Proton Irradiation Research Articles

Secondary neutron dosimetry for conformal FLASH proton therapy.

Cyclotron-based proton therapy systems utilize the highest proton energies to achieve an ultra-high dose rate (UHDR) for FLASH radiotherapy. The deep-penetrating range associated with this high energy can be modulated by inserting a uniform plate of proton-stopping material, known as a range shifter, in the beam path at the nozzle to bring the Bragg peak within the target while ensuring high proton transport efficiency for UHDR. Aluminum has been recently proposed as a range shifter material mainly due to its high compactness and its mechanical properties. A possible drawback lies in the fact that aluminum has a larger cross-sectionof producing secondary neutrons compared to conventional plastic range shifters. Accordingly, an increase in secondary neutron contamination was expected during the delivery of range-modulated FLASH proton therapy, potentially heightening neutron-induced carcinogenic risks to thepatient. We conducted neutron dosimetry using simulations and measurements to evaluate excess dose due to neutron exposure during UHDR proton irradiation with aluminum range shifters compared to plastic rangeshifters. Monte Carlo simulations in TOPAS were performed to investigate the secondary neutron production characteristics with aluminum range shifter during 225MeV single-spot proton irradiation. The computational results were validated against measurements with a pair of ionization chambers in an out-of-field region ( 30cm) and with a Proton Recoil Scintillator-Los Alamos rem meter in a far-out-of-field region (0.5-2.5m). The assessments were repeated with solid water slabs as a surrogate for the conventional range shifter material to evaluate the impact of aluminum on neutron yield. The results were compared with the International Electrotechnical Commission (IEC) standards to evaluate the clinical acceptance of the secondary neutronyield. For a range modulation up to 26cm in water, the maximum simulated and measured values of out-of-field secondary neutron dose equivalent per therapeutic dose with aluminum range shifter were found to be and , respectively, overall higher than the solid water cases (simulation: ; measurement: ). The maximum far out-of-field secondary neutron dose equivalent was found to be ( ) and ( ) for the simulations and rem meter measurements, respectively, also higher than the solid water counterparts (simulation: ( ) ; measurement: ( ) ). We conducted simulations and measurements of secondary neutron production under proton irradiation at FLASH energy with range shifters. We found that the secondary neutron yield increased when using aluminum range shifters compared to conventional materials while remaining well below the non-primary radiation limit constrained by the IECregulations.

Study of head and neck squamous cell carcinoma transcriptome after proton therapy

Aim. To evaluate changes in the transcriptome of head and neck squamous cell carcinoma (HNSCC) tissue cells in patients after proton therapy.Materials and methods. Biopsy material obtained from 3 HNSCC patients before and after proton therapy at a total dose of 10 isoGy was homogenized, purified, and concentrated. Then total RNA was isolated with further purification and concentration with the RNA Clean & Concentrator kit (Zymo Research). Library quantitation was assessed using the Qubit 2.0 instrument (Invitrogen, Life Technologies). After isolation of 1 μg total RNA for sequencing, libraries were prepared on the Illumina platform using the TruSeq RNA Sample Prep Kit v2 with a 10-cycle enrichment step according to the manufacturer’s recommendations. The quality of RNA and the resulting libraries was checked using the Agilent 2100 Bioanalyzer system (Agilent Tec. Inc., USA). The RIN parameter for RNA was at least 7. The library concentration was assessed by real-time PCR on the CFX96 Touch Real-Time PCR Detection System (Bio-Rad, USA). Final libraries were pooled in equimolar ratios before sequencing on the Illumina HiSeq 2500 platform using 50 base-pair paired-end reads. The Q20 parameter for all samples was > 97%, and the number of reads averaged 60.2 million per sample. Raw reads were processed using the RTA 1.17.21.3 and Casava 1.8.2 (Illumina). The enrichment analysis was performed using the PANTHER 17.0 software.Results. The transcriptome analysis of HNSCC after proton radiation therapy (5 x 2 isoGy) at a total dose of 10 isoGy revealed 1,414 significantly differentially expressed genes. The 10 most and least expressed genes and their associated signaling pathways were identified. A number of signaling pathways associated with the underexpressed genes were detected in HNSCC after proton therapy, such as: STAT5; PD-1 signaling pathway; marked MET-mediated activation of PTK2 signaling pathway, PDGF signaling; CD22-mediated regulation of BCR; and FCERI-mediated MAPK activation. In addition to the above signaling pathways, activation of collagen degradation, FCGR3A-mediated phagocytosis, and FCGR3A-mediated interleukin (IL)-10 synthesis are of interest. In the enrichment analysis among highly expressed genes, keratinization and biological oxidation processes were activated in HNSCC tissues after proton therapy.Conclusion. Proton therapy in HNSCC leads to overexpression of genes involved in the regulation of keratinization and biological oxidation processes as well as to underexpression of genes associated with suppression of signaling pathways: STAT5, PD-1, MET-mediated activation of PTK2 signaling pathway, PDGF signaling; CD22-mediated regulation of BCR; FCERI-mediated MAPK activation, collagen degradation, FCGR3A-mediated phagocytosis activation, and FCGR3A-mediated IL-10 synthesis. All signaling pathways of underexpressed genes function in HNSCC cells if there is no negative influence on the tumor from outside (irradiation or delivery of antitumor drugs). The predominance of suppressed signaling pathways over activated ones most likely indicates a decrease in the functional potential of cells after proton therapy. The dose-dependence of PT effects necessitates further study of changes in cellular and molecular-genetic signatures of HNSCC after proton irradiation with different doses.

