Performance of LGAD strip detectors for particle counting of therapeutic proton beams.

Objective. The performance of silicon detectors with moderate internal gain, named low-gain avalanche diodes (LGADs), was studied to investigate their capability to discriminate and count single beam particles at high fluxes, in view of future applications for beam characterization and on-line beam monitoring in proton therapy.Approach. Dedicated LGAD detectors with an active thickness of 55µm and segmented in 2 mm2strips were characterized at two Italian proton-therapy facilities, CNAO in Pavia and the Proton Therapy Center of Trento, with proton beams provided by a synchrotron and a cyclotron, respectively. Signals from single beam particles were discriminated against a threshold and counted. The number of proton pulses for fixed energies and different particle fluxes was compared with the charge collected by a compact ionization chamber, to infer the input particle rates.Main results. The counting inefficiency due to the overlap of nearby signals was less than 1% up to particle rates in one strip of 1 MHz, corresponding to a mean fluence rate on the strip of about 5 × 107p/(cm2·s). Count-loss correction algorithms based on the logic combination of signals from two neighboring strips allow to extend the maximum counting rate by one order of magnitude. The same algorithms give additional information on the fine time structure of the beam.Significance. The direct counting of the number of beam protons with segmented silicon detectors allows to overcome some limitations of gas detectors typically employed for beam characterization and beam monitoring in particle therapy, providing faster response times, higher sensitivity, and independence of the counts from the particle energy.

The Role of Carbon Ion Therapy in the Changing Oncology Landscape-A Narrative Review of the Literature and the Decade of Carbon Ion Experience at the Italian National Center for Oncological Hadrontherapy.

BACKGROUND: Currently, 13 Asian and European facilities deliver carbon ion radiotherapy (CIRT) for preclinical and clinical activity, and, to date, 55 clinical studies including CIRT for adult and paediatric solid neoplasms have been registered. The National Center for Oncological Hadrontherapy (CNAO) is the only Italian facility able to accelerate both protons and carbon ions for oncological treatment and research. METHODS: To summarise and critically evaluate state-of-the-art knowledge on the application of carbon ion radiotherapy in oncological settings, the authors conducted a literature search till December 2022 in the following electronic databases: PubMed, Web of Science, MEDLINE, Google Scholar, and Cochrane. The results of 68 studies are reported using a narrative approach, highlighting CNAO's clinical activity over the last 10 years of CIRT. RESULTS: The ballistic and radiobiological hallmarks of CIRT make it an effective option in several rare, radioresistant, and difficult-to-treat tumours. CNAO has made a significant contribution to the advancement of knowledge on CIRT delivery in selected tumour types. CONCLUSIONS: After an initial ramp-up period, CNAO has progressively honed its clinical, technical, and dosimetric skills. Growing engagement with national and international networks and research groups for complex cancers has led to increasingly targeted patient selection for CIRT and lowered barriers to facility access.

LIDAL, a Time-of-Flight Radiation Detector for the International Space Station: Description and Ground Calibration.

LIDAL (Light Ion Detector for ALTEA, Anomalous Long-Term Effects on Astronauts) is a radiation detector designed to measure the flux, the energy spectra and, for the first time, the time-of-flight of ions in a space habitat. It features a combination of striped silicon sensors for the measurement of deposited energy (using the ALTEA device, which operated from 2006 to 2012 in the International Space Station) and fast scintillators for the time-of-flight measurement. LIDAL was tested and calibrated using the proton beam line at TIFPA (Trento Institute for Fundamental Physics Application) and the carbon beam line at CNAO (National Center for Oncology Hadron-therapy) in 2019. The performance of the time-of-flight system featured a time resolution (sigma) less than 100 ps. Here, we describe the detector and the results of these tests, providing ground calibration curves along with the methodology established for processing the detector's data. LIDAL was uploaded in the International Space Station in November 2019 and it has been operative in the Columbus module since January 2020.

In Vitro Effects of Photon Beam and Carbon Ion Radiotherapy on the Perineural Invasion of Two Cell Lines of Neurotropic Tumours.

