced leukemia. Human CD34+ HSPCs were exposed to 6 MV X-rays, mid- and distal spread-out Bragg peak (SOBP) protons at doses ranging from 0.5 to 2 Gy. Persistent chromosomal damage was assessed with the micronucleus assay, while DNA damage induction and repair were analyzed with the γ-H2AX foci assay. No differences were found in induction and disappearance of γ-H2AX foci between 6 MV X-rays, mid- and distal SOBP protons at 1 Gy. A significantly higher number of micronuclei was found for distal SOBP protons compared to 6 MV X-rays and mid- SOBP protons at 0.5 and 1 Gy, while no significant differences in micronuclei were found at 2 Gy. In HSPCs, mid-SOBP protons are as damaging as conventional X-rays. Distal SOBP protons showed a higher number of micronuclei in HSPCs depending on the radiation dose, indicating possible changes of the in vivo biological response.

DNA damage response of haematopoietic stem and progenitor cells to high-LET neutron irradiation.

The radiosensitivity of haematopoietic stem and progenitor cells (HSPCs) to neutron radiation remains largely underexplored, notwithstanding their potential role as target cells for radiation-induced leukemogenesis. New insights are required for radiation protection purposes, particularly for aviation, space missions, nuclear accidents and even particle therapy. In this study, HSPCs (CD34+CD38+ cells) were isolated from umbilical cord blood and irradiated with 60Co γ-rays (photons) and high energy p(66)/Be(40) neutrons. At 2 h post-irradiation, a significantly higher number of 1.28 ± 0.12 γ-H2AX foci/cell was observed after 0.5 Gy neutrons compared to 0.84 ± 0.14 foci/cell for photons, but this decreased to similar levels for both radiation qualities after 18 h. However, a significant difference in late apoptosis was observed with Annexin-V+/PI+ assay between photon and neutron irradiation at 18 h, 43.17 ± 6.10% versus 55.55 ± 4.87%, respectively. A significant increase in MN frequency was observed after both 0.5 and 1 Gy neutron irradiation compared to photons illustrating higher levels of neutron-induced cytogenetic damage, while there was no difference in the nuclear division index between both radiation qualities. The results point towards a higher induction of DNA damage after neutron irradiation in HSPCs followed by error-prone DNA repair, which contributes to genomic instability and a higher risk of leukemogenesis.

Response of SOI microdosimeter in fast neutron beams: experiment and Monte Carlo simulations.

In this study, Monte Carlo codes, Geant4 and MCNP6, were used to characterize the fast neutron therapeutic beam produced at iThemba LABS in South Africa. Experimental and simulation results were compared using the latest generation of Silicon on Insulator (SOI) microdosimeters from the Centre for Medical Radiation Physics (CMRP). Geant4 and MCNP6 were able to successfully model the neutron gantry and simulate the expected neutron energy spectrum produced from the reaction by protons bombarding a 9Be target. The neutron beam was simulated in a water phantom and its characteristics recorded by the silicon microdosimeters; bare and covered by a 10B enriched boron carbide converter, at different positions. The microdosimetric quantities calculated using Geant4 and MCNP6 are in agreement with experimental measurements. The thermal neutron sensitivity and production of 10B capture products in the p+ boron-implanted dopant regions of the Bridge microdosimeter is investigated. The obtained results are useful for the future development of dedicated SOI microdosimeters for Boron Neutron Capture Therapy (BNCT). This paper provides a benchmark comparison of Geant4 and MCNP6 capabilities in the context of further applications of these codes for neutron microdosimetry.

The Impact of Dose Rate on DNA Double-Strand Break Formation and Repair in Human Lymphocytes Exposed to Fast Neutron Irradiation.

The lack of information on how biological systems respond to low-dose and low dose-rate exposures makes it difficult to accurately assess the carcinogenic risks. This is of critical importance to space radiation, which remains a serious concern for long-term manned space exploration. In this study, the γ-H2AX foci assay was used to follow DNA double-strand break (DSB) induction and repair following exposure to neutron irradiation, which is produced as secondary radiation in the space environment. Human lymphocytes were exposed to high dose-rate (HDR: 0.400 Gy/min) and low dose-rate (LDR: 0.015 Gy/min) p(66)/Be(40) neutrons. DNA DSB induction was investigated 30 min post exposure to neutron doses ranging from 0.125 to 2 Gy. Repair kinetics was studied at different time points after a 1 Gy neutron dose. Our results indicated that γ-H2AX foci formation was 40% higher at HDR exposure compared to LDR exposure. The maximum γ-H2AX foci levels decreased gradually to 1.65 ± 0.64 foci/cell (LDR) and 1.29 ± 0.45 (HDR) at 24 h postirradiation, remaining significantly higher than background levels. This illustrates a significant effect of dose rate on neutron-induced DNA damage. While no significant difference was observed in residual DNA damage after 24 h, the DSB repair half-life of LDR exposure was slower than that of HDR exposure. The results give a first indication that the dose rate should be taken into account for cancer risk estimations related to neutrons.

