Proton Irradiation Research Articles

Enhancing Proton Radiosensitivity of Chondrosarcoma Using Nanoparticle-Based Drug Delivery Approaches: A Comparative Study of High- and Low-Energy Protons

To overcome chondrosarcoma’s (CHS) high chemo- and radioresistance, we used polyethylene glycol-encapsulated iron oxide nanoparticles (IONPs) for the controlled delivery of the chemotherapeutic doxorubicin (IONPDOX) to amplify the cytotoxicity of proton radiation therapy. Human 2D CHS SW1353 cells were treated with protons (linear energy transfer (LET): 1.6 and 12.6 keV/µm) with and without IONPDOX. Cell survival was assayed using a clonogenic test, and genotoxicity was tested through the formation of micronuclei (MN) and γH2AX foci, respectively. Morphology together with spectral fingerprints of nuclei were measured using enhanced dark-field microscopy (EDFM) assembled with a hyperspectral imaging (HI) module and an axial scanning fluorescence module, as well as scanning electron microscopy (SEM) coupled with energy-dispersive X-Ray spectroscopy (EDX). Cell survival was also determined in 3D SW3153 spheroids following treatment with low-LET protons with/without the IONPDOX compound. IONPDOX increased radiosensitivity following proton irradiation at both LETs in correlation with DNA damage expressed as MN or γH2AX. The IONPDOX–low-LET proton combination caused a more lethal effect compared to IONPDOX–high-LET protons. CHS cell biological alterations were reflected by the modifications in the hyperspectral images and spectral profiles, emphasizing new possible spectroscopic markers of cancer therapy effects. Our findings show that the proposed treatment combination has the potential to improve the management of CHS.

First test beam of the DMAPS-based proton tracker at the pMBRT facility at the Curie Institute

Objective.Proton radiotherapy's efficacy relies on an accurate relative stopping power (RSP) map of the patient to optimise the treatment plan and minimize uncertainties. Currently, a conversion of a Hounsfield Units map obtained by a common x-ray computed tomography (CT) is used to compute the RSP. This conversion is one of the main limiting factors for proton radiotherapy. To bypass this conversion a direct RSP map could be obtained by performing a proton CT (pCT). The focal point of this article is to present a proof of concept of the potential of fast pixel technologies for proton tracking at clinical facilities.Approach.A two-layer tracker based on the TJ-Monopix1, a depleted monolithic active pixel sensor (DMAPS) chip initially designed for the ATLAS, was tested at the proton minibeam radiotherapy beamline at the Curie Institute. The chips were subjected to 100 MeV protons passing through the single slit collimator (0.4×20mm2) with fluxes up to1.3×107p s-1 cm-2. The performance of the proton tracker was evaluated with GEANT4 simulations.Main results.The beam profile and dispersion in air were characterized by an opening of 0.031 mm cm-1, and aσx=0.172mm at the position of the slit. The results of the proton tracking show how the TJ-Monopix1 chip can effectively track protons in a clinical environment, achieving a tracking purity close to 70%, and a position resolution below 0.5 mm; confirming the chip's ability to handle high proton fluxes with a competitive performance.Significance.This work suggests that DMAPS technologies can be a cost-effective alternative for proton imaging. Additionally, the study identifies areas where further optimization of chip design is required to fully leverage these technologies for clinical ion imaging applications.

Sustainable production of radionuclidically pure antimony-119

BackgroundRadiopharmaceutical therapy (RPT) uses radionuclides that decay via one of three therapeutically relevant decay modes (alpha, beta, and internal conversion (IC) / Auger electron (AE) emission) to deliver short range, highly damaging radiation inside of diseased cells, maintaining localized dose distribution and sparing healthy cells. Antimony-119 (119Sb, t1/2 = 38.19 h, EC = 100%) is one such IC/AE emitting radionuclide, previously limited to in silico computational investigation due to barriers in production, chemical separation, and chelation. A theranostic (therapeutic/diagnostic) pair can be formed with 119Sb’s radioisotopic imaging analogue 117Sb (t1/2 = 2.80 h, Eγ = 158.6 keV, Iγ = 85.9%, β+ = 262.4 keV, Iβ+ = 1.81%).ResultsWithin, we report techniques for sustainable and cost-effective production of pre-clinical quality and quantity, radionuclidically pure 119Sb and 117Sb, novel low energy photon measurement techniques for 119Sb activity determination, and physical yields for various tin target isotopic enrichments and thicknesses using (p, n) and (d, n) nuclear reactions. Additionally, we present a two-column separation providing a radioantimony yield of 73.1% ± 6.9% (N = 3) and tin separation factor of (6.8 ± 5.5) x 105 (N = 3). Apparent molar activity measurements for deuteron produced 117Sb using the chelator TREN-CAM were measured at 42.4 ± 25 MBq 117Sb/µmol (1.14 ± 0.68 mCi/µmol), and we recovered enriched 119Sn target material at a recycling efficiency of 80.2% ± 5.5% (N = 6) with losses of 11.6 mg ± 0.8 mg (N = 6) per production.ConclusionWe report significant steps in overcoming barriers in 119Sb production, chemical isolation and purification, enriched target material recycling, and chelation, helping promote accessibility and application of this promising therapeutic radionuclide. We describe a method for 119Sb activity measurement using its low energy gamma (23.87 keV), negating the need for attenuation correction. Finally, we report the largest yet-measured 119Sb production yields using proton and deuteron irradiation of natural and enriched targets and radioisotopic purity > 99.8% at end of purification.