Predicting the risk of neurocognitive decline after brain irradiation in adult patients with a primary brain tumor.

Deterioration of neurocognitive function in adult patients with a primary brain tumor is the most concerning side effect of radiotherapy. This study aimed to develop and evaluate normal-tissue complication probability (NTCP) models using clinical and dose-volume measures for 6-month, 1-year, and 2-year Neurocognitive Decline (ND) postradiotherapy. A total of 219 patients with a primary brain tumor treated with radical photon and/or proton radiotherapy (RT) between 2019 and 2022 were included. Controlled oral word association test, Hopkins verbal learning test-revised, and trail making test were used to objectively measure ND. A comprehensive set of potential clinical and dose-volume measures on several brain structures were considered for statistical modeling. Clinical, dose-volume and combined models were constructed and internally tested in terms of discrimination (area under the curve, AUC), calibration (mean absolute error, MAE), and net benefit. Fifty percent, 44.5%, and 42.7% of the patients developed ND at 6-month, 1-year, and 2-year time points, respectively. The following predictors were included in the combined model for 6-month ND: age at radiotherapy > 56 years (OR = 5.71), overweight (OR = 0.49), obesity (OR = 0.35), chemotherapy (OR = 2.23), brain V20 Gy ≥ 20% (OR = 3.53), brainstem volume ≥ 26 cc (OR = 0.39), and hypothalamus volume ≥ 0.5 cc (OR = 0.4). Decision curve analysis showed that the combined models had the highest net benefits at 6-month (AUC = 0.79, MAE = 0.021), 1-year (AUC = 0.72, MAE = 0.027), and 2-year (AUC = 0.69, MAE = 0.038) time points. The proposed NTCP models use easy-to-obtain predictors to identify patients at high risk of ND after brain RT. These models can potentially provide a base for RT-related decisions and post-therapy neurocognitive rehabilitation interventions.

Proton FLASH Radiotherapy Ameliorates Radiation-induced Salivary Gland Dysfunction and Oral Mucositis and Increases Survival in a Mouse Model of Head and Neck Cancer.

Head and neck cancer radiotherapy often damages salivary glands and oral mucosa, severely negatively impacting patients' quality of life. The ability of FLASH proton radiotherapy (F-PRT) to decrease normal tissue toxicity while maintaining tumor control compared with standard proton radiotherapy (S-PRT) has been previously demonstrated for several tissues. However, its potential in ameliorating radiation-induced salivary gland dysfunction and oral mucositis and controlling orthotopic head and neck tumor growth has not been reported. The head and neck area of C57BL/6 mice was irradiated with a single dose of radiotherapy (ranging from 14-18 Gy) or a fractionated dose of 8 Gy × 3 of F-PRT (128 Gy/second) or S-PRT (0.95 Gy/second). Following irradiation, the mice were studied for radiation-induced xerostomia by measuring their salivary flow. Oral mucositis was analyzed by histopathologic examination. To determine the ability of F-PRT to control orthotopic head and neck tumors, tongue tumors were generated in the mice and then irradiated with either F-PRT or S-PRT. Mice treated with either a single dose or fractionated dose of F-PRT showed significantly improved survival than those irradiated with S-PRT. F-PRT-treated mice showed improvement in their salivary flow. S-PRT-irradiated mice demonstrated increased fibrosis in their tongue epithelium. F-PRT significantly increased the overall survival of the mice with orthotopic tumors compared with the S-PRT-treated mice. The demonstration that F-PRT decreases radiation-induced normal tissue toxicity without compromising tumor control, suggests that this modality could be useful for the clinical management of patients with head and neck cancer.

