Showing papers by "G.A.P. Cirrone published in 2021"

The Proton-Boron Reaction Increases the Radiobiological Effectiveness of Clinical Low- and High-Energy Proton Beams: Novel Experimental Evidence and Perspectives

Abstract: Protontherapy is a rapidly expanding radiotherapy modality where accelerated proton beams are used to precisely deliver the dose to the tumor target but is generally considered ineffective against radioresistant tumors. Proton-Boron Capture Therapy (PBCT) is a novel approach aimed at enhancing proton biological effectiveness. PBCT exploits a nuclear fusion reaction between low-energy protons and 11B atoms, i.e. p+11B→ 3α (p-B), which is supposed to produce highly-DNA damaging α-particles exclusively across the tumor-conformed Spread-Out Bragg Peak (SOBP), without harming healthy tissues in the beam entrance channel. To confirm previous work on PBCT, here we report new in-vitro data obtained at the 62-MeV ocular melanoma-dedicated proton beamline of the INFN-Laboratori Nazionali del Sud (LNS), Catania, Italy. For the first time, we also tested PBCT at the 250-MeV proton beamline used for deep-seated cancers at the Centro Nazionale di Adroterapia Oncologica (CNAO), Pavia, Italy. We used Sodium Mercaptododecaborate (BSH) as 11B carrier, DU145 prostate cancer cells to assess cell killing and non-cancer epithelial breast MCF-10A cells for quantifying chromosome aberrations (CAs) by FISH painting and DNA repair pathway protein expression by western blotting. Cells were exposed at various depths along the two clinical SOBPs. Compared to exposure in the absence of boron, proton irradiation in the presence of BSH significantly reduced DU145 clonogenic survival and increased both frequency and complexity of CAs in MCF-10A cells at the mid- and distal SOBP positions, but not at the beam entrance. BSH-mediated enhancement of DNA damage response was also found at mid-SOBP. These results corroborate PBCT as a strategy to render protontherapy amenable towards radiotherapy-resilient tumor. If coupled with emerging proton FLASH radiotherapy modalities, PBCT could thus widen the protontherapy therapeutic index.

Hypoxia Transcriptomic Modifications Induced by Proton Irradiation in U87 Glioblastoma Multiforme Cell Line.

Abstract: In Glioblastoma Multiforme (GBM), hypoxia is associated with radioresistance and poor prognosis. Since standard GBM treatments are not always effective, new strategies are needed to overcome resistance to therapeutic treatments, including radiotherapy (RT). Our study aims to shed light on the biomarker network involved in a hypoxic (0.2% oxygen) GBM cell line that is radioresistant after proton therapy (PT). For cultivating cells in acute hypoxia, GSI's hypoxic chambers were used. Cells were irradiated in the middle of a spread-out Bragg peak with increasing PT doses to verify the greater radioresistance in hypoxic conditions. Whole-genome cDNA microarray gene expression analyses were performed for samples treated with 2 and 10 Gy to highlight biological processes activated in GBM following PT in the hypoxic condition. We describe cell survival response and significant deregulated pathways responsible for the cell death/survival balance and gene signatures linked to the PT/hypoxia configurations assayed. Highlighting the molecular pathways involved in GBM resistance following hypoxia and ionizing radiation (IR), this work could suggest new molecular targets, allowing the development of targeted drugs to be suggested in association with PT.

Fabrication of a hydrogenated amorphous silicon detector in 3-d geometry and preliminary test on planar prototypes

Abstract: Hydrogenated amorphous silicon (a-Si:H) can be produced by plasma-enhanced chemical vapor deposition (PECVD) of SiH4 (silane) mixed with hydrogen. The resulting material shows outstanding radiation hardness properties and can be deposited on a wide variety of substrates. Devices employing a-Si:H technologies have been used to detect many different kinds of radiation, namely, minimum ionizing particles (MIPs), X-rays, neutrons, and ions, as well as low-energy protons and alphas. However, the detection of MIPs using planar a-Si:H diodes has proven difficult due to their unsatisfactory S/N ratio arising from a combination of high leakage current, high capacitance, and limited charge collection efficiency (50% at best for a 30 µm planar diode). To overcome these limitations, the 3D-SiAm collaboration proposes employing a 3D detector geometry. The use of vertical electrodes allows for a small collection distance to be maintained while preserving a large detector thickness for charge generation. The depletion voltage in this configuration can be kept below 400 V with a consequent reduction in the leakage current. In this paper, following a detailed description of the fabrication process, the results of the tests performed on the planar p-i-n structures made with ion implantation of the dopants and with carrier selective contacts are illustrated.

