Biological effectiveness of He-3 and He-4 ion beams for cancer hadrontherapy: a study based on the BIANCA biophysical model.

While cancer therapy with protons and C-ions is continuously spreading, in the near future patients will be also treated with He-ions which, in comparison to photons, combine the higher precision of protons with the higher relative biological effectiveness (RBE) of C-ions. Similarly to C-ions, also for He-ions the RBE variation along the beam must be known as precisely as possible, especially for active beam delivery systems. In this framework the BIANCA biophysical model, which has already been applied to calculate the RBE along proton and C-ion beams, was extended to4He-ions and, following interface with the FLUKA code, was benchmarked against cell survival data on CHO normal cells and Renca tumour cells irradiated at different positions along therapeutic-like4He-ion beams at the Heidelberg Ion-beam Therapy centre, where the first He-ion patient will be treated soon. Very good agreement between simulations and data was obtained, showing that BIANCA can now be used to predict RBE following irradiation with all ion types that are currently used, or will be used soon, for hadrontherapy. Thanks to the development of a reference simulation database describing V79 cell survival for ion and photon irradiation, these predictions can be cell-type specific because analogous databases can be produced, in principle, for any cell line. Furthermore, survival data on CHO cells irradiated by a He-3 beam were reproduced to compare the biophysical properties of He-4 and He-3 beams, which is currently an open question. This comparison showed that, at the same depth, He-4 beams tend to have a higher RBE with respect to He-3 beams, and that this difference is also modulated by the considered physical dose, as well as the cell radiosensitivity. However, at least for the considered cases, no significant difference was found for the ratio between the RBE-weighted dose in the SOBP and that in the entrance plateau.

First benchmarking of the BIANCA model for cell survival prediction in a clinical hadron therapy scenario.

In the framework of RBE modelling for hadron therapy, the BIANCA biophysical model was extended to O-ions and was used to construct a radiobiological database describing the survival of V79 cells as a function of ion type (1 ⩽ Z ⩽ 8) and energy. This database allowed performing RBE predictions in very good agreement with experimental data. A method was then developed to construct analogous databases for different cell lines, starting from the V79 database as a reference. Following interface to the FLUKA Monte Carlo radiation transport code, BIANCA was then applied for the first time to predict cell survival in a typical patient treatment scenario, consisting of two opposing fields of range-equivalent protons or C-ions. The model predictions were found to be in good agreement with CHO cell survival data obtained at the Heidelberg ion-beam therapy (HIT) centre, as well as predictions performed by the local effect model (version LEM IV). This work shows that BIANCA can be used to predict cell survival and RBE not only for V79 and AG01522 cells, as shown previously, but also, in principle, for any cell line of interest. Furthermore, following interface to a transport code like FLUKA, BIANCA can provide predictions of 3D biological dose distributions for hadron therapy treatments, thus laying the foundations for future applications in clinics.

Investigation of single carbon ion fragmentation in water and PMMA for hadron therapy.

Carbon ion radiotherapy is an attractive alternative to conventional radiotherapy, especially in case of deep-seated and radio-resistant tumors. As a consequence of inelastic nuclear reactions between primary particles and patient's tissues, the primary carbon ions may undergo nuclear fragmentation. The resulting decrease of primary ions and production of secondary fragments have to be carefully considered for accurate dose calculations in the treatment planning systems. The experimental data currently available provide only general information on carbon ion fragmentation and are not sufficient to cover the entire range of beam energies, target configurations and compositions relevant for radiotherapy. Therefore, new investigations were carried out to analyse the outcomes of the inelastic nuclear reaction processes on a single-ion-based approach. Measurements were performed at HIT, using 430 MeV/u carbon ion beams crossing water and PMMA targets. Unique in this method is the possibility of measuring number and type of fragments produced from each single carbon ion, provided that they are within the acceptance of the experimental apparatus. Concerning the amount of residual carbon ions behind water and PMMA targets with the same water equivalent thickness (WET), no significant differences were found. The experimental attenuation curve was well reproduced by the simulations. However, in the experiments, differences were observed regarding the amount of secondary fragments produced in water and in PMMA targets with the same WET. Differences were also found between experiments and simulations. These findings should be considered when dosimetric measurements are performed with PMMA instead of water phantoms. The found differences between experiments and simulations may contribute to improve the nuclear interaction and fragmentation models in Monte Carlo codes.

Helium ion beam imaging for image guided ion radiotherapy.

BACKGROUND: Ion beam radiotherapy provides potential for increased dose conformation to the target volume. To translate it into a clinical advantage, it is necessary to guarantee a precise alignment of the actual internal patient geometry with the treatment beam. This is in particular challenging for inter- and intrafractional variations, including movement. Ion beams have the potential for a high sensitivity imaging of the patient geometry. However, the research on suitable imaging methods is not conclusive yet. Here we summarize the research activities within the "Clinical research group heavy ion therapy" funded by the DFG (KFO214). Our aim was to develop a method for the visualization of a 1 mm thickness difference with a spatial resolution of about 1 mm at clinically applicable doses. METHODS: We designed and built a dedicated system prototype for ion radiography using exclusively the pixelated semiconductor technology Timepix developed at CERN. Helium ions were chosen as imaging radiation due to their decreased scattering in comparison to protons, and lower damaging potential compared to carbon ions. The data acquisition procedure and a dedicated information processing algorithm were established. The performance of the method was evaluated at the ion beam therapy facility HIT in Germany with geometrical phantoms. The quality of the images was quantified by contrast-to-noise ratio (CNR) and spatial resolution (SR) considering the imaging dose. RESULTS: Using the unique method for single ion identification, degradation of the images due to the inherent contamination of the outgoing beam with light secondary fragments (hydrogen) was avoided. We demonstrated experimentally that the developed data processing increases the CNR by 350%. Consideration of the measured ion track directions improved the SR by 150%. Compared to proton radiographs at the same dose, helium radiographs exhibited 50% higher SR (0.56 ± 0.04lp/mm vs. 0.37 ± 0.02lp/mm) at a comparable CNR in the middle of the phantom. The clear visualization of the aimed inhomogeneity at a diagnostic dose level demonstrates a resolution of 0.1 g/cm2 or 0.6% in terms of water-equivalent thickness. CONCLUSIONS: We developed a dedicated method for helium ion radiography, based exclusively on pixelated semiconductor detectors. The achievement of a clinically desired image quality in simple phantoms at diagnostic dose levels was demonstrated experimentally.