Evaluation of specific RBE in different cells of hippocampus under high-dose proton irradiation in rats.

The study aimed to determine the specific relative biological effectiveness (RBE) of various cells in the hippocampus following proton irradiation. Sixty Sprague-Dawley rats were randomly allocated to 5 groups receiving 20 or 30Gy of proton or photon irradiation. Pathomorphological neuronal damage in the hippocampus was assessed using Hematoxylin-eosin (HE) staining. The expression level of NeuN, Nestin, Caspase-3, Olig2, CD68 and CD45 were determined by immunohistochemistry (IHC). The RBE range established by comparing the effects of proton and photon irradiation at equivalent biological outcomes. Proton20Gy induced more severe damage to neurons than photon20Gy, but showed no difference compared to photon30Gy. The RBE of neuron was determined to be 1.65. Similarly, both proton20Gy and proton30Gy resulted in more inhibition of oligodendrocytes and activation of microglia in the hippocampal regions than photon20Gy and photon30Gy. However, the expression of Olig2 was higher and CD68 was lower in the proton20Gy group than in the photon30Gy group. The RBE of oligodendrocyte and microglia was estimated to be between 1.1 to 1.65. For neural stem cells (NSCs) and immune cells, there were no significant difference in the expression of Nestin and CD45 between proton and photon irradiation (both 20 and 30Gy). Therefore, the RBE for NSCs and immune cell was determined to be 1.1. These findings highlight the varying RBE values of different cells in the hippocampus in vivo. Moreover, the actual RBE of the hippocampus may be higher than 1.1, suggesting that using as RBE value of 1.1 in clinical practice may underestimate the toxicities induced by proton radiation.

Comprehensive radiotherapy for pediatric Ewing Sarcoma: Outcomes of a prospective proton study

Background and purposePatients with Ewing Sarcoma (EWS) are treated with multimodality therapy which includes radiation therapy (RT) as an option for local control. We report on the efficacy after proton radiation therapy (PRT) to the primary site for localized and metastatic EWS. Materials and methodsForty-two children with EWS (33 localized, 9 metastatic) treated between 2007 and 2020 were enrolled on 2 prospective registry protocols for pediatric patients undergoing PRT. PRT was delivered by passive scatter (74 %), pencil-beam scanning (12 %) or mixed technique (14 %). Treated sites included the spine (45 %), pelvis/sacrum (26 %), skull/cranium (14 %), extraosseous (10 %), and chest wall (5 %). Median radiation dose was 54 Gy-RBE (range 39.6–55.8 Gy-RBE). Patients with metastatic disease received consolidative RT to metastatic sites (4 at the time of PRT to the primary site, 5 after completion of chemotherapy). Median follow-up time was 47 months after PRT. ResultsThe 4-year local control (LC), progression-free survival (PFS), and overall survival (OS) rates were 83 %, 71 %, and 86 %, respectively. All local failures (n = 6) were in-field failures. Tumor size ≥ 8 cm predicted for inferior 4-year LC (69 % vs 95 %, p = 0.04). 4-year PFS and OS rates were not statistically different in patients with localized versus metastatic disease (72 % vs 67 %, p = 0.70; 89 % vs 78 %, p = 0.38, respectively). ConclusionIn conclusion, LC for pediatric patients with EWS treated with PRT was comparable to that of historical patients who received photon-RT. Tumor size ≥ 8 cm predicted increased risk of local failure. Patients with metastatic disease, including non-pulmonary only metastases, received radiation therapy to all metastatic sites and had favorable survival outcomes.