Revision Surgeries After Proton vs Photon Postmastectomy Radiation Therapy in Prepectoral Implant-Based Breast Reconstruction.

Postmastectomy radiation therapy (PMRT) improves disease-free survival in breast cancer but reduces aesthetic satisfaction. Proton PMRT has gained popularity due to fewer systemic complications. There is a lack of data regarding revision surgeries for pre-pectoral implant-based breast reconstruction (PP-IBBR) following radiation. To compare the revision surgeries in PP-IBBR with photon versus proton PMRT. A single-institution retrospective cohort study included breast cancer patients undergoing mastectomy and PP-IBBR with PMRT (January 2020-October 2022) The mean follow-up duration for the cohort was 1056.4 days (2.89 years). Revision surgeries evaluated were fat grafting, conversion to autologous flaps, implant replacement, implant removal, capsulectomy, and scar revision. 116 PP-IBBR were divided into two cohorts: photon (75, 64.66%) and proton (41, 35.34%) radiation cohorts. Overall corrective surgeries were higher with photon (27.5% overall; 32.4% photon vs 19.5% proton, p=0.132). The odds of any revision surgery were nearly double with photon (OR=1.98), and the conversion to an autologous flap was significantly more likely with photon (OR=4.55, p=0.025). Multivariable analysis showed an increased tendency for photon therapy patients to require any revision surgeries (OR=1.62, p=0.359), autologous flaps (OR=5.97, p=0.049), fat grafting (OR=1.52, p=0.664) and scar revision (OR=4.51, p=0.273). Compared to proton therapy, traditional photon therapy has a higher conversion rate to autologous flaps with PP-IBBR. Photon therapy had higher rates of overall revision surgeries, however not statistically significant. Proton therapy is safer, with fewer revision surgeries, warranting larger studies and broader utilization.

A simulation framework for preclinical proton irradiation workflow.

&#xD;The integration of proton beamlines with X-ray imaging/irradiation platforms has opened up possibilities for image-guided Bragg peak irradiations in small animals. Such irradiations allow selective targeting of normal tissue substructures and tumours. However, their small size and location pose challenges in designing experiments. This work presents a simulation framework useful for optimizing beamlines, imaging protocols, and design of animal experiments. The usage of the framework is demonstrated, mainly focusing on the imaging part.&#xD;Approach:&#xD;The fastCAT toolkit was modified with Monte Carlo (MC)-calculated primary and scatter data of a small animal imager for the simulation of micro-CT scans. The simulated CT of a mini-calibration phantom from fastCAT was validated against a full MC TOPAS CT simulation. A realistic beam model of a preclinical proton facility was obtained from beam transport simulations to create irradiation plans in matRad. Simulated CT images of a digital mouse phantom were generated using single-energy CT (SECT) and dual-energy CT (DECT) protocols and their accuracy in proton stopping power ratio (SPR) estimation and their impact on calculated proton dose distributions in a mouse were evaluated.&#xD;Main Results:&#xD;The CT numbers from fastCAT agree within 11 HU with TOPAS except for materials at the centre of the phantom. Discrepancies for central inserts are caused by beam hardening issues. The root mean square deviation in the SPR for the best SECT (90kV/Cu) and DECT (50kV/Al-90kV/Al) protocols are 3.7% and 1.0%, respectively. Dose distributions calculated for SECT and DECT datasets revealed range shifts <0.1 mm, gamma pass rates (3%/0.1mm) greater than 99%, and no substantial dosimetric differences for all structures. The outcomes suggest that SECT is sufficient for proton treatment planning in animals.&#xD;Significance:&#xD;The framework is a useful tool for the development of an optimized experimental configuration without using animals and beam time.&#xD.

