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• Linear energy transfer affect local control of lung cancer with carbon-ion radiotherapy. • LET d in iGTV in the local recurrence group was lower than the local control group. • LET d distribution within iGTV should be routinely assessed in CIRT for lung cancer. High linear energy transfer (LET) radiation exhibits stronger tumor-killing effect. However, the correlation between LET and the therapeutic efficacy in Carbon-ion radiotherapy (CIRT) for locally advanced non-small-cell lung cancer (LA-NSCLC) is currently not clear. This study aimed to investigate the relationship between the dose-averaged LET (LET d) distribution within tumor and local recurrence for LA-NSCLC treated with CIRT. An analysis of 62 consecutive patients with LA-NSCLC who underwent CIRT from 2018 to 2022 was conducted. The LET d distribution was calculated based on their treated plans, and the correlation between local recurrence and LET d , relative biological effectiveness (RBE)-weighted doses (D RBE) and clinical factors was investigated. Receiver operating characteristic (ROC) curve, log-rank test, and Cox regression analysis were performed based on that. 16 patients were defined as local recurrence. Overall survival (OS) and local control (LC) at 24 months were 76.9 % and 73.2 %, respectively. The mean LET d in internal gross tumor volume (iGTV) in the local recurrence group was 48.7 keV/µm, significantly lower than the mean LET d of 53.2 keV/µm in the local control group (p = 0.016). No significant difference was observed in D RBE between the local recurrence and local control groups. ROC curve analysis indicated that a percentage of 88 % of volume in iGTV receiving at least 40 keV/µm (V 40 k e V / μ m) is the optimal threshold for predicting local recurrence (Area under curve (AUC) = 0.7636). The log-rank test and Cox regression analysis revealed that the LET d value covering 98 % volume of iGTV ( LET d 98 %) was a significant risk factor for LC (p = 0.020). Our study revealed an association between LET d distribution and local recurrence in patients with LA-NSCLC. These findings suggest that lower LET d may increase the probability of local recurrence. We suggest that LET d distribution within iGTV should be routinely assessed in CIRT for lung cancer. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the performance of the BeO-based myOSLchip system (RadPro International GmbH, Remscheid, Germany) for dosimetry of proton and electron radiotherapy beams. Although beryllium oxide (BeO) has been recognised as a promising material for luminescence dosimetry in radiotherapy, this research extends beyond material properties and examines the entire BeO-based dosimetry system, including the detector, holder, and readout components. Packages of myOSLchip dosimeters were irradiated either in a (70 − 230) MeV proton beam or in a 16 MeV electron beam. The readouts were carried out using the portable myOSLchip reader. In the electron beam, tests on the precision, dose response up to 100 Gy and dose-rate effects of the system were carried out. In the proton beam, the system was tested for its dose response (up to 10 Gy), fading, and linear energy transfer (LET) response. For proton irradiations, the myOSLchip BeO OSLDs exhibited stability within 2% over 135 days, as well as a linear dose response in the tested range, (0. 1 − 10) Gy. The efficiency showed a reduction for proton beams with LET values (for water) above 0.6 keV/ μ m, with up to 40% loss in efficiency at 4 keV/ μ m. For the electron irradiations, they showed a linear dose–response up to 20 Gy and dose-rate independence, with a constant response at least up to 2.99 × 105 Gy s−1. Using individual dosimeter sensitivity correction, the precision for a single dosimeter was around 3.5% (standard deviation of the data of all dosimeters) and for a package comprising four dosimeters was 1.7% (standard deviation of the mean of the four dosimeters). These findings suggest the myOSLchip system's potential as a reliable alternative to existing dosimetry systems in clinical applications. • A single-detector BeO-based dosimetry system was investigated in proton and electron beams. • Performances tested include precision, dose response, dose-rate effects, fading and LET response. • A reduced efficiency was observed at LET values > 0.6 keV/ μ m. • The performances indicated the system's capability to be used for clinical applications. [ABSTRACT FROM AUTHOR]