Research on proton displacement damage effects in charge-domain accumulation type TDI CMOS image sensors

TDI CMOS image sensors are the most widely used photodetectors in space earth observation and multispectral imaging. The displacement damage caused by high-energy proton irradiation in the space environment leads to the continuous degradation of TDI CMOS image sensor parameters, seriously affecting its performance, reliability, and service life. This paper focuses on a space-based TDI CMOS image sensor chip and carries out 3 MeV proton irradiation tests and post-irradiation annealing tests to obtain the change rules of optical and electrical parameters. The degradation mechanism of sensitive parameters of TDI CMOS image sensors caused by proton irradiation is analyzed, and the sensitive region of proton displacement damage are discussed. The study demonstrates that after proton irradiation, the parameters especially full well capacity and temporal dark noise of the device degrade less, with small sensitivity to proton irradiation. However, the dark current, CTE, and pixel column FPN significantly degrade, and the degree of degradation is linearly related to the proton irradiation dose. In addition, the test also obtained the short-term and long-term annealing changes of sensitive parameters after proton irradiation of TDI CMOS image sensors, providing scientific advice for TDI CMOS image sensors space proton radiation effect tests and evaluations. The research results of this paper provide important references for the evaluation of radiation effects, on-orbit performance estimation, and radiation resistance reinforcement of space-based TDI CMOS image sensors.

РАДИАЦИОННО-ЗАЩИТНЫЙ КОМПОЗИЦИОННЫЙ МАТЕРИАЛ НА ОСНОВЕ ОТХОДОВ РУДНЫХ МИНЕРАЛОВ И КАМНЕПЕРЕРАБОТКИ

Abstract. The relevance of the research topic lies in the fact that currently there is a steady tendency to increase the amount of electromagnetic radiation (EMR) occurring in the human environment, which negatively affects the healthy indoor environment and determines the focus of experimental research on protecting humans from factors hazardous to health. This article is devoted to the possibility of creating radioprotective building materials from man-made waste from various deposits of Armenia. Research is aimed at creating a comfortable living area inside buildings through the development of radioprotective sandwich-type materials that reduce the impact of EMR on human health. Work was carried out in the direction of developing samples of radio-absorbing structures and selecting radio-absorbing fillers. The laboratory obtained samples from stone processing waste and waste from the extraction of ore minerals with a density from -1500 to 2000 kg/m3, as well as samples based on expanded perlite and a mineral binder with a density of 250-300 kg/m3 as an internal heat-insulating layer and transferred to the National Scientific Laboratory named after A.I.Alikhanyan (Yerevan Institute of Physics) for proton irradiation. In this work, the samples were subjected to proton irradiation, since it is a component of cosmic radiation, as well as EMR and is capable of penetrating through layers of matter depending on its composition and properties. Some physical and mechanical properties of the resulting materials, such as compressive strength and water absorption, were also studied. In addition, the article contains a review of foreign experience in obtaining radioprotective materials with various types of radiation. At this stage, only proton irradiation has been studied, but work in this direction continues. 
 Subject of study: development of radioprotective materials of the “sandwich” type.
 Materials and methods: waste of aluminosilicate rocks (tuffs) and waste from the extraction of ore minerals were used. The method of proton irradiation of the obtained materials was used.
 Results: radioprotective materials have been developed that reduce EMR.
 Conclusions: The possibility of obtaining radioprotective materials by introducing ore mineral mining waste into the composition of the composite material has been confirmed.

Radiation hardness of ultrabroadband spintronic terahertz emitters: En-route to a space-qualified terahertz time-domain gas spectrometer

The radiation hardness of ultrabroadband spintronic terahertz emitters against γ and proton irradiation is investigated. We find that irradiation doses equivalent to those experienced by a space instrument en-route to and operated on Mars have a minor effect on the performance of the emitters. In particular, the ultrawide emission spectrum ranging from 0.1–30 THz, which covers a large part of the vibrational fingerprint region, remains unchanged. These results make this emitter type highly interesting as an essential building block for broadband gas sensors based on terahertz time-domain spectroscopy for future space missions.

Effect of proton irradiation on the sensitivity of CO2 sensors based on SnO2 and SnO–SnO2 heterojunctions

Gas sensors are integral to space exploration and development projects. However, few studies have examined the effects of proton irradiation on the performance of semiconductor gas sensors. This study fills this gap by investigating the effect of proton irradiation on the sensitivity of CO2 semiconducting sensors, specifically SnO2 and SnO–SnO2 heterojunction types. In SnO2-based sensors, sensitivity was indicated to remain stable at low fluence and increase at higher fluences owing to proton-induced oxygen vacancy formations, mainly. Meanwhile, in SnO–SnO2 heterojunction sensors, it was found to decrease at low fluences and increase significantly at higher fluences owing to changes in the electrical properties of SnO. These findings suggest that proton irradiation can enhance sensor sensitivity, enabling potential applications in radiation-prone environments, such as outer space. This study contributes to the understanding of the effects of proton irradiation on semiconductor gas sensors and paves the way for their development.

