Validation of Geant4 nuclear reaction models for hadrontherapy and preliminary results with SMF and BLOB

Reliable nuclear fragmentation models are of utmost importance in hadrontherapy, where Monte Carlo (MC) simulations are used to compute the input parameters of the treatment planning software, to validate the deposited dose calculation, to evaluate the biological effectiveness of the radiation, to correlate the bþ emitters production in the patient body with the delivered dose, and to allow a non- invasive treatment verification. Despite of its large use, the models implemented in Geant4 have shown severe limitations in reproducing the measured secondaries yields in ions interaction below 100 MeV/A, in term of production rates, angular and energy distributions [1–3]. We will present a benchmark of the Geant4 models with double-differential cross sec- tion and angular distributions of the secondary fragments produced in the 12C fragmentation at 62 MeV/A on thin carbon target, such a benchmark includes the recently implemented model INCL++ [4,5]. Moreover, we will present the preliminary results, obtained in simulating the same interaction, with SMF [6] and BLOB [7]. Both, SMF and BLOB are semiclassical one-body approaches to solve the Boltzmann-Langevin equation. They include an identical treatment of the mean-field propagation, on the basis of the same effective interaction, but they differ in the way fluctuations are included. In particular, while SMF employs a Uehling-Uhlenbeck collision term and introduces fluctuations as projected on the density space, BLOB introduces fluctuations in full phase space through a modified collision term where nucleon-nucleon correlations are explicitly involved. Both of them, SMF and BLOB, have been developed to sim- ulate the heavy ion interactions in the Fermi-energy regime. We will show their capabilities in describing 12C fragmentation foreseen their implementation in Geant4

Radiobiological studies on the 62 MeV therapeutic proton beam at lns catania: I. survival of HTB140 melanoma cells

The aim of this study was to determine the initial inactivation of cells induced by high-energy proton beam designed for the treatment of eye melanoma. Exponentially growing HTB140 cells were exposed to an unmodulated 62 MeV proton beam delivered over the single dose range from 8 Gy to 24 Gy. Position of samples was in the zone of the Bragg peak, having high LET values. Surviving fractions were evaluated at 6, 24 and 48 h post-irradiation. The survival curves exhibited a well-known shoulder, decreasing for doses higher than 8 Gy. Therefore, a significant dose dependent early cell inactivation after single delivery of 16 Gy to 24 Gy to the cell monolayer was observed. With the increase of the post-irradiation incubation time, a better killing effect, as the consequence of clonogenic survival, was detected.Physical chemistry 2004 : 7th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 21-23 September 200

Radiobiological studies on the 62 MeV therapeutic proton beam at lns catania: II. facs analyses of HTB140 melanoma cells

The objective of this study was to determine whether apoptosis and cell cycle redistribution were influenced by high-LET irradiation. Exponentially growing HTB140 cells were exposed to an unmodulated 62 MeV proton beam, within the Bragg peak, delivered over the single dose range from 8 Gy to 24 Gy. At 6 h post-irradiation, there was a low level of early apoptosis. At 48 h irradiated cells were more damaged, showing the increase in number of apoptotic nuclei. The dose dependent cell cycle phase distribution was detected at 48 h post-irradiation. The cell population exhibited phase redistribution toward G2/M phase.Physical chemistry 2004 : 7th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 21-23 September 200

Carbon ions of different linear energy transfer (LET) values induce apoptosis & G2 cell cycle arrest in radio-resistant melanoma cells

