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Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths worldwide with limited treatment options due to extensive radiation and chemotherapy resistance. Monotherapy with immune checkpoint blockade showed no survival benefit. A combination of immunomodulation and radiotherapy may offer new treatment strategies, as demonstrated for non-small cell lung cancer. Radiation-induced anti-tumour immunity is mediated through cytosolic nucleic acid sensing pathways that drive the expression of interferon beta-1 (IFNB1) and proinflammatory cytokines. Methods: Human PDAC cell lines (PANC-1, MIA PaCa-2, BxPC-3) were treated with X-rays and protons. Immunogenic cell death was measured based on HMGB1 release. Cytosolic dsDNA and dsRNA were analysed by immunofluorescence microscopy. Cell cycle progression, MHC-I and PD-L1 expression were determined by flow cytometry. Galectin-1 and IFNB1 were measured by ELISA. The expression levels and the phosphorylation status of the cGAS/STING and RIGI/ MAVS signalling pathways were analysed by western blotting, the expression of IFNB1 and proinflammatory cytokines was determined by RT-qPCR and genome-wide by RNA-seq. CRISPR-Cas9 knock-outs and inhibitors were used to elucidate the relevance of STING, MAVS and NF-κB for radiation-induced IFNB1 activation. Results: We demonstrate that a clinically relevant X-ray hypofractionation regimen (3x8 Gy) induces immunogenic cell death and activates IFNB1 and proinflammatory cytokines. Fractionated radiation induces G2/M arrest and accumulation of cytosolic DNA in PDAC cells, which partly originates from mitochondria. RNA-seq analysis shows a global upregulation of type I interferon response and NF- κB signalling in PDAC cells following 3x8 Gy. Radiation-induced immunogenic response is regulated by STING, MAVS and NF- κB. In addition to immunostimulation, radiation also induces immunosuppressive galectin-1. No significant changes in MHC-I or PD-L1 expression were observed. Moreover, PDAC cell lines show similar radiation-induced immune effects when exposed to single-dose protons or photons. Conclusion: Our findings provide a rationale for combinatorial radiation-immunomodulatory treatment approaches in PDAC using conventional photon-based or proton beam radiotherapy. [ABSTRACT FROM AUTHOR]

This work aimed to characterize a dedicated phantom for assessing the dose near metal implants for radiotherapy with photons and protons. A dosimetry audit phantom was redesigned to position a Gafchromic EBT-3 film within a bisected titanium pedicle screw (6.5 mm diameter). The mass density and the water equivalent thickness (WET) of the phantom material were determined. The phantom was irradiated using a photon arc and a horizontal proton beam in combination with a couch rotation of 20°, with three repeated measurements each. Treatment plans utilizing a single field covering the screw and the EBT-3 film were optimized to deliver a physical dose of 2 Gy using a collapsed cone and Monte Carlo dose engine for photons and protons, respectively. The mass density and the WET of the phantom were determined as (1.033 ± 0.010) gcm-3 and (1.022 ± 0.013), respectively. Ionisation chamber measurements agreed within 1% (photons) and 0.5% (protons) with the calculated dose values. Relative photon dosimetry measurements using EBT-3 films revealed an agreement between measured and calculated horizontal profiles within the confidence interval for areas beyond 5 mm from the center. For photon plans, significant deviations of more than 10% were found at the interfaces between phantom material and screw. The proton measurements showed a gradual decrease of 3% across both profiles. In contrast to photon plans, no dose increase was measured within the screw, but significant dose fluctuations (>5%) in the beam's exit region. This study showed that the behavior of dose engine is affected by metal implants and thus dosimetric measurements are highly recommended. The presented phantom can serve as foundation for dedicated end-2-end phantoms. [ABSTRACT FROM AUTHOR]