ACR-ARS Practice Parameter for the Performance of Proton Beam Therapy

PurposeThis practice parameter for the performance of proton beam radiation therapy was revised collaboratively by the American College of Radiology (ACR) and the American Radium Society (ARS). This practice parameter was developed to serve as a tool in the appropriate application of proton therapy in the care of cancer patients or other patients with conditions in which radiation therapy is indicated. It addresses clinical implementation of proton radiation therapy, including personnel qualifications, quality assurance (QA) standards, indications, and suggested documentation. Materials and MethodsThis practice parameter for the performance of proton beam radiation therapy was developed according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters – Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ARS. ResultsThe qualifications and responsibilities of personnel, such as the proton center Chief Medical Officer or Medical Director, Radiation Oncologist, Radiation Physicist, Dosimetrist and Therapist, are outlined, including the necessity for continuing medical education. Proton therapy standard clinical indications and methodologies of treatment management are outlined by disease site and treatment group (e.g. pediatrics) including documentation and the process of proton therapy workflow and equipment specifications. Additionally, this proton therapy practice parameter updates policies and procedures related to a quality assurance and performance improvement program (QAPI), patient education, infection control, and safety. ConclusionAs proton therapy becomes more accessible to cancer patients, policies and procedures as outlined in this practice parameter will help ensure quality and safety programs are effectively implemented to optimize clinical care.

Modeling Field Line Curvature Scattering Loss of 1–10 MeV Protons During Geomagnetic Storms

AbstractThe proton radiation belt contains high fluxes of adiabatically trapped protons varying in energy from ∼one to hundreds of megaelectron volts (MeV). At large radial distances, magnetospheric field lines become stretched on the nightside of Earth and exhibit a small radius of curvature RC near the equator. This leads protons to undergo field line curvature (FLC) scattering, whereby changes to the first adiabatic invariant accumulate as field strength becomes nonuniform across a gyroorbit. The outer boundary of the proton belt at a given energy corresponds to the range of magnetic L shell over which this transition to nonadiabatic motion takes place, and is sensitive to the occurrence of geomagnetic storms. In this work, we first find expressions for nightside equatorial RC and field strength Be as functions of Dst and L* to fit the TS04 field model. We then apply the Tu et al. (2014, https://doi.org/10.1002/2014ja019864) condition for nonadiabatic onset to solve the outer boundary L*, and refine our expression for RC to achieve agreement with Van Allen Probes observations of 1–50 MeV proton flux over the 2014–2018 era. Finally, we implement this nonadiabatic onset condition into the British Antarctic Survey proton belt model (BAS‐PRO) to solve the temporal evolution of proton fluxes at L ≤ 4. Compared with observations, BAS‐PRO reproduces storm losses due to FLC scattering, but there is a discrepancy in mid‐2017 that suggests a ∼5 MeV proton source not accounted for. Our work sheds light on outer zone proton belt variability at 1–10 MeV and demonstrates a useful tool for real‐time forecasting.

Feasibility study of CSNS as an ATLAS ITk sensor QA irradiation site

The current ATLAS Inner Detector will undergo a complete upgrade in order to meet the requirements of the High Luminosity Large Hadron Collider (HL-LHC). The new Inner Tracker (ITk) will be made completely of silicon sensors fabricated by Hamamatsu Photonics K.K. (HPK). Quality Assurance (QA) is focused on providing confidence that quality requirements will be fulfilled in production such as irradiation tolerance and testing specification for the mini sensors. The Associated Proton beam Experiment Platform (APEP) beam line at the China Spallation Neutron Source (CSNS) was commissioned in 2022. This study focused on verifying the feasibility of CSNS as an ITk sensor QA irradiation site. A low-temperature Peltier cold box has been developed to keep the irradiation sensor samples at −15 °C. Several fluence points have been studied from 5.1×1014 neq/cm2 to 1.6×1015 neq/cm2, measured with the activation of the aluminium foils. The post-irradiation measurements (IV, CV, and CCE) are done under cold temperatures (−8 °C for IV and CV, −20 °C for CCE), after annealing for 80 min at 60 °C. Test results show CSNS could be a suitable proton irradiation site for the ATLAS ITk sensor project, after formal site qualification.