Real-time radioluminescence two-dimensional coatings have potential as dosemeters in proton and carbon therapeutic beams. We investigated coatings made of nano and micro-(C 44 H 38 P 2)MnCl 4 and (C 38 H 36 P 2)MnBr 4 crystals mixed with a water-equivalent substrate. The response of the radioluminescence signal of the coatings along the Bragg curves presented an ionization quenching effect, but less prominent than what has been observed in our previous works using Al 2 O 3 :X (X = C and C,Mg) coatings. We hypothesize that this results from their lower crystal sizes and effective atomic number (Z eff). Combined experimental results and Monte Carlo simulations resulted in correction factors to address the linear energy transfer dependence and restore the constant response for particle therapy beams. The quenching correction method was applied to the studied proton and carbon ion beams and yielded the best results for the nano-(C 44 H 38 P 2)MnCl 4, coating, followed by the micro-(C 44 H 38 P 2)MnCl 4 , nano-(C 38 H 36 P 2)MnBr 4 , and micro-(C 38 H 36 P 2)MnBr 4. • Real-time RL coatings developed for proton and carbon ion dosimetry, using nano and micro crystals. • Quenching effects in RL coatings less prominent than Al 2 O 3 :C and Al 2 O 3 :C,Mg due to lower crystal sizes and Zeff. • Quenching correction best in nano-(C44H38P2)MnCl4 coating, followed by other tested coatings. [ABSTRACT FROM AUTHOR]

Extreme waves pose a significant threat to coastal structures. Focused wave, representing the average shape of extreme waves, is frequently employed to simulate extreme waves. Despite its convenience of generating large amplitude waves, the nonlinearity evolution of focused wave during propagation has been seldom explored. It is obvious that the nonlinearity would influence the wave shape and energy structure during focusing. This study investigates the temporal and spatial nonlinearity evolution experimentally and numerically. The experiment was conducted in a wave tank using a piston-type wavemaker. The numerical model was set up with geometry adopted from physical experiment in the commercial software FLUENT. The turbulence model RNG k–ε was employed, while the volume of fraction method was used to capture the air-water interface. The high-order harmonics were extracted from the recorded wave elevations by the four-phase decomposing method. The evolution of high-order harmonics and the energy structure were obtained. It is validated that the high-order harmonics can be reasonably estimated by multiplying linear harmonics by harmonic coefficients calculated by Stokes III or V wave theory. This paper enhances the understanding of temporal and spatial nonlinearity evolution of focused wave, which would be helpful for structure design and site selection. • The first four order harmonics are extracted based on four-phase decomposing method. • Nonlinearity increases with the energy transferring from linear harmonic to high order harmonics. • Quasi-quantitative features of energy structure and harmonic coefficients are obtained. • The profiles of focused wave group can be reconstructed satisfactorily with harmonic coefficients and linear harmonic. [ABSTRACT FROM AUTHOR]

Protons and carbon ions each confer dosimetric advantages over photons, yet of these modalities, only carbon ion radiotherapy (CIRT) delivers densely ionizing, high linear energy transfer (LET) radiation which results in more complex DNA damage and an increased relative biological effectiveness (RBE) compared to low LET photons. However, our classical understanding of RBE does not account for potential microenvironmental effects. We therefore performed a multi-institutional, multi-omics analysis to understand how CIRT shifts the contexture of the tumor immune microenvironment in pancreatic cancer. Murine pancreatic cancer cell lines derived from KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx1-CreERTM; Rosa26YFP/YFP (KPCY) mice which exhibit low T-cell infiltration (6419c5) vs. high T-cell infiltration (2838c3) were studied. These tumor cell lines were implanted subcutaneously into wild-type (WT) C57BL/6J or immunodeficient NSG mice and irradiated 7 days later. CIRT was performed at an LET d of ∼100 keV/μm in the mid-spread-out Bragg peak (SOBP) while low LET photon treatments were performed using orthovoltage X-rays or 137Cs γ-rays. Clonogenic assays were performed to determine the RBE, and proteomics was performed by mass spectrometry on cell culture supernatant 24 hours post-radiation. 6419c5 flank tumors were dissociated 7 days post-10 Gy of CIRT or X-rays and single cell RNA-sequencing (scRNA-seq) was performed on sorted live cells. Clonogenic assays in both cell lines revealed a CIRT RBE of 1.76 compared to photons. Despite these cell lines exhibiting similar clonogenic survival after CIRT in vitro, the response to CIRT in vivo was notably different between them in tumor growth experiments. There was a similar tumor growth delay with 10 Gy CIRT in both WT and NSG mice with 6419c5 tumors. However, 2838c3 responded to 10 Gy CIRT with a significantly longer tumor growth delay in WT vs. NSG mice (P < 0.05), suggesting that tumor infiltrating T lymphocytes contribute to tumor control after CIRT. Overlap analysis of common differentially expressed proteins related to CIRT from both cell lines identified a unique signature of CIRT with 25 upregulated and 5 downregulated proteins. scRNA-seq identified that CIRT upregulates genes and pathways associated with the response to type I interferons and with antigen presentation across populations including tumor cells, dendritic cells, and T/NK cells 7 days post-irradiation when compared to an equivalent physical dose of X-rays. CIRT not only exhibited an increased RBE, but it also generated a unique tumor immune microenvironment characterized by transcriptional evidence of a type I interferon response and enhanced antigen presentation when compared to low LET radiation. Tumor growth experiments further suggest that effective immune activation could contribute to the augmented in vivo RBE of CIRT. [ABSTRACT FROM AUTHOR]