Dosimetry in MRgPT: Impact of magnetic fields on TLD dose response during proton irradiation.

Proton beam therapy, when integrated with MRI guidance, presents complex dosimetric challenges due to interactions with magnetic fields. Prior research has emphasized the nuanced impact of magnetic fields on dosimetry. For thermoluminescent dosimeters (TLDs) the electron-return effect, alongside small air cavities surrounding the pellets, can lead to nonuniform dose distributions. Future MR-guided proton therapy will require reliable methods for end-to-end tests and dosimetric audits, which so far are often performed using TLDs equipped with phantoms. This implicates the necessity of accounting for theseinteractions. This study investigates the influence of magnetic fields on TLDs at two proton energies, using magnetic field strengths of 0, 0.25, and , aiming to clarify their impact on dose measurementaccuracy. The study was conducted at a synchrotron-based ion beam therapy beam line, enhanced by a resistive dipole magnet for creating magnetic fields up to to simulate MR-guided proton therapy. Individual correction factors were applied for TLD measurements. The impact of air gaps on the TLD signal was evaluated using three dedicated TLD holders with air gaps of 0.1, 0.25, and 0.5 mm surrounding the TLD pellets using the highest available proton energy of . Additionally, the influence of the magnetic field strength on the TLD response was evaluated for two proton energies of and . The study found no statistically significant variation in TLD dose response attributable to changes in the air gap or the presence of magnetic fields. A power analysis indicated an upper limit on a potential change in dose-response as small as 1.5%. The findings suggested that the impact of air gap variations and magnetic field strengths on the TLD response was below the detection threshold of TLD sensitivity. This emphasizes the suitability of TLDs for dose measurement in MR-guided proton therapy, indicating that additional correction factors may not be necessary despite the influence of magneticfields.

A Fast 3D Range-Modulator Delivery Approach: Validation of the FLUKA Model on a Varian ProBeam System Including a Robustness Analysis

A 3D range-modulator (RM), optimized for a single energy and a specific target shape, is a promising and viable solution for the ultra-fast dose delivery in particle therapy. The aim of this work was to investigate the impact of potential beam and modulator misalignments on the dose distribution. Moreover, the FLUKA Monte Carlo model, capable of simulating 3D RMs, was adjusted and validated for the 250 MeV single-energy proton irradiation from a Varian ProBeam system. A 3D RM was designed for a cube target shape rotated 45° around two axes using a Varian-internal research version of the Eclipse treatment planning software, and the resulting dose distribution was simulated in a water phantom. Deviations from the ideal alignment were introduced, and the dose distributions from the modified simulations were compared to the original unmodified one. Finally, the FLUKA model and the workflow were validated with base-line data measurements and dose measurements of the manufactured modulator prototype at the HollandPTC facility in Delft. The adjusted FLUKA model, optimized particularly in the scope of a single-energy FLASH irradiation with a PMMA pre-absorber, demonstrated very good agreement with the measured dose distribution resulting from the 3D RM. Dose deviations resulting from modulator-beam axis misalignments depend on the specific 3D RM and its shape, pin aspect ratio, rotation angle, rotation point, etc. A minor modulator shift was found to be more relevant for the distal dose distribution than for the spread-out Bragg Peak (SOBP) homogeneity. On the other hand, a modulator tilt (rotation away from the beam axis) substantially affected not only the depth dose profile, transforming a flat SOBP into a broad, Gaussian-like distribution with increasing rotation angle, but also shifted the lateral dose distribution considerably. This work strives to increase awareness and highlight potential pitfalls as the 3D RM method progresses from a purely research concept to pre-clinical studies and human trials. Ensuring that gantry rotation and the combined weight of RM, PMMA, and aperture do not introduce alignment issues is critical. Given all the other range and positioning uncertainties, etc., not related to the modulator, the RM must be aligned with an accuracy below 1° in order to preserve a clinically acceptable total uncertainty budget. Careful consideration of critical parameters like the pin aspect ratio and possibly a novel robust modulator geometry optimization are potential additional strategies to mitigate the impact of positioning on the resulting dose. Finally, even the rotated cube 3D modulator with high aspect ratio pin structures (~80 mm height to 3 mm pin base width) was found to be relatively robust against a slight misalignment of 0.5° rotation or a 1.5 mm shift in one dimension perpendicular to the beam axis. Given a reliable positioning and QA concept, the additional uncertainties introduced by the 3D RM can be successfully managed adopting the concept into the clinical routine.