Primary mucosal melanoma (PMM) and pancreatic ductal adenocarcinoma (PDAC) are two aggressive malignancies, characterized by intrinsic radio-chemoresistance and neurotropism, a histological feature resulting in frequent perineural invasion (PNI), supported by neurotrophic factors secreted in the tumour microenvironment (TME), such as neurotrophin-3 (NT-3). Carbon-ion radiotherapy (CIRT) could represent an effective option in unresectable PMM and PDAC. Only a few data about the effects of CIRT on PNI in relation to NT-3 are available in the literature, despite the numerous pieces of evidence revealing the peculiar effects of this type of radiation on tumour cell migration. This in vitro study investigated for the first time the response of PMM and PDAC cells to NT-3 and evaluated the effects of conventional photon beam radiotherapy (XRT) and CIRT on cell viability, proliferation, and migration. Our results demonstrated the greater capacity of C-ions to generally decrease cell viability, proliferation, and migration, while the addition of NT-3 after both types of irradiation determined an increase in these features, maintaining a dose-dependent trend and acting more effectively as a chemoattractant than inductor in the case of migration.

In-vivo range verification analysis with in-beam PET data for patients treated with proton therapy at CNAO.

Morphological changes that may arise through a treatment course are probably one of the most significant sources of range uncertainty in proton therapy. Non-invasive in-vivo treatment monitoring is useful to increase treatment quality. The INSIDE in-beam Positron Emission Tomography (PET) scanner performs in-vivo range monitoring in proton and carbon therapy treatments at the National Center of Oncological Hadrontherapy (CNAO). It is currently in a clinical trial (ID: NCT03662373) and has acquired in-beam PET data during the treatment of various patients. In this work we analyze the in-beam PET (IB-PET) data of eight patients treated with proton therapy at CNAO. The goal of the analysis is twofold. First, we assess the level of experimental fluctuations in inter-fractional range differences (sensitivity) of the INSIDE PET system by studying patients without morphological changes. Second, we use the obtained results to see whether we can observe anomalously large range variations in patients where morphological changes have occurred. The sensitivity of the INSIDE IB-PET scanner was quantified as the standard deviation of the range difference distributions observed for six patients that did not show morphological changes. Inter-fractional range variations with respect to a reference distribution were estimated using the Most-Likely-Shift (MLS) method. To establish the efficacy of this method, we made a comparison with the Beam's Eye View (BEV) method. For patients showing no morphological changes in the control CT the average range variation standard deviation was found to be 2.5 mm with the MLS method and 2.3 mm with the BEV method. On the other hand, for patients where some small anatomical changes occurred, we found larger standard deviation values. In these patients we evaluated where anomalous range differences were found and compared them with the CT. We found that the identified regions were mostly in agreement with the morphological changes seen in the CT scan.

Factors released by low and high-LET irradiated fibroblasts modulate migration and invasiveness of pancreatic cancer cells.

Introduction: Radiotherapy represents a major treatment option for patients with pancreatic cancer, however, its benefits remain limited also due to the ability of cancer cells to migrate to the surrounding tissues. Low-LET ionizing radiation is well known to promote tumor cell migration and invasion, nevertheless, little data provided by studies using high-LET radiation has led to ambiguous findings. What is hypothesized to be fundamental in the modulation of migration of tumor cells exposed to ionizing radiation is the influence of the microenvironment. Therefore, the properties of cells that populate the tumor stroma cannot be ignored when studying the influence of radiation on the migratory and invasive capacity of cancer cells. This is especially important in the case of pancreatic malignancies that are characterized by an abundance of stromal cells, including cancer-associated fibroblasts, which are known to orchestrate the cross-talk with tumor cells. Aim: The current study aims to investigate whether the presence of factors released by irradiated fibroblasts affects the migratory and invasive capacity of pancreatic cancer cells exposed to different doses of photons or C-ions. Materials and methods: AsPC-1 and AG01522 cells were irradiated with the same dose of photons or C-ions at room temperature. Through Boyden chamber assay, we tested whether factors secreted by irradiated fibroblasts may influence tumor cell migration, while the invasiveness of AsPC-1 cells was assessed using matrigel precoated inserts in which medium collected from non-irradiated (0 Gy), photon and C-ion irradiated fibroblasts, was added. Data were analyzed by Student t-test using GraphPad software. The mean ± s.d. was determined with a significance level of p<0.05. Results: In the presence of conditioned medium collected from 1 Gy and 2 Gy photon irradiated fibroblasts, the number of migrated tumor cells increased (P<0.0360, P<0.0001) but decreased at 4 Gy dose (P<0.002). There was a trend of reduction in migration (P<0.0460, P<0.038, P<0.0024, P<0.0002), as well as a decrease in invasiveness (P<0.0525, P<0.0035, P<0.0868, P<0.0310) after exposure to 0.5 Gy, 1 Gy, 2 Gy and 4 Gy of C-ions. Conclusions: The presence of irradiated fibroblasts affected the invasiveness capability of pancreatic cancer cells, probably by the reciprocal release of soluble factors whose production is differently modulated after high or low-LET radiation. Understanding the effects of irradiation on the metastatic potential of pancreatic cancer cells is of utmost importance for improving the outcome and tailoring the therapeutic approach. This challenging scenario requires a continuous and multidisciplinary approach that involves clinicians together with researcher experts in oncological and radiation treatment. In the last years, including preclinical experiences in a multidisciplinary approach has proved to be a winning strategy in clinical oncological research.