To evaluate the feasibility and dosimetric superiority of spot-scanning proton arc therapy (SPArc) for ocular melanoma, in comparison to Intensity Modulated Proton Therapy Six ocular melanoma cases, varying in size (large/small) and anatomical locations (posterior/anterior/optic disc), were planned with 3-field IMPT (3F-IMPT) and SPArc for dosimetric comparison. With a target dose normalized to 50 cGE, 3.5% range uncertainty were used in both groups for robust optimization. Dose to organs-at risk (OARs) were analyzed. The mean dose averaged linear energy transfer (LET d) were calculated with dose threshold of voxels receiving no less than 20% of the maximum dose. SPArc demonstrated a consistently superior dose distribution compared to 3F-IMPT in all cases. Notably, SPArc achieved improved dose sparing of lens and cornea in tumor situated in the posterior segment and optic disc region, where the lens and cornea were in the beam path. Specifically, for the four cases involving tumors in the posterior segment or optic disc, the median maximum dose (Dmax) to the lens with IMPT and SPArc was 30.61 cGy and 10.62 cGy, respectively. SPArc achieved a 65.3% reduction in the lens's Dmax. A similar outcome was observed for the mean dose (Dmean) to the cornea, with SPArc achieving a 76.7% reduction in the Cornea Dmean. Additionally, SPArc presented an increased LET d within the target area while reducing the LET d in OARs abutting the target. Particularly, the median of mean LETd for tumors was 3.90 keV/µm with IMPT compared to 4.14 keV/µm with SPArc. For the lens, the median of mean LETd was significantly lower with SPArc at 0.60 keV/µm, compared to 1.92 keV/µm with IMPT. As an innovative proton therapy approach, SPArc without utilizing the compensator and blocks or MLCs has demonstrated dosimetric superiority and adaptability in treating ocular melanomas situated in the posterior segment and optic disc region, especially in scenarios where sparing of the lens and cornea is crucial. [ABSTRACT FROM AUTHOR]

To characterize the association of linear energy transfer and dose with radiation (RT) necrosis after pencil beam scanning proton therapy in pediatric posterior fossa tumors using a case-control framework. From December 2019 to October 2022, patients ≤ 18 years of age treated with first line proton therapy for primary tumors in the posterior fossa and with at least 6 months of follow up were retrospectively identified. Follow-up MRI scans were assessed for imaging changes concerning for RT necrosis defined as new T1 enhancement +/- T2/FLAIR change within the RT field not associated with tumor recurrence. These necrosis cases were matched with control cases in a 1:2 fashion based on age, sex, dose, and follow-up time from proton therapy. Dose (GyRBE) and dose-averaged LET (LETd) maps were computed in a treatment planning system using Monte Carlo simulation. Voxel-wise data for targets and normal structures were exported and analyzed using a programming environment and R. Comparisons between cases and controls were assessed using Fisher's exact test and Wilcoxon rank sum test for categorical and continuous variables, respectively. A total of 33 patients met criteria for inclusion in the final analysis (24 controls, 9 cases). Mean age was 6.6 years (STD = 4.77) with a median follow up time of 24.1 months. Most common tumors were medulloblastoma (54.5%) and ependymoma (33.3%). Median dose was 54 GyRBE [range 50.4-59.4 GyRBE]. Within the case-control matched cohort (18 controls, 9 cases), there were no significant differences in age, sex, time to follow up, tumor location, dose, and use of concurrent chemotherapy. Mean time to necrotic imaging finding was 4.47 months (STD = 2.03). Three patients were symptomatic with ataxia and/or dysmetria, two of whom had multifocal necrosis and one required steroids and bevacizumab. Cases demonstrated significantly higher brainstem D50 (p = 0.02) and D40 (p = 0.02). Volumetric LETd parameters were not different between cases and controls. However, when using a combined metric of higher brainstem dose (> 47.5GyRBE) and higher LETd (>3.8 keV/µm), a greater proportion of cases compared to controls met this metric (88.9% vs. 42.1%, p = 0.04). Combined effects of higher dose and higher LETd may contribute to greater necrosis risk after pencil beam scanning proton therapy in children with posterior fossa tumors. [ABSTRACT FROM AUTHOR]