A novel methodology to assess linear energy transfer and relative biological effectiveness in proton therapy using pairs of differently doped thermoluminescent detectors.

A new methodology for assessing linear energy transfer (LET) and relative biological effectiveness (RBE) in proton therapy beams using thermoluminescent detectors is presented. The method is based on the different LET response of two different lithium fluoride thermoluminescent detectors (LiF:Mg,Ti and LiF:Mg,Cu,P) for measuring charged particles. The relative efficiency of the two detector types was predicted using the recently developed Microdosimetric d(z) Model in combination with the Monte Carlo code PHITS. Afterwards, the calculated ratio of the expected response of the two detector types was correlated with the fluence- and dose- mean values of the unrestricted proton LET. Using the obtained proton dose mean LET as input, the RBE was assessed using a phenomenological biophysical model of cell survival. The aforementioned methodology was benchmarked by exposing the detectors at different depths within the spread out Bragg peak (SOBP) of a clinical proton beam at iThemba LABS. The assessed LET values were found to be in good agreement with the results of radiation transport computer simulations performed using the Monte Carlo code GEANT4. Furthermore, the estimated RBE values were compared with the RBE values experimentally determined by performing colony survival measurements with Chinese Hamster Ovary (CHO) cells during the same experimental run. A very good agreement was found between the results of the proposed methodology and the results of the in vitro study.

Malignant salivary gland tumours: can fast neutron therapy results point the way to carbon ion therapy?

BACKGROUND AND PURPOSE: To evaluate the outcome of malignant salivary gland tumours treated with neutron therapy to assess the potential for other high linear energy transfer (LET) beams. MATERIALS AND METHODS: Neutrons at iThemba LABS are produced by the reaction of 66MeV protons on a beryllium target. A median dose 20.4Gy, in 12 fractions in 4weeks or 15 fractions in 5weeks, was given to 335 patients with 176 irresectable, 104 macroscopically residual and 55 unresected tumours. RESULTS: Locoregional control was 60.6% at 5years and 39.1% at 10years and DSS was 66.8% and 53.7% at 5 and 10years respectively. In the univariate analysis T4, >4cm, high grade, squamous carcinoma, unresected and irresectable tumours, and positive nodes were significantly worse for LRC. In the multivariate analysis tumours >6cm, squamous carcinoma, irresectable tumours and nodes were significantly worse for LRC. Tumours >6cm, high grade, squamous carcinoma and nodes were significantly worse for DSS. Neither LRC nor DSS was influenced by age, sex, site, dose, fractionation or for initial or recurrent disease. CONCLUSIONS: Neutron therapy appears to be the treatment of choice for macroscopically incompletely excised and irresectable salivary gland tumours with improved survival rates. Further improvement may be achieved with other high LET modalities with a superior dose profile, such as carbon ions.

Fluence correction factors in plastic phantoms for clinical proton beams.

In recent codes of practice for reference dosimetry in clinical proton beams using ionization chambers, it is recommended to perform the measurement in a water phantom. However, in situations where the positioning accuracy is very critical, it could be more convenient to perform the measurement in a plastic phantom. In proton beams, a similar approach as in electron beams could be applied by introducing fluence correction factors in order to account for the differences in particle fluence distributions at equivalent depths in plastic and water. In this work, fluence correction factors as a function of depth were determined for proton beams with different energies using the Monte Carlo code PTRAN for PMMA and polystyrene with reference to water. The influence of non-elastic nuclear interaction cross sections was investigated. It was found that differences in proton fluence distributions are almost entirely due to differences in non-elastic nuclear interaction cross sections between the plastic materials and water. For proton beams with energies lower than 100 MeV, for which the contributions from non-elastic interactions become small compared to the total dose, the fluence corrections are smaller than 1%. For beams with energies above 200 MeV, depending on the cross sections dataset for non-elastic nuclear interactions, fluence corrections of 2-5% were found at the largest depths. The results could, with an acceptable accuracy, be represented as a correction per cm penetration of the beam, yielding values between 0.06% and 0.15% per cm for PMMA and 0.06% to 0.20% per cm for polystyrene. Experimental information on these correction factors was obtained from depth dose measurements in PMMA and water. The experiments were performed in 75 MeV and 191 MeV non-modulated and range-modulated proton beams. From the experiments, values ranging from 0.03% to 0.15% per cm were obtained. A decisive answer about which dataset for non-elastic nuclear interactions would result in a better representation of the measurements could not be given. We conclude that below 100 MeV, dosimetry could be performed in plastic phantoms without a dramatic loss of accuracy. On the other hand, in clinical high-energy proton beams, where accurate positioning in water is in general not an issue, substantial correction factors would be required for converting dose measurements in a plastic phantom to absorbed dose to water. It is therefore not advisable to perform absorbed dose measurements nor to measure depth dose distributions in a plastic phantom in high-energy proton beams.