Synergistic effect of proton irradiation and electrical stress on high-speed 850 nm vertical-cavity surface-emitting lasers

The synergistic effect significantly impact VCSEL's reliability for potential applications in spatial data communication. The synergistic effect of 3 MeV proton irradiation and electrical stress on 850 nm high-speed VCSELs is investigated. The degradation of VCSEL slow down under the influence of bias current. However, device degradation is more pronounced during irradiation under high bias current density. Low frequency noise (LFN) analysis results indicate that defects induced by proton irradiation are the primary cause of the optical-electrical parameter degradation in the device. The bias current density significantly influences the final defect yield, leading to variations in the degree of degradation after irradiation at different bias currents. At a bias current density of 6.03 × 105 A/m2, the degradation of the modulation bandwidth is reduced in comparison to the unbiased state. A mechanism investigation into the synergistic effect of proton irradiation and electrical stress on VCSELs lends support for accurately evaluating the radiation hardness of optical communication system composed of VCSELs in harsh radiation environments.

Concurrent Atezolizumab Plus Bevacizumab and High-Dose External Beam Radiotherapy for Highly Advanced Hepatocellular Carcinoma.

Atezolizumab plus bevacizumab (atezo-bev) has been recommended for advanced hepatocellular carcinoma (HCC). High-dose external beam radiotherapy (RT) is recognized for its excellent local tumor control. The efficacy and safety of concurrent atezo-bev with RT for highly advanced HCC has been minimally explored. In this preliminary retrospective study, we assessed patients with highly advanced HCC, characterized by Vp4 portal vein thrombosis or tumors exceeding 50% of liver volume, who received concurrent atezo-bev and RT (group A). Group A included 13 patients who received proton radiation at a dose of 72.6 GyE in 22 fractions, and one patient who received photon radiation at a dose of 54 Gy in 18 fractions. This group was compared with 34 similar patients treated atezo-bev alone as a control (group B). The primary objectives were to evaluate the objective response rate (ORR), overall survival (OS), and safety. Baseline characteristics were similar between groups, except for a higher incidence of Vp4 portal vein thrombosis in group A (78.6% vs. 21.4%, P = .05). Group A achieved a higher ORR (50.0% vs. 11.8%, P < .01) and a longer OS (not reached vs. 5.5 months, P = .01) after a median follow-up of 5.2 months. Multivariate analysis indicated that concurrent RT independently favored longer OS (hazard ratio: 0.18; 95% CI, 0.05-0.63, P < .01). Group A did not increase any grade adverse events (78.6% vs. 58.8%, P = .19) or severe adverse events of grade ≥ 3 (14.3% vs. 14.7%, P = .97) compared to group B. The concurrent high-dose external beam radiotherapy appears to safely enhance the effectiveness of atezolizumab plus bevacizumab for highly advanced patients with HCC. Further studies are warranted to confirm these findings.

Void Formation and Radiation‐Induced Ion Migration in Perovskite Solar Cells under 10 MeV Proton Radiation

Perovskite solar cell (PSC) technology is a promising candidate for space applications because of its high power‐to‐weight ratio, low‐cost fabrication process, and good tolerance to high‐energy particle radiation. In this work, perovskite films and resultant high‐efficiency PSCs are assessed under 10 MeV proton radiation at fluences in the range 1e12–1e14 p cm−2, which are equivalent to 1 to 100 years in geostationary orbit (GEO) without any shielding or cover. For the first time, void formation and material ablation are detected on perovskite films, indicating structural damage of the materials under the proton radiation. Furthermore, ions inside the devices especially Au and Pb ions are displaced to underlying layers under the proton bombardment. These lead to the degradation of PSCs to ≈89% of the initial performance (from 24.1% to 21.4%) at the highest dose. The experimental results are supported by previous simulation works with a good fit in all optoelectronic parameters. This study provides insights into the degradation mechanism of PSCs under proton radiation and paves the way for the utilization of PSCs in space applications.

