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Background and Purpose: Proton Minibeam Radiation Therapy (pMBRT) is an unconventional radiation technique based on a strong modulation of the dose deposition. Due to its specific pattern, pMBRT involves several dosimetry (peak and valley doses, peak-to-valley dose ratio (PVDR)) and geometrical parameters (beam width, spacing) that can influence the biological response. This study aims at contributing to the efforts to deepen the comprehension of how the various parameters relate to central biological mechanisms, particularly anti-tumor immunity, and how these correlations affect treatment outcomes with the goal to fully unleash the potential of pMBRT. We also evaluated the effects of X-ray MBRT to further elucidate the influence of peak dose and dose heterogeneity., Methods and Materials: An orthotopic rat model of glioblastoma underwent several pMBRT configurations. The impact of different dosimetric parameters on survival and on the modulation of crucial mechanisms for pMBRT, such as immune response, was investigated. The latter was assessed by immunohistochemistry and flow cytometry at 7 days post-irradiation., Results: Survival was improved across the various pMBRT regimens via maintaining a minimum valley dose as well as a higher dose heterogeneity, which is driven by peak dose. While the mean dose did not impact immune infiltration, a higher PVDR promoted a less immunosuppressive microenvironment., Conclusions: Our results suggest that both tumor eradication, and immune infiltration are associated with higher dose heterogeneity. Higher dose heterogeneity was achieved by optimizing the peak dose, as well as maintaining a minimum valley dose. These parameters contributed to direct tumor eradication as well as reduction of immunosuppression, which is a departure from the more immunosuppressive tumor environment found in conventional proton therapy that delivers uniform dose distributions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Electron radiotherapy has long been preferred to photons for the treatment of superficial lesions because of its physical characteristics (high dose at the surface, rapid decrease in depth). Other characteristics (penumbra, heterogeneity on an oblique or irregular surface) make them difficult to use. In most indications (skin cancers, head and neck, medulloblastoma), with technical progress, in some cases they have been replaced by intensity-modulated conformal radiotherapy, brachytherapy and contact therapy. Other indications (drainage of mesotheliomas or irradiation of benign lesions) have disappeared. The low frequency of use leads to problems of safety and cost-effectiveness. However, modern photon radiotherapy techniques are still less effective than electrons in specific indications such as total skin irradiation (mycosis fungoides) or certain thin chest wall irradiations after total mastectomy, reirradiation or paediatric treatments without protons. Flash therapy, initiated by electrons, has been developed over the last 10 years, providing high-dose irradiation in an extremely short time. Initial results show good efficacy, with fewer side effects than with conventional radiotherapy. These results are leading to clinical technological developments on a larger scale. Although it has been replaced in most indications by more modern techniques, electron radiotherapy remains essential for targeted indications in specialised centres. The emergence of flash therapy will lead to new indications, on machines equipped with this new technology, which have yet to be defined and are currently the responsibility of specialised teams., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

\textbf{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 (HU) 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.

\textbf{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 (pMBRT) beamline at the Curie Institute. The chips were subjected to 100 MeV protons passing through the single slit collimator (0.4$\times$20 mm$^2$) with fluxes up to $1.3 \times 10^7$ p/s/cm$^2$. The performance of the proton tracker was evaluated with GEANT4 simulations.



\textbf{Main Results:} 
The beam profile and dispersion in air were characterized by an opening of 0.031~mm/cm, and a $\sigma_x=0.172$~mm 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.

\textbf{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., (Creative Commons Attribution license.)