Brain volume loss after cranial irradiation: a controlled comparison study between photon vs proton radiotherapy for WHO grade 2-3 gliomas.

Radiation therapy (RT) is an integral treatment component in patients with glioma but associated with neurotoxicity. Proton RT (PRT), as compared with photon RT (XRT), reduces excess radiation to nontarget tissue. We used a retrospective method to evaluate brain imaging metrics of neurotoxicity after treatment with PRT and XRT for glioma. We analyzed brain volume change in thirty-four patients with WHO grade 2-3 gliomas treated with either PRT (n = 17) or XRT (n = 17). Both groups were carefully matched by demographic/clinical criteria and assessed longitudinally for two years post-radiotherapy. Brain volume change was measured as ventricular volume expansion in the tumor free hemisphere (contralateral to RT target) as a proxy indicator of brain volume loss. We further assessed the impact of volumetric changes on cognition in PRT patients, who completed neuropsychological testing as part of an outcome study. We found significant ventricular volume increases in the contralesional hemisphere in both groups at two years post-RT (F(1, 31) = 18.45, p < 0.000, partial η2 = 0.373), with greater volume change observed in XRT (26.55%) vs. PRT (12.03%) (M = 12.03%, SD = 16.26; F(1,31) = 4.26, p = 0.048, partial η2 = 0.121). Although, there was no group-level change on any cognitive test in PRT treated patients, individual changes on cognitive screening, working memory, processing speed and visual memory tasks correlated with contralesional brain volume loss. This study suggests progressive brain volume loss following cranial irradiation, with greater severity after XRT vs. PRT. Radiation-induced brain volume loss appears to be associated with measurable cognitive changes on an individual level. Prospective studies are warranted to validate these findings and their impacts on long-term cognitive function and quality of life. An improved understanding of the structural and functional consequences of cranial radiation is essential to develop neuroprotective strategies.

Controlling directional emission of ions attached on the surface of nanoparticles

Abstract The interaction between lasers and nanoparticles holds significant theoretical and practical importance. Here, we investigate the near-field enhancement effects on silver nanotriangles and nanodiscs under ultrafast laser pulses, as well as the dynamics of protons and ions attached to the nanoparticle surfaces. By adjusting the size parameters of the nanoparticles, we explore the near-field enhancement effects and proton emission dynamics at different laser wavelengths. The results demonstrate that nanoparticles with varying morphologies substantially impact the proton momentum spectrum. The directional proton emission of nanotriangle structures is more pronounced compared to that of nanodiscs, and this effect can be further enhanced by adjusting the laser wavelength. Additionally, manipulating the thickness of particles also controls the Mie scattering phenomenon of light. Finally, we qualitatively discuss the emission processes of alpha particles and 9C6+ heavy ions. This research has important implications for proton and heavy ion radiotherapy in cancer treatment and targeted drug delivery, while providing theoretical foundations for understanding, characterizing, and controlling experimental studies of nanosystems with significant potential for expanding research into microdynamic behavior in complex nanomaterial superstructures.

Proton Radiation Therapy: A Systematic Review of Treatment-Related Side Effects and Toxicities

Cancer is the second leading cause of death worldwide. Around half of all cancer patients undergo some type of radiation therapy throughout the course of their treatment. Photon radiation remains (RT) the most widely utilized modality of radiotherapy despite recent advancements in proton radiation therapy (PBT). PBT makes use of the particle’s biological property known as the Bragg peak to better spare healthy tissue from radiation damage, with data to support that this treatment modality is less toxic than photon RT. Hence, proton radiation dosimetry looks better compared to photon dosimetry; however, due to proton-specific uncertainties, unexpected acute, subacute, and long-term toxicities can be encountered. Reported neurotoxicity resulting from proton radiation treatments include radiation necrosis, moyamoya syndrome, neurosensory toxicities, brain edema, neuromuscular toxicities, and neurocognitive toxicities. Pulmonary toxicities include pneumonitis and fibrosis, pleural effusions, and bronchial toxicities. Pericarditis, pericardial effusions, and atrial fibrillations are among the cardiac toxicities related to proton therapy. Gastrointestinal and hematological toxicities are also found in the literature. Genitourinary toxicities include urinary and reproductive-related toxicities. Osteological, oral, endocrine, and skin toxicities have also been reported. The side effects will be comparable to the ones following photon RT, nonetheless at an expected lower incidence. The toxicities collected mainly from case reports and clinical trials are described based on the organs affected and functions altered.