Design, optimization, and testing of ridge filters for proton FLASH radiotherapy at TRIUMF: The HEDGEHOG

TRIUMF has recently developed and implemented a workflow to design and fabricate application-specific ridge filters, which is a key upgrade to enable research using ultra-high (FLASH) dose rate beam delivery at its Proton Therapy Research Centre. These static ridge filters, called HEDGEHOGs, replace the rotating modulator wheels used to create a spread-out Bragg peak (SOBP) during conventional proton radiotherapy beam delivery, which are incompatible with the fast irradiation times of clinical doses at FLASH dose rates at TRIUMF. Initial beam commissioning of HEDGEHOGs demonstrated that they produce spread-out Bragg peaks matching their design parameters. Additional studies of some of the design parameters, including SOBP widths as well as different pin diameters and fabrication options (material, 3D printer technology) have now been completed. Based on those studies, the use of liquid medium printers (resin, jet) instead of filament printers is recommended. These studies also demonstrate that the lateral dose uniformity of the beam at 36.5 cm from the HEDGEHOG location is acceptable even with relatively large 7 mm base-diameter pins. The code base and workflow are made publicly available and can easily be adapted to other facilities. The feasibility of adapting the HEDGEHOG workflow to other beam lines or facilities was validated on a second proton beam line at the same facility at which the HEDGEHOG workflow was developed.

Abstract 2881: Comparing the effects of proton and photon therapy on promoting cancer aggressiveness in ovarian cancer and glioblastoma

Abstract Ovarian cancer is the 12th most common cancer among women in the United States and the 5th leading cause of cancer-related death for women. About 80% of the patients are diagnosed at stages III or IV, classified as High-Grade Serous Ovarian Cancer (HGSOC). HGSOC is highly aggressive, exhibiting an 80% recurrence rate within 24 months after cancer treatment. Brain and nervous system cancer ranks as the 10th leading cause of cancer-related death in the U.S., with Glioblastoma Multiforme (GBM) accounting for 47.7% of all brain cancer cases. GBM is the most aggressive primary brain cancer, with a 90% recurrence rate and a 4% 2-year survival rate. Patients with these cancers encounter limited treatment options, and the recurrence of cancer exacerbates these challenges. Therefore, a deeper understanding of the factors contributing to cancer treatment-induced aggressiveness is greatly needed. In our study, we first examined the treatment efficacy of proton and photon radiation by conducting apoptosis assays. Our findings demonstrate that proton radiation is significantly more effective at eliminating both HGSOC and GBM cells compared to photon radiation. Subsequently, we assessed the level of cancer aggressiveness in the surviving cells after radiation exposure by measuring stemness and epithelial-mesenchymal transition (EMT) levels. While proton radiation proved to be more effective in eliminating a greater number of cancer cells, we hypothesize that both proton and photon irradiation promote cancer aggressiveness in the surviving cells of HGSOC and GBM. To assess the stemness and EMT level of cancer cells following radiation, we integrated a SORE6-GFP reporter to identify the cancer stem cell population expressing SOX2/OCT4 and a 3’ UTR-ZEB1-GFP reporter to detect the cell population with mesenchymal traits. Cells transduced with the reporters were treated with 0, 1, 2, 4, and 8 Gy of 250 MeV proton and 6 MeV photon beams, and at 72 hours post-radiation, GFP levels were measured via flow cytometry. Our data demonstrated a dose-dependent increase in stemness and EMT levels in live cells after both types of radiation. Furthermore, cancer cells exposed to radiation were harvested at 72 hours and 240 hours post-radiation for RT-qPCR analysis. Our preliminary data indicate an upregulation of stemness genes including POU5F1 and SOX2, as well as EMT transcription factor genes ZEB1, SNAI1, and TWIST1 in response to both types of radiation in most cell lines. These findings indicate that both proton and photon radiation therapies promote cancer aggressiveness in the surviving cancer cells. Citation Format: Yeonkyu Jung, Ann Morcos, Aaron Keniston, Ashley Antonissen, Sharon Asariah, Antonella Bertucci, Marcelo Vazquez, Juli Unternaehrer. Comparing the effects of proton and photon therapy on promoting cancer aggressiveness in ovarian cancer and glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2881.