Ultrasound-assisted carbon ion dosimetry and range measurement using injectable polymer-shelled phase-change nanodroplets: in vitro study.

Methods allowing for in situ dosimetry and range verification are essential in radiotherapy to reduce the safety margins required to account for uncertainties introduced in the entire treatment workflow. This study suggests a non-invasive dosimetry concept for carbon ion radiotherapy based on phase-change ultrasound contrast agents. Injectable nanodroplets made of a metastable perfluorobutane (PFB) liquid core, stabilized with a crosslinked poly(vinylalcohol) shell, are vaporized at physiological temperature when exposed to carbon ion radiation (C-ions), converting them into echogenic microbubbles. Nanodroplets, embedded in tissue-mimicking phantoms, are exposed at 37 °C to a 312 MeV/u clinical C-ions beam at different doses between 0.1 and 4 Gy. The evaluation of the contrast enhancement from ultrasound imaging of the phantoms, pre- and post-irradiation, reveals a significant radiation-triggered nanodroplets vaporization occurring at the C-ions Bragg peak with sub-millimeter shift reproducibility and dose dependency. The specific response of the nanodroplets to C-ions is further confirmed by varying the phantom position, the beam range, and by performing spread-out Bragg peak irradiation. The nanodroplets' response to C-ions is influenced by their concentration and is dose rate independent. These early findings show the ground-breaking potential of polymer-shelled PFB nanodroplets to enable in vivo carbon ion dosimetry and range verification.

Biomedical Research Programs at Present and Future High-Energy Particle Accelerators.

Biomedical applications at high-energy particle accelerators have always been an important section of the applied nuclear physics research. Several new facilities are now under constructions or undergoing major upgrades. While the main goal of these facilities is often basic research in nuclear physics, they acknowledge the importance of including biomedical research programs and of interacting with other medical accelerator facilities providing patient treatments. To harmonize the programs, avoid duplications, and foster collaboration and synergism, the International Biophysics Collaboration is providing a platform to several accelerator centers with interest in biomedical research. In this paper, we summarize the programs of various facilities in the running, upgrade, or construction phase.

The Role of Particle Therapy in the Risk of Radio-induced Second Tumors: A Review of the Literature.

One of the most important late side-effects of radiation therapy is the development of radiation-induced secondary malignancies. In the last years, this topic has significantly influenced treatment decision-making as the number of long-term cancer survivors has significantly increased with advances in treatment modalities. All efforts are being made to prevent the incidence of tumors induced by radiation. In this review article we summarize the current knowledge about treatment-related secondary cancers with a particular attention to hadrontherapy.

Mixed particle beam for simultaneous treatment and online range verification in carbon ion therapy: Proof-of-concept study.