Background: Carbon ion beams are well accepted as densely ionizing radiation with a high linear energy transfer (LET). However, the current clinical practice does not fully exploit the highest possible dose‐averaged LET (LETd) and, consequently, the biological potential in the target. This aspect becomes worse in larger tumors for which inferior clinical outcomes and corresponding lower LETd was reported. Purpose: The vicinity to critical organs in general and the inferior overall survival reported for larger sacral chordomas treated with carbon ion radiotherapy (CIRT), makes the treatment of such tumors challenging. In this work it was aimed to increase the LETd in large volume tumors while maintaining the relative biological effectiveness (RBE)‐weighted dose, utilizing the LETd optimization functions of a commercial treatment planning system (TPS). Methods: Ten reference sequential boost carbon ion treatment plans, designed to mimic clinical plans for large sacral chordoma tumors, were generated. High dose clinical target volumes (CTV‐HD) larger than 250cm3$250 \,{\rm cm}^{3}$ were considered as large targets. The total RBE‐weighted median dose prescription with the local effect model (LEM) was DRBE,50%=73.6Gy$\textrm {D}_{\rm RBE, 50\%}=73.6 \,{\rm Gy}$ in 16 fractions (nine to low dose and seven to high dose planning target volume). No LETd optimization was performed in the reference plans, while LETd optimized plans used the minimum LETd (Lmin) optimization function in RayStation 2023B. Three different Lmin values were investigated and specified for the seven boost fractions: Lmin=60keV/μm$\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$, Lmin=80keV/μm$\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ and Lmin=100keV/μm$\textrm {L}_{\rm min}=100 \,{\rm keV}/{\umu }{\rm m}$. To compare the LETd optimized against reference plans, LETd and RBE‐weighted dose based goals similar to and less strict than clinical ones were specified for the target. The goals for the organs at risk (OAR) remained unchanged. Robustness evaluation was studied for eight scenarios (±3.5%$\pm 3.5\%$ range uncertainty and ±3mm$\pm 3 \,{\rm mm}$ setup uncertainty along the main three axes). Results: The optimization method with Lmin=60keV/μm$\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ resulted in an optimal LETd distribution with an average increase of LETd,98%${\rm {LET}}_{{\rm {d,}}98\%}$ (and LETd,50%${\rm {LET}}_{{\rm {d,}}50\%}$) in the CTV‐HD by 8.9±1.5keV/μm$8.9\pm 1.5 \,{\rm keV}/{\umu }{\rm m}$ (27%$27\%$) (and 6.9±1.3keV/μm$6.9\pm 1.3 \,{\rm keV}/{\umu }{\rm m}$ (17%$17\%$)), without significant difference in the RBE‐weighted dose. By allowing ±5%$\pm 5\%$ over‐ and under‐dosage in the target, the LETd,98%${\rm {LET}}_{{\rm {d,}}98\%}$ (and LETd,50%${\rm {LET}}_{{\rm {d,}}50\%}$) can be increased by 11.3±1.2keV/μm$11.3\pm 1.2 \,{\rm keV}/{\umu }{\rm m}$ (34%$34\%$) (and 11.7±3.4keV/μm$11.7\pm 3.4 \,{\rm keV}/{\umu }{\rm m}$ (29%$29\%$)), using the optimization parameters Lmin=80keV/μm$\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$. The pass rate for the OAR goals in the LETd optimized plans was in the same level as the reference plans. LETd optimization lead to less robust plans compared to reference plans. Conclusions: Compared to conventionally optimized treatment plans, the LETd in the target was increased while maintaining the RBE‐weighted dose using TPS LETd optimization functionalities. Regularly assessing RBE‐weighted dose robustness and acquiring more in‐room images remain crucial and inevitable aspects during treatment. [ABSTRACT FROM AUTHOR]

In order to overcome the resistance to radiotherapy in human chondrosarcoma cells, the prevention from efficient DNA repair with a combined treatment with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor AZD7648 was explored for carbon ion (C-ion) as well as reference photon (X-ray) irradiation (IR) using gene expression analysis, flow cytometry, protein phosphorylation, and telomere length shortening. Proliferation markers and cell cycle distribution changed significantly after combined treatment, revealing a prominent G2/M arrest. The expression of the G2/M checkpoint genes cyclin B, CDK1, and WEE1 was significantly reduced by IR alone and the combined treatment. While IR alone showed no effects, additional AZD7648 treatment resulted in a dose-dependent reduction in AKT phosphorylation and an increase in Chk2 phosphorylation. Twenty-four hours after IR, the key genes of DNA repair mechanisms were reduced by the combined treatment, which led to impaired DNA repair and increased radiosensitivity. A time-dependent shortening of telomere length was observed in both cell lines after combined treatment with AZD7648 and 8 Gy X-ray/C-ion IR. Our data suggest that the inhibition of DNA-PKcs may increase sensitivity to X-rays and C-ion IR by impairing its functional role in DNA repair mechanisms and telomere end protection. [ABSTRACT FROM AUTHOR]