Phase-change ultrasound contrast agents for proton range verification: towards an in vivo application

Objective.In proton therapy, range uncertainties prevent optimal benefit from the superior depth-dose characteristics of proton beams over conventional photon-based radiotherapy. To reduce these uncertainties we recently proposed the use of phase-change ultrasound contrast agents as an affordable and effective range verification tool. In particular, superheated nanodroplets can convert into echogenic microbubbles upon proton irradiation, whereby the resulting ultrasound contrast relates to the proton range with high reproducibility. Here, we provide a firstin vivoproof-of-concept of this technology.Approach.First, thein vitrobiocompatibility of radiation-sensitive poly(vinyl alcohol) perfluorobutane nanodroplets was investigated using several colorimetric assays. Then,in vivoultrasound contrast was characterized using acoustic droplet vaporization (ADV) and later using proton beam irradiations at varying energies (49.7 MeV and 62 MeV) in healthy Sprague Dawley rats. A preliminary evaluation of thein vivobiocompatibility was performed using ADV and a combination of physiology monitoring and histology.Main results.Nanodroplets were non-toxic over a wide concentration range (<1 mM). In healthy rats, intravenously injected nanodroplets primarily accumulated in the organs of the reticuloendothelial system, where the lifetime of the generated ultrasound contrast (<30 min) was compatible with a typical radiotherapy fraction (<5 min). Spontaneous droplet vaporization did not result in significant background signals. Online ultrasound imaging of the liver of droplet-injected rats demonstrated an energy-dependent proton response, which can be tuned by varying the nanodroplet concentration. However, caution is warranted when deciding on the exact nanodroplet dose regimen as a mild physiological response (drop in cardiac rate, granuloma formation) was observed after ADV.Significance.These findings underline the potential of phase-change ultrasound contrast agents forin vivoproton range verification and provide the next step towards eventual clinical applications.

Thermal properties of MB2-WC (M = Ti, Zr, Hf) and tungsten and their stability after deuterium plasma exposure

The thermal properties of ultra-high temperature ceramics (UHTCs) in the MB2-WC (M = Ti, Zr, Hf) system and tungsten were studied for potential application as plasma-facing materials in fusion power plants. The sintered UHTC and tungsten samples were subjected to deuterium plasma or protons irradiation. Thermal diffusivity was measured using the laser flash method, and superficial thermal conductivity was analyzed through atomic force microscopy. Results showed that the thermal properties did not degrade when exposed to relevant environments and remained stable over a range of temperatures, unlike the reference tungsten material. Thermal conductivity ranged from 61 to 68 W m−1 K−1 for TiB2-2(WC-6Co), from 53 to 63 W m−1 K−1 for ZrB2-6WC, from 67 to 75 W m−1 K−1 for HfB2-6WC, and from 180 to 119 W m−1 K−1 for tungsten across the temperature range from room temperature to 1200 °C. The increasing trend of thermal effusivity, over 19000 J s−0.5 m−2 K−1 at 1200 °C, justifies further testing and of UHTC materials for fusion applications.

AVATAR 2.0: next level communication systems for radiotherapy through face-to-face video, biofeedback, translation, and audiovisual immersion.

This paper discusses an advanced version of our audiovisual-assisted therapeutic ambience in radiotherapy (AVATAR) radiolucent display systems designed for pediatric radiotherapy, enabling anesthesia-free treatments, video communication, and biofeedback. The scope of the AVATAR system is expanded here in two major ways: (i) through alternative mounting systems to accommodate a broader range of radiotherapy machines (specifically to fit robotic-arm and toroidal geometry photon radiotherapy and proton radiotherapy systems) and (ii) through additional hardware to provide video-calling, optimized audio for clear communication, and combined video inputs for biofeedback, translation, and other advanced functionalities. Because robustness requires strong parts and radio-transparency requires thin, light parts, three-dimensional printing was used to rapidly prototype hollow structures and to iteratively improve robustness. Two system designs were made: one that mounts superior and another that mounts inferior to the patient's head. Radiation dose measurements and calculations were conducted to assess dose perturbations at surface and depth due to the screen. For 6-MV volumetric modulated arc therapy (VMAT) plans, with and without the screen, the mean and maximum dose differences inside the planning target volume were 0.2% and 2.6% of the 200 cGy prescription, respectively. For a single static beam through the screen, the maximum measured excess surface dose was 13.4 ± 0.5%, and the largest measured dose attenuation at 5-cm water-equivalent depth was 2.1 ± 0.2%. These percentages are relative to the dose without the screen at those locations. The radiolucent screen systems provided here are shown to give minimal dosimetric effects on megavoltage VMAT photon treatments. For static beams, however, surface dose effects should be considered when these beams pass through the thickest components of the screen. Design files are also provided.