© 2016, Indian Council of Medical Research. All rights reserved. Background & objectives: The main goal when treating malignancies with radiation is to deprive tumour cells of their reproductive potential. One approach is to induce tumour cell apoptosis. This study was conducted to evaluate the ability of carbon ions (12C) to induce apoptosis and cell cycle arrest in human HTB140 melanoma cells. Methods: In this in vitro study, human melanoma HTB140 cells were irradiated with the 62 MeV/n carbon (12C) ion beam, having two different linear energy transfer (LET) values: 197 and 382 keV/μm. The dose range was 2 to 16 Gy. Cell viability was estimated by the sulforhodamine B assay seven days after irradiation. The cell cycle and apoptosis were evaluated 48 h after irradiation using flow cytometry. At the same time point, protein and gene expression of apoptotic regulators were estimated using the Western blot and q-PCR methods, respectively. Results: Cell viability experiments indicated strong anti-tumour effects of12C ions. The analysis of cell cycle showed that12C ions blocked HTB140 cells in G2 phase and induced the dose dependent increase of apoptosis. The maximum value of 21.8 per cent was attained after irradiation with LET of 197 keV/μm at the dose level of 16 Gy. Pro-apoptotic effects of12C ions were confirmed by changes of key apoptotic molecules: the p53, Bax, Bcl-2, poly ADP ribose polymerase (PARP) as well as nuclear factor kappa B (NFκB). At the level of protein expression, the results indicated significant increases of p53, NFκB and Bax/Bcl-2 ratio and PARP cleavage. The Bax/Bcl-2 mRNA ratio was also increased, while no change was detected in the level of NFκB mRNA. Interpretation & conclusions: The present results indicated that anti-tumour effects of12C ions in human melanoma HTB140 cells were accomplished through induction of the mitochondrial apoptotic pathway as well as G2 arrest

Response of Human HTB140 Melanoma Cells to Conventional Radiation and Hadrons

Conventional radiotherapy with X-and gamma-rays is one of the common and effective treatments of cancer. High energy hadrons, i.e., charged particles like protons and (12)C ions, due to their specific physics and radiobiological advantages are increasingly used. In this study, effectiveness of different radiation types is evaluated on the radio-resistant human HTB140 melanoma cells. The cells were irradiated with gamma-rays, the 62 MeV protons at the Bragg peak and in the middle of the spread-out Bragg peak (SOBP), as well as with the 62 MeV/u (12)C ions. The doses ranged from 2 to 24 Gy. Cell survival and proliferation were assessed 7 days after irradiation, whereas apoptosis was evaluated after 48 h. The acquired results confirmed the high radio-resistance of cells, showing better effectiveness of protons than gamma-rays. The best efficiency was obtained with (12)C ions due to higher linear energy transfer. All analyzed radiation qualities reduced cell proliferation. The highest proliferation was detected for (12)C ions because of their large killing capacity followed by small induction of reparable lesions. This enabled unharmed cells to preserve proliferative activity. Irradiations with protons and (12)C ions revealed similar moderate pro-apoptotic ability that is in agreement with the level of cellular radio-resistance

Response of Human HTB140 Melanoma Cells to Conventional Radiation and Hadrons

Conventional radiotherapy with X-and gamma-rays is one of the common and effective treatments of cancer. High energy hadrons, i.e., charged particles like protons and (12)C ions, due to their specific physics and radiobiological advantages are increasingly used. In this study, effectiveness of different radiation types is evaluated on the radio-resistant human HTB140 melanoma cells. The cells were irradiated with gamma-rays, the 62 MeV protons at the Bragg peak and in the middle of the spread-out Bragg peak (SOBP), as well as with the 62 MeV/u (12)C ions. The doses ranged from 2 to 24 Gy. Cell survival and proliferation were assessed 7 days after irradiation, whereas apoptosis was evaluated after 48 h. The acquired results confirmed the high radio-resistance of cells, showing better effectiveness of protons than gamma-rays. The best efficiency was obtained with (12)C ions due to higher linear energy transfer. All analyzed radiation qualities reduced cell proliferation. The highest proliferation was detected for (12)C ions because of their large killing capacity followed by small induction of reparable lesions. This enabled unharmed cells to preserve proliferative activity. Irradiations with protons and (12)C ions revealed similar moderate pro-apoptotic ability that is in agreement with the level of cellular radio-resistance

Geant4 simulation model of electromagnetic processes in oriented crystals for the accelerator physics

Electromagnetic processes of charged particles interaction with oriented crystals provide a wide variety of innovative applications such as beam steering, crystal-based extraction/collimation of leptons and hadrons in an accelerator, a fixed-target experiment on magnetic and electric dipole moment measurement, X-ray and gamma radiation source for radiotherapy and nuclear physics and a positron source for lepton and muon colliders, a compact crystalline calorimeter as well as plasma acceleration in the crystal media. One of the main challenges is to develop an up-to-date, universal and fast simulation tool to simulate these applications. We present a new simulation model of electromagnetic processes in oriented crystals implemented into Geant4, which is a toolkit for the simulation of the passage of particles through matter. We validate the model with the experimental data as well as discuss the advantages and perspectives of this model for the applications of oriented crystals mentioned above.Comment: 18 pages, 9 figure