Objective: 3D printing has seen use in many fields of imaging and radiation oncology, but applications in (anthropomorphic) phantoms, especially for particle therapy, are still lacking. The aim of this work was to characterize various available 3D printing methods and epoxy-based materials with the specific goal of identifying suitable tissue surrogates for dosimetry applications in particle therapy. Methods: 3D-printed and epoxy-based mixtures of varying ratios combining epoxy resin, bone meal, and polyethylene powder were scanned in a single-energy computed tomography (CT), a dual-energy CT, and a μCT scanner. Their CT-predicted attenuation was compared to measurements in a 148.2 MeV proton and 284.7 MeV/u carbon ion beam. The sample homogeneity was evaluated in the respective CT images and in the carbon beam, additionally via widening of the Bragg peak. To assess long-term stability attenuation, size and weight measurements were repeated after 6-12 months. Results: Four 3D-printed materials, acrylonitrile butadiene styrene polylactic acid, fused deposition modeling printed nylon, and selective laser sintering printed nylon, and various ratios of epoxy-based mixtures were found to be suitable tissue surrogates. The materials' predicted stopping power ratio matched the measured stopping power ratio within 3% for all investigated CT machines and protocols, except for μCT scans employing cone beam CT technology. The heterogeneity of the suitable surrogate samples was adequate, with a maximum Bragg peak width increase of 11.5 ± 2.5%. The repeat measurements showed no signs of degradation after 6-12 months. Conclusion: We identified surrogates for soft tissue and low- to medium-density bone among the investigated materials. This allows low-cost, adaptable phantoms to be built for quality assurance and end-to-end tests for particle therapy. [ABSTRACT FROM AUTHOR]

Background: The combination of magnetic resonance imaging and proton therapy offers the potential to improve cancer treatment. The magnetic field (MF)‐dependent change in the dosage of ionization chambers in magnetic resonance imaging‐integrated proton therapy (MRiPT) is considered by the correction factor kB⃗,M,Q$k_{\vec{B},M,Q}$, which needs to be determined experimentally or computed via Monte Carlo (MC) simulations. Purpose: In this study, kB⃗,M,Q$k_{\vec{B},M,Q}$ was both measured and simulated with high accuracy for a plane‐parallel ionization chamber at different clinical relevant proton energies and MF strengths. Material and methods: The dose‐response of the Advanced Markus chamber (TM34045, PTW, Freiburg, Germany) irradiated with homogeneous 10 ×$\times$ 10 cm 2$^2$ quasi mono‐energetic fields, using 103.3, 128.4, 153.1, 223.1, and 252.7 MeV proton beams was measured in a water phantom placed in the MF of an electromagnet with MF strengths of 0.32, 0.5, and 1 T. The detector was positioned at a depth of 2 g/cm 2$^2$ in water, with chamber electrodes parallel to the MF lines and perpendicular to the proton beam incidence direction. The measurements were compared with TOPAS MC simulations utilizing COMSOL‐calculated 0.32, 0.5, and 1 T MF maps of the electromagnet. kB⃗,M,Q$k_{\vec{B},M,Q}$ was calculated for the measurements for all energies and MF strengths based on the equation: kB⃗,M,Q=MQMQB⃗$k_{\vec{B},M,Q}=\frac{M_\mathrm{Q}}{M_\mathrm{Q}^{\vec{B}}}$, where MQB⃗$M_\mathrm{Q}^{\vec{B}}$ and MQ$M_\mathrm{Q}$ were the temperature and air‐pressure corrected detector readings with and without the MF, respectively. MC‐based correction factors were determined as kB⃗,M,Q=DdetDdetB⃗$k_{\vec{B},M,Q}=\frac{D_\mathrm{det}}{D_\mathrm{det}^{\vec{B}}}$, where DdetB⃗$D_\mathrm{det}^{\vec{B}}$ and Ddet$D_\mathrm{det}$ were the doses deposited in the air cavity of the ionization chamber model with and without the MF, respectively. Furthermore, MF effects on the chamber dosimetry are studied using MC simulations, examining the impact on the absorbed dose‐to‐water (DW$D_{W}$) and the shift in depth of the Bragg peak. Results: The detector showed a reduced dose‐response for all measured energies and MF strengths, resulting in experimentally determined kB⃗,M,Q$k_{\vec{B},M,Q}$ values larger than unity. For all energies and MF strengths examined, kB⃗,M,Q$k_{\vec{B},M,Q}$ ranged between 1.0065 and 1.0205. The dependence on the energy and the MF strength was found to be non‐linear with a maximum at 1 T and 252.7 MeV. The MC simulated kB⃗,M,Q$k_{\vec{B},M,Q}$ values agreed with the experimentally determined correction factors within their standard deviations with a maximum difference of 0.6%. The MC calculated impact on DW$D_{W}$ was smaller 0.2 %. Conclusion: For the first time, measurements and simulations were compared for proton dosimetry within MFs using an Advanced Markus chamber. Good agreement of kB⃗,M,Q$k_{\vec{B},M,Q}$ was found between experimentally determined and MC calculated values. The performed benchmarking of the MC code allows for calculating kB⃗,M,Q$k_{\vec{B},M,Q}$ for various ionization chamber models, MF strengths and proton energies to generate the data needed for a proton dosimetry protocol within MFs and is, therefore, a step towards MRiPT. [ABSTRACT FROM AUTHOR]