Repeated γ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\gamma $$\\end{document} irradiation and thermal annealing via built-in thermo-electric coolers of Si avalanche photodiodes

When operating in space, on-board Silicon Geiger-Mode Avalanche Photodiodes (GM-APDs) are exposed to radiation damage that result in an increase in dark count rates. Thermal annealing has been found to mitigate the damage, although prior studies have largely focused on annealing following a single session of proton irradiation. This work reports that thermal annealing can be performed simply with the built-in thermo-electric coolers of the GM-APDs. Annealing was also done in 10 min intervals for a clearer view of the recovery curve. Mitigation of damage from repeated γ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\gamma $$\\end{document} radiation was observed from the: (1) halving of the increase in dark count rates on average and (2) outperformance of room temperature annealing (25∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$25\\,^{\\circ }$$\\end{document}C) by 33%\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\%$$\\end{document}. Additionally, we show that heavy doses of γ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\gamma $$\\end{document} radiation (21 krad) have a probability of causing Random Telegraph Signals in GM-APDs that can be suppressed by lowering the operating temperature.

CYRAD: a translational study assessing immune response to radiotherapy by photons or protons in postoperative head and neck cancer patients through circulating leukocyte subpopulations and cytokine levels

BackgroundRadiotherapy has both immunostimulant and immunosuppressive effects, particularly in radiation-induced lymphopenia. Proton therapy has demonstrated potential in mitigating this lymphopenia, yet the mechanisms by which different types of radiation affect the immune system function are not fully characterized. The Circulating Immunes Cells, Cytokines and Brain Radiotherapy (CYRAD) trial aims to compare the effects of postoperative X-ray and proton radiotherapy on circulating leukocyte subpopulations and cytokine levels in patients with head and neck (CNS and ear nose throat) cancer.MethodsCYRAD is a prospective, non-randomized, single-center non interventional study assessing changes in the circulating leukocyte subpopulations and cytokine levels in head and neck cancer patients receiving X-ray or proton radiotherapy following tumor resection. Dosimetry parameters, including dose deposited to organs-at-risk such as the blood and cervical lymph nodes, are computed. Participants undergo 29 to 35 radiotherapy sessions over 40 to 50 days, followed by a 3-month follow-up. Blood samples are collected before starting radiotherapy (baseline), before the 11th (D15) and 30th sessions (D40), and three months after completing radiotherapy. The study will be conducted with 40 patients, in 2 groups of 20 patients per modality of radiotherapy (proton therapy and photon therapy). Statistical analyses will assess the absolute and relative relationship between variations (depletion, recovery) in immune cells, biomarkers, dosimetry parameters and early outcomes.DiscussionPrevious research has primarily focused on radiation-induced lymphopenia, paying less attention to the specific impacts of radiation on different lymphoid and myeloid cell types. Early studies indicate that X-ray and proton irradiation may lead to divergent outcomes in leukocyte subpopulations within the bloodstream. Based on these preliminary findings, this study aims to refine our understanding of how proton therapy can better preserve immune function in postoperative (macroscopic tumor-free) head and neck cancer patients, potentially improving treatment outcomes.Protocol versionVersion 2.1 dated from January 18, 2023.Trial registrationThe CYRAD trial is registered from October 19, 2021, at the US National Library of Medicine, ClinicalTrials.gov ID NCT05082961.

Unveiling the origin of XMM-Newton soft proton flares. I. Design and validation of a response matrix for proton spectral analysis