Investigation of mixed ion fields in the forward direction for 220.5 MeV/u helium ion beams: comparison between water and PMMA targets.

Currently there is a rising interest in helium ion beams for radiotherapy. For benchmarking of the physical beam models used in treatment planning, there is a need for experimental data on the composition and spatial distribution of mixed ion fields. Of particular interest are the attenuation of the primary helium ion fluence and the build-up of secondary hydrogen ions due to nuclear interactions. The aim of this work was to provide such data with an enhanced precision. Moreover, the validity and limits of the mixed ion field equivalence between water and PMMA targets were investigated. Experiments with a 220.5 MeV/u helium ion pencil beam were performed at the Heidelberg Ion-Beam Therapy Center in Germany. The compact detection system used for ion tracking and identification was solely based on Timepix position-sensitive semiconductor detectors. In comparison to standard techniques, this system is two orders of magnitude smaller, and provides higher precision and flexibility. The numbers of outgoing helium and hydrogen ions per primary helium ion as well as the lateral particle distributions were quantitatively investigated in the forward direction behind water and PMMA targets with 5.2-18 cm water equivalent thickness (WET). Comparing water and PMMA targets with the same WET, we found that significant differences in the amount of outgoing helium and hydrogen ions and in the lateral particle distributions arise for target thicknesses above 10 cm WET. The experimental results concerning hydrogen ions emerging from the targets were reproduced reasonably well by Monte Carlo simulations using the FLUKA code. Concerning the amount of outgoing helium ions, significant differences of 3-15% were found between experiments and simulations. We conclude that if PMMA is used in place of water in dosimetry, differences in the dose distributions could arise close to the edges of the field, in particular for deep seated targets.

Caspase-3 activation in human melanoma A375 cell line by a novel selective sigma-2 agonist.

Two novel 8-azabicyclo[3.2.1]octan-3-ol derivatives, 11a and 11b, with high affinity for sigma-2 receptors and a very good sigma-1/sigma-2 selectivity ratio were synthesized. In comparison with several well established sigma-2 selective ligands, 11 b showed a very low sigma-1 receptor affinity. Functional assays demonstrated that 11b acts as an agonist and in A-375 human melanoma cell line is able to lower levels of procaspase-3, thus confirming a potential major role for sigma-2 pure agonists in the treatment of rapid proliferating melanoma cells.

Design and synthesis of new bifunctional sigma-1 selective ligands with antioxidant activity.

Herein we report the synthesis of new bifunctional sigma-1 (σ1)-selective ligands with antioxidant activity. To achieve this goal, we combined the structure of lipoic acid, a universal antioxidant, with an appropriate sigma aminic moiety. Ligands 14 and 26 displayed high affinity and selectivity for σ1 receptors (Kiσ1 = 1.8 and 5.5 nM; Kiσ2/σ1 = 354 and 414, respectively). Compound 26 exhibited in vivo antiopioid effects on kappa opioid (KOP) receptor-mediated analgesia. In rat liver and brain mitochondria (RLM, RBM), this compound significantly reduced the swelling and the oxidation of thiol groups induced by calcium ions. Our results demonstrate that the tested compound has protective effects against oxidative stress.

Hepatitis B and hepatitis C virus infections in dermatological patients in west Sicily: a seroepidemiological study.

OBJECTIVES: To evaluate the relative frequencies and molecular epidemiological features of viral hepatitis types B and C in dermatological patients in our geographical area. METHODS: We determined the hepatitis B virus (HBV) and hepatitis C virus (HCV) antibodies and the hepatitis B virus surface antigen (HBsAg) in a cohort of 677 dermatological patients admitted to the Department of Dermatology of Palermo. An 8-mL blood sample was taken from all subjects. The following assays were used: HBsAg, anti-HB core (antigen) (anti-HBc), anti-HB surface (antigen) (anti-HBs), anti-HB early (antigen) (anti-Hbe) and anti-HCV antibodies using enzyme-linked immunosorbent assay. RESULTS: One hundred and eighty-nine (27.91%) of the 677 dermatological patients were positive for anti-HBc, anti-HBs, anti-HBe and/or anti-HCV antibodies. In particular 22% (149 patients) were anti-HBc, anti-HBs or anti-HBe positive, reflecting exposure to HBV, and six patients (0.88%) were chronic carriers of HBsAg; 2.36% of the dermatological patients (16 persons) were anti-HCV positive. Tests showed that 24 subjects (3.52%) were infected with hepatitis B or C. The peaks in the age bands were in the 55-80-year-old age groups. CONCLUSIONS: This study confirms a high rate of HBV and HCV exposure with chronic carriers in our dermatological patients. We assume that the high prevalence of HCV and HBV in dermatological patients is more likely to be age related than to represent a true and direct association with dermatological diseases in general. Definite conclusions will only be available after large epidemiological studies that can establish or refute an aetiological and pathogenetic role of HBV and HCV in certain skin diseases associated with liver infection.