PURPOSE: Radiation therapy with ion beams provides a better conformation and effectiveness of the dose delivered to the tumor with respect to photon beams. This implies that a small uncertainty or variation in the crossed tissue shape and density may lead to a more important underdosage of the tumor and/or an overdosage of the surrounding healthy tissue. Although the online control of beam fluence and transverse position is well managed by an appropriate beam delivery system, the online measurement of the longitudinal position of the Bragg peak inside the patient is still an open issue. In this paper we propose a proof-of-concept study of a technique that would allow the online verification of the patient thickness along the beam direction, which could permit detecting a subset of possible range error causes, such as morphological variations. METHODS: The nuclei 12 C and 4 He have the same magnetic rigidity: the two species could be accelerated together in an accelerator and a mixed particle beam delivered to the patient. In the same medium and with the same energy per nucleon, the range of 4 He2+ is about three times the 12 C6+ one. It is, thus, conceivable to achieve a dual goal with a single mixed beam: carbon, stopping into the tumor, is appointed to cure, while helium, emerging from the patient, to control: by detecting and measuring the residual range and position of He, it would be possible to determine the integrated relative stopping power of the patient and prove that it is the expected one. For the detection of helium particles, a plastic scintillator and an optical sensor are proposed. Being helium ions not available at CNAO, the detection system has been characterized using a proton beam. Nevertheless, since the light emitted by a proton is less than the one produced by a helium ion, the helium signal is expected to be more pronounced than the proton one (for the same number of particles). To predict the magnitude of the light signal measured by the sensor, two Monte Carlo models have been setup and validated by measuring the photons per pixel impinging on the sensor. To deal with the many optical issues and to reliably describe the physical process, some corrections have been included into the models. RESULTS: The predictions of both the models are in good agreement with the measurements (within the 20% in terms of absolute photons per pixel). The proposed detection system is able to measure the range of a proton beam with sub-millimetrical precision also in the presence of the background produced by carbon ion fragments and discrepancies in the expected range were detected with a resolution better than 1 mm. CONCLUSIONS: Although many technical issues have still to be addressed for a real implementation in a clinical environment, the preliminary results of this study suggest that a surrogate of real-time verification of the beam range inside the patient during a treatment with carbon ions is possible by adding a small fraction of helium ions to the primary beam.

Union of light ion therapy centers in Europe (ULICE EC FP7) - Objectives and achievements of joint research activities.

Under the umbrella of the European Network for Light Ion Therapy (ENLIGHT), the project on Union of Light Ion Centers in Europe (ULICE), which was funded by the European Commission (EC/FP7), was carried out from 2009 to 2014. Besides the two pillars on Transnational Access (TNA) and Networking Activities (NA), six work packages formed the pillar on Joint Research Activities (JRA). The current manuscript focuses on the objectives and results achieved within these research work packages: "Clinical Research Infrastructure", "Biologically Based Expert System for Individualized Patient Allocation", "Ion Therapy for Intra-Fractional Moving Targets", "Adaptive Treatment Planning for Ion Radiotherapy", "Carbon Ion Gantry", "Common Database and Grid Infrastructures for Improving Access to Research Infrastructures". The objectives and main achievements are summarized. References to either publications or open access deliverables from the five year project work are given. Overall, carbon ion radiotherapy is still not as mature as photon or proton radiotherapy. Achieved results and open questions are reflected and discussed in the context of the current status of carbon ion therapy and particle and photon beam therapy. Most research topics covered in the ULICE JRA pillar are topical. Future research activities can build upon these ULICE results. Together with the continuous increase in the number of particle therapy centers in the last years ULICE results and proposals may contribute to the further growth of the overall particle therapy field as foreseen with ENLIGHT and new joint initiatives such as the European Particle Therapy Network (EPTN) within the overall radiotherapy community.

Study of the magnets used for a mobile isocenter carbon ion gantry.

A conceptual design of a mobile isocenter carbon ion gantry was carried out in the framework of the Particle Training Network for European Radiotherapy (PARTNER) and Union of Light Ion Centres in Europe (ULICE) projects. To validate the magnets used in this gantry, Finite Element Method (FEM) simulations were performed with COMSOL multiphysics; the purpose was to evaluate the magnetic field quality and the influence of additional support structures for correctors, 90° bending dipole and quadrupoles, both in dynamic and static regimes. Due to the low ramp rates, the dynamic effects do not disturb the homogeneity and the magnetic field level. The differences between the stationary field and the corresponding dynamic field after the end of the ramps are in the order of 10(-4); it implies that the magnets can be operated without significant field lag at the nominal ramp rate. However, even in static regime the magnetic length of corrector magnet decreases by 5% when the rotator mechanical structure is considered. The simulations suggest an optimization phase of the correctors in the rotator.