Low-energy ($&lt;$ 300 keV) protons entering the field of view of XMM-Newton can scatter with the X-ray mirror surface and reach the focal plane. They are observed in the form of a sudden increase in the background level, the so-called soft proton flares, affecting up to 40&lt;!PCT!&gt; of the mission observing time. Soft protons can hardly be disentangled from true X-ray events and cannot be rejected on board. All future high throughput grazing incidence X-ray telescopes operating outside the radiation belts are potentially affected by soft proton-induced contamination that must be foreseen and limited since the design phase. In-flight XMM-Newton 's observations of soft protons represent a unique laboratory to validate and improve our understanding of their interaction with the mirror, optical filters, and X-ray instruments. At the same time, such models would link the observed background flares to the primary proton population encountered by the telescope, converting XMM-Newton into a monitor for soft protons. We built a Geant4 simulation of XMM-Newton including a verified mass model of the X-ray mirror, the focal plane assembly, and the EPIC MOS and pn-CCDs. Analytical computations and, when available, laboratory measurements collected from literature were used to verify the correct modelling of the proton scattering and transmission to the detection plane. Similarly to the instrument X-ray response, we encoded the energy redistribution and proton transmission efficiency into a redistribution matrix file (RMF), mapping the probability that a proton from 2 to 300 keV is detected in a certain detector channel, and an auxiliary response file (ARF), storing the grasp towards protons. Both files were formatted according to the standard NASA calibration database and any compliant X-ray data analysis tool can be used to simulate or analyse soft proton-induced background spectra. An overall systematic uncertainty of 30&lt;!PCT!&gt; was assumed on the basis of the estimated accuracy of the mirror geometry and transmission models. For the validation, three averaged soft proton spectra, one for each filter configuration, were extracted from a collection of 13 years of MOS observations of the focused non X-ray background and analysed with Xspec . A similar power-law distribution is found for the three filter configurations, plus black-body-like emission below tens of keV used as a correction factor, based on the dedicated spectral analysis of 55 in-flight proton flares presented in Paper II. The best-fit model is in agreement with the power-law distribution predicted from independent measurements for the XMM-Newton orbit, spent mostly in the magnetosheath and nearby regions. For the first time we are able to link detected soft proton flares with the proton radiation environment in the Earth's magnetosphere, while proving the validity of the simulation chain in predicting the background of future missions. Benefiting from this work and contributions from the Athena instrument consortia, we also present the response files for the Athena mission and updated estimates for its focused charged background.

Pediatric Metastatic Extracranial High-Grade Glioma: A Case Report and Literature Review

Abstract We report a case of a 10-year-old male with a right frontal diffuse pediatric-type high-grade glioma (HGG), H3-wildtype (WT) and IDH-WT, diagnosed at the age of 9 years, who underwent gross total resection, 60 Gy focal proton radiation in 30 fractions to the resection cavity with concurrent temozolomide followed by maintenance chemotherapy with temozolomide and lomustine. One month after completion of maintenance chemotherapy, he developed subcutaneous swelling in the right temporal region and was treated with antibiotics for presumed lymphadenitis. Two months later, he developed a recurrent painless right parietal soft tissue mass that failed to respond to antibiotic therapy. This prompted evaluation by MRI which revealed new enhancing masses in the cerebellum and extracranial soft tissue mass in right temporal region. He underwent gross total resection of both masses. Pathologic analysis confirmed both masses as recurrent HGG. Molecular markers, however, differed between the two sites of recurrence. He proceeded to complete hypofractionated proton therapy to sites of recurrence. Three months later he was found to have tumor dissemination into the spine and brain for which he received proton therapy to the whole spine and brain. Due to the presence of CDK4 amplification at diagnosis and at both sites of tumor recurrence, he then received palliative treatment with the CDK4/6 inhibitor, abemaciclib, for the final five months of his life. Since extracranial HGG is a rare presentation, with few cases reported in the pediatric population, we report this case and review previously published literature.

Superior antitumor immune response achieved with proton over photon immunoradiotherapy is amplified by the nanoradioenhancer NBTXR3

Recent findings suggest that immunoradiotherapy (IRT), combining photon radiotherapy (XRT) or proton radiotherapy (PRT) with immune checkpoint blockade, can enhance systemic tumor control. However, the comparative efficacy of XRT and PRT in IRT remains understudied. To address this, we compared outcomes between XRT + αPD1 and PRT + αPD1 in murine αPD1-resistant lung cancer (344SQR). We also assessed the impact of the nanoparticle radioenhancer NBTXR3 on both XRT + αPD1 and PRT + αPD1 for tumor control and examined the tumor immune microenvironment using single-cell RNA sequencing (scRNAseq). Additionally, mice cured by NBTXR3 + PRT + αPD1 were rechallenged with three lung cancer cell lines to evaluate memory antitumor immunity. PRT + αPD1 showed superior local tumor control and abscopal effects compared to XRT + αPD1. NBTXR3 + PRT + αPD1 significantly outperformed NBTXR3 + XRT + αPD1 in tumor control, promoting greater infiltration of antitumor lymphocytes into irradiated tumors. Unirradiated tumors treated with NBTXR3 + PRT + αPD1 had more NKT cells, CD4 T cells, and B cells, with fewer Tregs, than those treated with NBTXR3 + XRT + αPD1. NBTXR3 + PRT + αPD1 also stimulated higher expression of IFN-γ, GzmB, and Nkg7 in lymphocytes, reduced the TGF-β pathway, and increased tumor necrosis factor alpha expression compared to NBTXR3 + XRT + αPD1. Moreover, NBTXR3 + PRT + αPD1 resulted in greater M1 macrophage polarization in both irradiated and unirradiated tumors. Mice achieving remission through NBTXR3 + PRT + αPD1 exhibited a robust memory immune response, effectively inhibiting growth of subsequent tumors from three distinct lung cancer cell lines. Proton IRT combined with NBTXR3 offers enhanced tumor control and survival rates over photon-based treatments in managing αPD1-resistant lung cancer, indicating its potential as a potent systemic therapy.Graphical