Proton radiotherapy (PRT) enables the delivery of dose to a target without significant exit dose, offering a key physical distribution difference in comparison with X-ray radiotherapy (XRT). PRT additionally delivers increased linear energy transfer (LET) at the distal edge of the beam path, a property providing enhanced radiobiologic effect. The etiology of these radiobiological differences remain unclear; here, phosphoproteomic analysis is employed to evaluate differences between low and high LET PRT in vitro. hTERT-RPE1 cells were treated with 8 Gy photon-equivalent doses of entrance or Bragg Peak PRT, representing low-LET and high-LET radiobiological treatments, respectively. This was accomplished using a 76.8 MeV spot scanning proton beam, a mini pyramid filter, and 25 mm range shifter in the nozzle, with four cell culture 6-well plates fitted in a phantom such that wells were exposed to either low LET (2.2 keV/μm) or high LET (7.0 keV/μm) portions of the proton beam. Cells were harvested at 1h, 4h, 8h and 24h timepoints. Phosphoproteomic analysis was performed through isolation of (phospho)peptides and 18-plex tandem mass tag labeling through an optimized institutional platform. These sample sets were computationally analyzed for changes in phosphopeptide signaling. A total of 13782 phosphosites were detected across all samples. Analysis of phosphopeptide changes across timepoints revealed a core set of shared peptide changes seen after both entrance and Bragg Peak proton radiation. However, it also revealed distinct groups of peptides for entrance vs Bragg Peak protons. For high-LET Bragg Peak protons, AKT1 and PLK1 substrates were upregulated at one hour, whereas CSNK2A1 and CSNK2A2 substrates were upregulated in low-LET protons. At 4h, high-LET protons exhibit upregulation of PRKDC substrates vs. low-LET proton upregulation of CSNK2A1 and AURKB substrates; at both 4h and 8h, high-LET proton demonstrates upregulated CDK4 and CDC7 substrates with low-LET protons showing upregulated BUB1B and PLK1 substrates. At all timepoints, high-LET proton demonstrated decline in BUB1B and BUB1 substrates, while low-LET proton demonstrated decreased ABL1 and MAPK8. Low- and high-LET proton radiotherapy induce distinct phosphopeptide changes. High-LET protons appear to promote stronger activity of key S-phase kinases CDK4 and CDC7 while low-LET protons more strongly activate mitotic-type checkpoints involving BUB1B and PLK1. Correlation with transcriptomics is ongoing. [ABSTRACT FROM AUTHOR]