Molecular Investigation on a Triple Negative Breast Cancer Xenograft Model Exposed to Proton Beams

Specific breast cancer (BC) subtypes are associated with bad prognoses due to the absence of successful treatment plans. The triple-negative breast cancer (TNBC) subtype, with estrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) negative receptor status, is a clinical challenge for oncologists, because of its aggressiveness and the absence of effective therapies. In addition, proton therapy (PT) represents an effective treatment against both inaccessible area located or conventional radiotherapy (RT)-resistant cancers, becoming a promising therapeutic choice for TNBC. Our study aimed to analyze the in vivo molecular response to PT and its efficacy in a MDA-MB-231 TNBC xenograft model. TNBC xenograft models were irradiated with 2, 6 and 9 Gy of PT. Gene expression profile (GEP) analyses and immunohistochemical assay (IHC) were performed to highlight specific pathways and key molecules involved in cell response to the radiation. GEP analysis revealed in depth the molecular response to PT, showing a considerable immune response, cell cycle and stem cell process regulation. Only the dose of 9 Gy shifted the balance toward pro-death signaling as a dose escalation which can be easily performed using proton beams, which permit targeting tumors while avoiding damage to the surrounding healthy tissue

Fluence Beam Monitor for High-Intensity Particle Beams Based on a Multi-Gap Ionization Chamber and a Method for Ion Recombination Correction

This work presents the tests of a multi-gap detector (MGD), composed of three parallel-plate ionization chambers (ICs) with different gap widths, assembled to prove the capability of correcting for charge volume recombination which is expected to occur when high fluence rates are delivered. Such beam conditions occur with a compact accelerator for charged particle therapy developed to reduce the costs, to accomplish faster treatments and to exploit different beam delivery techniques and dose rates as needed, for example, for range modulation and FLASH irradiations, respectively. The MGD was tested with carbon ions at the Centro Nazionale di Adroterapia Oncologica (CNAO Pavia, Italy), and with protons in two different beam lines: at Bern University Hospital with continuous beams and at the Laboratori Nazionale del Sud (Catania, Italy) of the Italian National Center of Nuclear Physics (INFN) with pulsed beams. For each accelerator, we took measurements with different beam intensities (up to the maximum rate of ionization achievable) and changed the detector bias voltage (V) in order to study the charge collection efficiency. Charge recombination models were used to evaluate the expected collected charge and to measure the linearity of the rate of ionization with the beam fluence rate. A phenomenological approach was used to determine the collection efficiency (f1) of the chamber with thinnest gap from the relative efficiencies, f1/f2 and f1/f3, exploiting the condition that, for each measurement, the three chambers were exposed to the same rate of ionization. Results prove that two calibration curves can be determined and used to correct the online measurements for the charge losses in the ICs for recombination

Proton-irradiated breast cells: molecular points of view

Breast cancer (BC) is the most common cancer in women, highly heterogeneous at both the clinical and molecular level. Radiation therapy (RT) represents an efficient modality to treat localized tumor in BC care, although the choice of a unique treatment plan for all BC patients, including RT, may not be the best option. Technological advances in RT are evolving with the use of charged particle beams (i.e. protons) which, due to a more localized delivery of the radiation dose, reduce the dose administered to the heart compared with conventional RT. However, few data regarding proton-induced molecular changes are currently available. The aim of this study was to investigate and describe the production of immunological molecules and gene expression profiles induced by proton irradiation. We performed Luminex assay and cDNA microarray analyses to study the biological processes activated following irradiation with proton beams, both in the non-tumorigenic MCF10A cell line and in two tumorigenic BC cell lines, MCF7 and MDA-MB-231. The immunological signatures were dose dependent in MCF10A and MCF7 cell lines, whereas MDA-MB-231 cells show a strong pro-inflammatory profile regardless of the dose delivered. Clonogenic assay revealed different surviving fractions according to the breast cell lines analyzed. We found the involvement of genes related to cell response to proton irradiation and reported specific cell line- and dose-dependent gene signatures, able to drive cell fate after radiation exposure. Our data could represent a useful tool to better understand the molecular mechanisms elicited by proton irradiation and to predict treatment outcome