Abstract 696: Proton radiation and Seco-Duocarmycin SA: A synergistic strategy unveiling new frontiers in glioblastoma multiforme therapy

Abstract Glioblastoma multiforme (GBM) is one of the most aggressive brain cancers with a 6.9% five-year survival rate. More effective therapies are needed as standard treatments, which include surgery, radiation, and chemotherapy are inefficient due to radio-chemo-resistance and relapse. The goal of this project is to investigate the efficacy of seco-duocarmycin SA (sDSA) as an anticancer drug, alone and the potential synergy of combining proton radiation and sDSA in human GBM cell lines. Proton therapy offers numerous advantages in treating cancers because of its superior dose distribution and biological effects. sDSA is an exceptionally potent agent that selectively alkylates DNA at the N3 position of adenine, making it of great interest as a therapeutic drug. We hypothesize that by pairing sDSA with proton radiation, a more dynamic effect will result, which will amplify their collective power, unleashing an enhanced cytotoxicity against human GBM cells. GBM cell lines (T98G and LN18) were exposed to graded doses and concentrations of protons and sDSA respectively in order to evaluate cellular changes in proliferation, survival, cell cycle, apoptosis/necrosis induction, and DNA damage. Results show that proton radiation and sDSA when used alone induce a dose-dependent decrease of cell proliferation, an increase in foci formation, and an increase in G2/M phase arrest in LN18 and T98G cells. The data also illustrates that the combination of proton radiation and sDSA synergistically enhances these effects. The utilization of proton radiation in conjunction with sDSA against GBM represents an innovative and previously unexplored approach. Currently, the cellular mechanisms of sDSA cytotoxicity are not well understood or studied, and even less is known regarding the effects when combined with proton radiation. This study serves as a vital cornerstone in unraveling the biological response of GBM cells when confronted with proton radiation and sDSA, paving the way for the future development of a more precise and potent combination therapy. Citation Format: Ann Morcos, Antonella Bertucci, Ryan Nicholaus Fuller, Nathan Robert Wall, Marcelo Eduardo Vazquez. Proton radiation and Seco-Duocarmycin SA: A synergistic strategy unveiling new frontiers in glioblastoma multiforme therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 696.

Abstract 6036: Flash proton radiotherapy mitigates radiation-induced salivary gland dysfunction and oral mucositis in mice

Abstract Background- Recent studies have reported that ultra-high dose rate “FLASH” Proton radiation therapy (F-PRT) decreases normal tissue toxicity while maintaining tumor-controlling efficacy compared to Standard Proton RT (S-PRT), that are used for patient treatments. However, although highly efficacious in eliminating tumors, damage to the otherwise healthy salivary glands and oral mucosa is often unavoidable in patients with head and neck cancer, leaving patients with lifelong xerostomia and other comorbidities. Aim- In this study, we aimed to investigate the effect of F-PRT on radiation-induced oral mucositis and salivary gland dysfunction and in controlling orthotopic tumor growth. Methods- The head and neck area of C57Bl/6 mice was irradiated with a single dose of 16 Gy or a fractionated dose of 8 Gy x 3 of F-PRT (128Gy/s) or S-PRT (0.95 Gy/s). Oral mucositis was analyzed by histopathological examination. Radiation-induced xerostomia was studied by measuring the saliva flow rate of mice. To examine the ability of F-PRT to control orthotopic head and neck tumors, tongue tumors were generated in mice and then irradiated with F-PRT/S-PRT. Results- Following irradiation with a single dose or a fractionated dose, saliva flow was reduced by both treatments. However, the F-PRT-treated mice showed a significant improvement in salivary flow at 14 days (p&amp;lt;0.05) and 28 days (p&amp;lt;0.005) post irradiation. Expression of AQP5 was found to be significantly down-regulated at 2, 5, 10, and 14 days post irradiation with S-PRT. However, mice irradiated with F-PRT showed a significant restoration of the AQP5 expression post-RT. Oral mucositis started to appear on day 14, which showed more severity on day 28 post-irradiation with S-PRT. Histopathological analysis showed the presence of lingual gland atrophy only in the tongue of mice treated with S-PRT 28 and 60 days post-irradiation. F-PRT ameliorates radiation-induced jawbone loss compared to S-PRT as observed in mice irradiated either with a single dose or in a fractionated regime. The surviving fraction of F-PRT-treated mice with orthotopic tongue tumors was significantly ameliorated compared to S-PRT-treated mice. Conclusion- This study demonstrates that F-PRT minimizes radiation-induced normal tissue toxicity after irradiation in mice’s head and neck region. Moreover, the ability of F-PRT to control orthotopic head and neck tumors further determines the efficacy of this modality for clinical applications. Citation Format: Priyanka Chowdhury, Anastasia Velalopoulou, Ioannis Verginadis, George Morcos, Michele Kim, James Metz, Lei Dong, Alexander Lin, Constantinos Koumenis. Flash proton radiotherapy mitigates radiation-induced salivary gland dysfunction and oral mucositis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6036.