Radiation-induced skin toxicity (RIST), in the forms of radiation dermatitis (RD) and/or skin hyperpigmentation (SH) is an important endpoint affecting quality of life. In this study, proton radiobiological effectiveness (1.1RBE) and linear energy transfer (LET)–dependent RBE (LET-RBE) doses were calculated and corelated as predictors for RD. The dose thresholds were compared between proton and photon treatments. Patients treated with intensity-modulated proton therapy (IMPT) and photon therapy (3DCRT and VMAT) at an academic proton center in 2022 and 2023 were retrospectively analyzed in this IRB approved study. For the IMPT group, we investigated 11 lumpectomy and 19 mastectomy Caucasian patients and 16 African-American lumpectomy patients without chemotherapy. All the patients were prescribed to a dose of 50.4 Gy (RBE = 1.1) in 28 fractions, to the targets (cropped by 3 mm or 5 mm from the skin surface), followed by a 9 -16.2 Gy boost to surgical scars. For the photon therapy group, 11 Caucasian and 8 African-American lumpectomy patients prescribed either 266 ×16 cGy or 200 × 25 cGy and boost by 200 × 5 cGy were studied. Toxicity scores were recorded weekly during the course of treatment. For each patient, the skin was contoured with 3 mm inside from the patient surface, within 50% isodose line, for 1.1RBE and LET-RBE proton dose and photon physical dose analysis. For IMPT plans, the LETd was calculated using a Monte-Carlo dose engine and then 3 RBE models were employed to convert the LET to RBE dose. The averaged RBE dose from the 3 models were used for our analysis. Skin D 10% (Gy) was calculated as dosimetric parameter for RD prediction. Surprisingly, no correlation between RD and the full course skin D 10% were found, however, there was strong correlation found between RD and accumulated skin D 10% on the day when the RD was reported. For the proton group, RD scores were positively correlated with both the accumulated 1.1RBE D 10% (the correlation coefficient r = 0.727, 0.617and 0.885 for Caucasian lumpectomy, Caucasian mastectomy and African-American lumpectomy patients respectively) and LET-RBE D 10% (r = 0.762, 0.575, 0.889 for Caucasian lumpectomy, Caucasian mastectomy and African-American lumpectomy patients respectively). For the photon group, RD scores were positively correlated with physical D 10% dose with r = 0.96 and 0.86 for African-American and Caucasian patients respectively. Furthermore, the mean of the accumulated proton 1.1RBE D 10% was 41 Gy, much less than the threshold 50.25 Gy from photon therapy, but was 48 Gy when the LET effect was considered (LET-RBE D 10%). Breast skin dose toxicity shows strong evidence of LET-RBE effect for breast cancer patients undergoing proton beam therapy, compared to photon beam therapy. [ABSTRACT FROM AUTHOR]

Fast Neutron Radiotherapy (NRT) is a high linear energy transfer modality that can overcome tumor radioresistance to conventional radiotherapy (RT). This may be particularly beneficial in the palliative recurrent/metastatic setting. An ideal dose-fractionation in this setting is unknown. This study evaluates clinical and early toxicity outcomes of short course (2-4 fraction) palliative hypofractionated NRT (hNRT). Clinical characteristics, oncologic treatment history, clinical (tumor shrinkage and/or symptom response) and radiographic responses were reviewed in a single-institution, IRB-approved retrospective review of patients who received at least one palliative treatment course with 3D conformal hNRT from 11/2016 to 12/2022. Twenty-seven patients with Stage IV cancer received hNRT at median age of 79yr (range = 47–100) with median follow-up of 5.4mo (range = 0.1-75.6). Histology included squamous (n = 7), urothelial (n = 6), Merkel (n = 5), adenocarcinoma (n = 3), renal cell (n = 2), and other (n = 4). Median hNRT dose was 6 Gy in 3 fractions (range = 3.45-10 Gy, 2-4 fractions), equivalent to around 18-30 Gy of x-rays. There were 48 hNRT treatment courses across 32 unique anatomic sites, which included head-and-neck (HN) (n = 14), bone (n = 5), genitourinary (n = 4), non-HN lymph nodes (n = 7), and non-HN skin (n = 2). Twenty-three unique treatment sites (across 19 patients) received a single hNRT course, whereas nine sites (across 9 patients) received 2-4 successive courses (median 37d between courses). 16 patients (60%) were on concurrent systemic therapy and 8 sites (25%) were previously irradiated with photon RT. Median overall survival time from the end of the first hNRT course was 400d (95% CI = 221-not reached). Of treatment sites receiving one hNRT course, 18 (78%) of 23 had clinical response, and 11 of 13 (85%) sites with radiographic follow-up had radiographic response. Of sites receiving 2 or more successive courses, 9 (100%) of 9 had clinical response and 6 of 8 (75%) sites with radiographic follow-up had radiographic response. Of 8 sites previously irradiated with photon RT, 6 (75%) had a clinical response of which 4 (50%) had a concurrent radiographic response. Of 20 sites receiving hNRT for pain relief/bleeding, 3 (15%) had symptom stability and 17 (85%) had partial-to-full clinical response, 11 of which had symptom progression at a median of 145d post-response. Of 12 sites receiving hNRT to slow disease progression and/or stimulate an immune response (n = 11 on concurrent immunotherapy or ADT), 10 (83%) had partial-to-full clinical response with radiographically stable-to-improved disease and 1 had radiographic progression. Overall, RTOG Grade 2 (n = 1) or 3 (n = 2) side effects were uncommon. No patients experienced pain flares. Most patients treated with hNRT had symptom relief and radiographic response. None had pain flares and high-grade side effects were rare. Single or repeat-course hNRT may be a safe and effective method of palliation. [ABSTRACT FROM AUTHOR]