Differential plasma cytokine variation following X-ray or proton brain irradiation using machine-learning approaches

PurposeX-ray and proton irradiation have been reported to induce distinct modifications in cytokine expression in vitro and in vivo, suggesting a dissimilar inflammatory response between X-rays and protons. We aimed to investigate the differences in cytokine profiles early following fractionated brain irradiation with X-rays or protons and their relationship with leukocyte subpopulations in rodents. Materials and methodsOur study utilized data from 80 tumor-free mice subjected to X-ray or proton brain irradiation in four fractions of 2.5Gy. Sixteen non-irradiated mice were used as the controls. Blood was collected 12h postirradiation to examine the profile of 13 cytokines. Correlation analysis, principal component analysis (PCA), and tree-based modeling were used to investigate the relationship between cytokine levels and leukocyte subpopulation variations following irradiation in the blood. ResultsRegardless of the irradiation type, brain irradiation resulted in a notable elevation in the plasma levels of IFN-γ and MCP-1. The use of either X-ray or proton beam had differential effect on plasma cytokine levels following brain irradiation. Specifically, X-ray irradiation was associated with significantly increased plasma levels of IFN-β, IL-12p70, and IL-23, along with a decreased level of IL-1α, in comparison to proton irradiation. Correlation analysis revealed distinct cytokine regulatory patterns between X-ray and proton brain irradiation. PCA highlighted the association of MCP-1, IL-6, TNF-α, IL-17A, and IFN-γ with neutrophils, monocytes, and naïve T-cells following X-ray irradiation. TNF-α and IL-23 levels correlated with naïve CD4+-cells following proton irradiation. Tree-based models demonstrated that high TNF-α level resulted in an increase in naïve T-cells, neutrophils, and monocytes, whereas low IL-6 level was associated with decreases in these cell counts. ConclusionOur findings revealed distinct inflammatory responses induced by X-ray irradiation in contrast to proton brain irradiation, as demonstrated by the differential regulation of cytokines in the bloodstream. Moreover, the study highlighted the association between specific cytokine levels and various leukocyte subpopulations. Further investigation is essential to accurately determine the impact of proton and X-ray brain irradiation on the inflammatory response and the efficacy of radiotherapy treatment.

Combining clinostating and proton irradiation for modeling the space environment: a case study with a Chernobyl accession of Arabidopsis thaliana

Purpose The study of mechanisms of plant responses to extreme conditions, particularly, microgravity and ionizing radiation, is crucial for space exploration. Modern space biology of plants focuses on increasing plant tolerance to harsh conditions of space environment. Given the limited access to the International Space Station, we designed and assembled the 3D clinostat for mimicking microgravity, which, in combination with proton irradiation, allows simulating space conditions. As a case study for testing the device, we studied the effect of clinostating on Arabidopsis thaliana accession originating from the Chernobyl exclusion zone. Materials and Methods Using the combined clinostating and proton irradiation, we simulated the conditions of long-term space flight for Arabidopsis thaliana plants of the Chernobyl accession – progeny of chronically irradiated plants, grown from field-collected (Masa-0) and laboratory-cultivated (Masa-0-1) seeds, and for wild-type Col-8. The clinostating and irradiation of plants were also carried out separately. Plant responses were studied as photosynthetic and phenotypic endpoints of seedlings. Results and Conclusions Parameters of chlorophyll fluorescence estimated immediately after exposure showed that Masa-0-1 plants were resistant to the simulated space conditions, while Masa-0 demonstrated modulation of non-photochemical fluorescence quenching. Proton irradiation generally inhibited photosynthesis of Masa-0, Masa-0-1, and Col-8 seedlings. The combined effect of irradiation and clinostating modulated the photosynthetic activity of Col-8 seedlings. The leaf area of seedlings did not change after exposure to simulated conditions. The 3D clinostat model and software are published along with this article for researchers interested in the field of space biology.