Radiobiological Outcomes, Microdosimetric Evaluations and Monte Carlo Predictions in Eye Proton Therapy

Abstract: CATANA (Centro di AdroTerapia ed Applicazioni Nucleari Avanzate) was the first Italian protontherapy facility dedicated to the treatment of ocular neoplastic pathologies. It is in operation at the LNS Laboratories of the Italian Institute for Nuclear Physics (INFN-LNS) and to date, 500 patients have been successfully treated. Even though proton therapy has demonstrated success in clinical settings, there is still a need for more accurate models because they are crucial for the estimation of clinically relevant RBE values. Since RBE can vary depending on several physical and biological parameters, there is a clear need for more experimental data to generate predictions. Establishing a database of cell survival experiments is therefore useful to accurately predict the effects of irradiations on both cancerous and normal tissue. The main aim of this work was to compare RBE values obtained from in-vitro experimental data with predictions made by the LEM II (Local Effect Model), Monte Carlo approaches, and semi-empirical models based on LET experimental measurements. For this purpose, the 92.1 uveal melanoma and ARPE-19 cells derived from normal retinal pigmented epithelium were selected and irradiated in the middle of clinical SOBP of the CATANA proton therapy facility. The remarkable results show the potentiality of using microdosimetric spectrum, Monte Carlo simulations and LEM model to predict not only the RBE but also the survival curves.

Biological Impact of Target Fragments on Proton Treatment Plans: An Analysis Based on the Current Cross-Section Data and a Full Mixed Field Approach.

Abstract: Clinical routine in proton therapy currently neglects the radiobiological impact of nuclear target fragments generated by proton beams. This is partially due to the difficult characterization of the irradiation field. The detection of low energetic fragments, secondary protons and fragments, is in fact challenging due to their very short range. However, considering their low residual energy and therefore high LET, the possible contribution of such heavy particles to the overall biological effect could be not negligible. In this context, we performed a systematic analysis aimed at an explicit assessment of the RBE (relative biological effectiveness, i.e., the ratio of photon to proton physical dose needed to achieve the same biological effect) contribution of target fragments in the biological dose calculations of proton fields. The TOPAS Monte Carlo code has been used to characterize the radiation field, i.e., for the scoring of primary protons and fragments in an exemplary water target. TRiP98, in combination with LEM IV RBE tables, was then employed to evaluate the RBE with a mixed field approach accounting for fragments’ contributions. The results were compared with that obtained by considering only primary protons for the pristine beam and spread out Bragg peak (SOBP) irradiations, in order to estimate the relative weight of target fragments to the overall RBE. A sensitivity analysis of the secondary particles production cross-sections to the biological dose has been also carried out in this study. Finally, our modeling approach was applied to the analysis of a selection of cell survival and RBE data extracted from published in vitro studies. Our results indicate that, for high energy proton beams, the main contribution to the biological effect due to the secondary particles can be attributed to secondary protons, while the contribution of heavier fragments is mainly due to helium. The impact of target fragments on the biological dose is maximized in the entrance channels and for small α/β values. When applied to the description of survival data, model predictions including all fragments allowed better agreement to experimental data at high energies, while a minor effect was observed in the peak region. An improved description was also obtained when including the fragments’ contribution to describe RBE data. Overall, this analysis indicates that a minor contribution can be expected to the overall RBE resulting from target fragments. However, considering the fragmentation effects can improve the agreement with experimental data for high energy proton beams.

In-field and out-of-field microdosimetric characterisation of a 62 MeV proton beam at CATANA.

Abstract: Purpose A 5 and 10 μm thin silicon on insulator (SOI) 3D mushroom microdosimeter was used to characterise both the in-field and out-of-field of a 62 MeV proton beam. Methods The SOI mushroom microdosimeter consisted of an array of cylindrical sensitive volumes (SVs), developed by the Centre for Medical Radiation Physics, University of Wollongong, was irradiated with 62 MeV protons at the CATANA (Centro di AdroTerapia Applicazioni Nucleari Avanzate) facility in Catania, Italy, a facility dedicated to the radiation treatment of ocular melanomas. Dose mean lineal energy, ( y D ¯ ), values were obtained at various depths in PMMA along a pristine and spread out Bragg peak (SOBP). The measured microdosimetric spectra at each position were then used as inputs into the modified Microdosimetric Kinetic Model (MKM) to derive the RBE for absorbed dose in a middle of the SOBP 2Gy (RBED ). Microdosimetric spectra were obtained with both the 5 and 10 μm 3D SOI microdosimeters, with a focus on the distal part of the BP. The in-field and out-of-field measurement configurations along the Bragg curve were modelled in Geant4 for comparison with experimental results. Lateral out-of-field measurements were performed to study secondary particles' contribution to normal tissue's dose, up to 12 mm from the edge of the beam field, and quality factor and dose equivalent results were obtained. Results Comparison between experimental and simulation results showed good agreement between one another for both the pristine and SOBP beams in terms of y D ¯ and RBED . Though a small discrepancy between experiment and simulation was seen at the entrance of the Bragg curve, where experimental results were slightly lower than Geant4. The dose equivalent value measured 12 mm from the edge of the target volume was 1.27 ± 0.15 mSv/Gy with a Q ¯ value of 2.52 ± 0.30, both of which agree within uncertainty with Geant4 simulation. Conclusions These results demonstrate that SOI microdosimeters are an effective tool to predict RBED in-field as well as dose equivalent monitoring out-of-field to provide insight to probability of second cancer generation.