Proton arc therapy (PAT) using spot-scanning shows promise in clinical benefits, but faces challenges in treatment robustness and efficiency as well as control the optimization complexity within reasonable order of magnitude. To address these challenges, we present a novel mid-range proton arc therapy (MRPAT) strategy with monoenergetic beam per control point and a low-complexity global optimization framework. In mid-range beam selection, our principal aim is that Bragg peaks can sweep across the central part of the target after full arc delivery. Thus, the sole mid-range energy layer for each control point is defined as the beam range through the target isocenter, measured by the water equivalent path length (WEPL). The advantages of using mid-range beam are three-fold. First, positioning mid-range spots near the target center establishes a buffer zone, reducing uncertainties such as proton beam range, respiratory motion, and setup errors. Second, the delivered dose primarily comes from Bragg peak, enhancing linear energy transfer (LET) for greater relative biological effectiveness (RBE). Last is efficient delivery, as the WEPL varies smoothly with the beam angle, energy layer switching would take little time and be performed while gantry rotating. For spot intensity optimization, we adopted the global optimization framework previously presented by our team. The spot dose is modeled by kernel decomposition (KD), and calculation is speeded up by Fast Fourier Transform. In contrast to conventional fluence map optimization that needs to pre-calculate and store a huge dose deposition matrix, the KD model only requires to store a shift-invariant kernel obtained from the Monte Carlo method, which greatly reduces both spatial and temporal complexities. The feasibility study of the MRPAT framework was performed on a two-dimensional cylindrical homogeneous phantom with a centrally located target surrounded by four organs at risk (OARs). The MRPAT plan was compared with a single-field (field-1) plan and a conventional PAT (full-arc) plan both with full-energy. The optimization results are summarized in the table. The field-1 plan received more dose in the entrance path and OARs compared with two arc plans. The MRPAT plan achieved similar target coverage and improved OAR sparing compared with full-arc PAT plan, but MRPAT utilized less energy layer and spots. Furthermore, it is important to note that MRPAT plan saves 10-fold computation time compared to the full-arc PAT plan. The novel MRPAT framework demonstrated its ability to generate plan quality comparable to full-energy PAT delivery within less optimization time. Key advantages of MRPAT include offering the potential to maximize LET for enhanced RBE and establishing robust plans by leveraging mid-range spots. [ABSTRACT FROM AUTHOR]

Proton ARC therapy has garnered significant attention due to its ability to improve dose and linear energy transfer (LET) conformality to treatment targets. However, frequent energy layer changes, especially energy jumps, can hinder treatment delivery efficiency. In this study, we propose a novel proton ARC treatment planning method that employs a multi-arc strategy without energy switching within each arc (rotation). The objective of employing the multi-arc and constant-energy-per-arc method is to efficiently deliver proton ARC while simultaneously optimizing plan quality. The proposed method initiates with optimization degrees of freedom equivalent to the number of energy layers, employing one arc per energy layer. Subsequently, a subset of arcs (typically 3 to 5) is selected using a novel block orthogonal matching pursuit (BOMP) optimization algorithm. The spot weights on these selected arcs are then optimized while adhering to the minimum-monitor-unit deliverability constraint. To validate the method, the proposed BOMP algorithm is compared with (1) the heuristic-search (HS) method, where each arc is individually optimized and then the arcs with the best plan quality are jointly selected for final plan optimization; and (2) the conventional (CONV) method, employing a variable-energy arc with multiple energy layers per beam angle. Compared to HS, BOMP has comparable or even better plan quality, which validates the effectiveness of BOMP algorithm. Compared to CONV, BOMP provides superior plan quality, and a substantial reduction of the energy layer switching time to a few seconds in total: for example, in a head-and-neck (HN) case, when the same target normalization was applied, BOMP had a reduction of optimization objective value from 0.33 to 0.26 (using 3 arcs) or 0.23 (using 5 arcs), max target dose from 117.37% to 113.10% or 110.84%, and energy layer switching time (T E) from 759.4s to 1.4s or 2.8s which is negligible compared to CONV. Similarly, the results of lung case also show a reduction of optimization objective value from 0.25 to 0.19, max target dose from 118.97% to 115.72% and a substantial reduction of T E from 1090.5s to 1.4s. For the first time, a multi-arc and constant-energy-per-arc method is proposed for proton ARC RT. Since there is no need to switch energies in each arc, the novel proton ARC treatment planning method can substantially reduce energy layer switching time to a negligible level, without compromising the plan quality (in fact with an improvement of plan quality), compared to CONV. [ABSTRACT FROM AUTHOR]