Testing of planar hydrogenated amorphous silicon sensors with charge selective contacts for the construction of 3D- detectors

Abstract: Hydrogenated Amorphous Silicon (a-Si:H) is a material well known for its intrinsic radiation hardness and is primarily utilized in solar cells as well as for particle detection and dosimetry. Planar p-i-n diode detectors are fabricated entirely by means of intrinsic and doped PECVD of a mixture of Silane (SiH4) and molecular Hydrogen. In order to develop 3D detector geometries using a-Si:H, two options for the junction fabrication have been considered: ion implantation and charge selective contacts through atomic layer deposition. In order to test the functionality of the charge selective contact electrodes, planar detectors have been fabricated utilizing this technique. In this paper, we provide a general overview of the 3D fabrication project followed by the results of leakage current measurements and x-ray dosimetric tests performed on planar diodes containing charge selective contacts to investigate the feasibility of the charge selective contact methodology for integration with the proposed 3D detector architectures.

Handling and dosimetry of laser-driven ion beams for applications

Abstract: The acceleration processes based on the coherent interaction of high-power lasers with matter are, by now, one of the most interesting topics in the field of particle acceleration, becoming day by day a real alternative to conventional approaches. Some of the extraordinary peculiarities of laser–matter interaction, such as the production of multi-species (gamma, X-rays, electrons, protons and ions), short-pulsed and intense beams are particularly attracting for many applications as well as for fundamental physics. In particular, laser-accelerated protons, if well controlled in terms of final energy spread, divergence and dose rate, could lead to investigate new research regimes in the field of medical physics, as well as in radiobiological applications. Many approaches are currently being developed aiming at optimizing the laser–target interaction mechanism and at collecting and selecting through dedicated transport beamlines the laser-accelerated proton beams in a future perspective to use them for the medical and radiobiological applications with a reduced uncertainty. An overview of the main parameters characterizing the laser-accelerated protons and of the transport, diagnostics and dosimetry solutions, currently adopted from the laser community, will be provided in this contribution.

Feasibility Study and Perspectives of proton Dielectric Laser Accelerators (p-DLA): from nanosource to accelerator scheme

Abstract: In this paper we discuss the possibility to generate and accelerate proton nanobeams in fully dielectric laser-driven accelerators (p-DLAs). High gradient on-chip optical-power dielectric laser accelerators (DLAs) could represent one of the most promising way towards future miniaturized particle accelerator. A primary challenge for DLAs are small beam apertures having a size of the order of the driving laser wavelength where low charge high-repetition (or also CW) ultralow emittance nanobeams have to be transported. For electrons beams generation and acceleration, intense research activities are ongoing, and several demonstrations have been already obtained by using electrons nanotip (or flat photocathode) sources feeding dielectric microstructures. In this article we aim at the possibility to integrate a nanosource for the generation of a light ion or proton nano-beams suitable for the subsequent acceleration into sub-relativistic (low-beta) p-DLA stages. Such integration includes the idea to use a proton dielectric radiofrequency quadrupole (p-DRFQ) for bridging the gap between the accelerator front-end and the drift-tube and high-beta sections. The paper has been prepared as a white book including state-of-art technologies and new solutions that now put the ambitious frontier of a fully nanostructured proton accelerator into reach. Conceptual studies of p-DLAs here presented could enable table-top proton nano-beams for several applications: proton beam writing, nuclear reaction analysis at sub-micrometer scales, the construction of miniaturized Proton-Boron Nuclear Fusion based Reactors, biological analysis at the micrometer scale, ion beam analysis at the sub-cellular level, mini-beams ion therapy to spare the shallow tissues, proton irradiation of transistors, compact proton linac for neutron generation.