Radiopharmaceutical therapy (RPT) may enhance tumor response to immune checkpoint inhibitors (ICI), yet the effects of emitted radiation type, linear energy transfer, treatment timing, and dose rate have not been elucidated. To evaluate these parameters and mechanisms of response to RPT+ICI, we used NM600, an alkylphosphocholine analog that is selectively taken up by most tumors. We hypothesized that 225Ac-NM600 would enhance therapeutic response to ICI therapy to a greater extent than 90Y- or 177Lu-NM600 in murine tumors. Dosimetry was performed using the Monte Carlo-based RAPID platform utilizing PET/CT or SPECT/CT and/or ex vivo biodistribution. C57BL/6 mice bearing syngeneic B78 melanoma (immunogenic) or MC38 colorectal cancer (poorly immunogenic) received 2 Gy from 90Y-,177Lu-, or 225Ac-NM600, or no radiation (RT) on day 1 +/- ICI (anti-CTLA4 + anti-PDL1) on days -3/0/3 (early), 4/7/10 (intermediate), or 11/14/17 (delayed). Mice were monitored for tumor growth and survival. Blood and splenocyte memory cell populations from complete responders were evaluated by flow cytometry. CD8+ depletion studies were performed with MC38-bearing mice treated with 2 Gy RPT or no RT on day 1 +/- ICI. B78 melanoma tumors treated with 2 Gy 90Y-/177Lu-/225Ac-NM600 or external beam radiation therapy + ICI or ICI alone were harvested on day 15 and CD45+ cells were isolated by density gradient centrifugation. Single cell RNA-sequencing (scRNA-seq) and T cell receptor sequencing (TCR seq) were performed on these cell populations. Statistical significance was determined by two-way ANOVA (flow) or Kaplan-Meier with log-rank testing (therapy). 90Y-/177Lu-/or 225Ac-NM600 delivering 2 Gy mean tumor dose promoted tumor regression and improved survival when combined with ICIs in syngeneic mice bearing B78 or MC38 tumors. Regardless of the administered isotope, this combination was optimized with early ICI administration (days -3/0/3) relative to day 1 RPT. 90Y-NM600+ICI produced the greatest anti-tumor response for MC38, whereas high LET alpha particle radiation from 225Ac-NM600 was most effective with ICIs against the poorly immunogenic B78 model. Flow cytometry, depletion studies, and scRNA and TCR seq illuminated mechanisms of response to 90Y-,177Lu-, or 225Ac-NM600+ICI. CD8+ depletion studies confirmed that the MC38 tumor response to RPT+ICI required CD8+ T cells. Paired scRNA and TCR seq of B78 tumors elucidated the critical role of CD8+ T cells in the anti-tumor response to 90Y-, 177Lu-, and 225Ac-NM600+ICI, with 225Ac-NM600+ICI leading to diversified effector T cell responses with key shared clonotypes between CD8+ effector and memory cells. Antitumor immune response can be achieved with appropriate application of α- or β- emitting RPT in combination with ICIs in diverse murine tumor models. [ABSTRACT FROM AUTHOR]

PURPOSE: Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. METHODS AND MATERIALS: Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. RESULTS: The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. CONCLUSIONS: Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.

Simulation of water radiolysis and the subsequent chemistry provides important information on the effect of ionizing radiation on biological material. The Geant4 Monte Carlo toolkit has added chemical processes via the Geant4-DNA project. The TOPAS tool simplifies the modeling of complex radiotherapy applications with Geant4 without requiring advanced computational skills, extending the pool of users. Thus, a new extension to TOPAS, TOPAS-nBio, is under development to facilitate the configuration of track-structure simulations as well as water radiolysis simulations with Geant4-DNA for radiobiological studies. In this work, radiolysis simulations were implemented in TOPAS-nBio. Users may now easily add chemical species and their reactions, and set parameters including branching ratios, dissociation schemes, diffusion coefficients, and reaction rates. In addition, parameters for the chemical stage were re-evaluated and updated from those used by default in Geant4-DNA to improve the accuracy of chemical yields. Simulation results of time-dependent and LET-dependent primary yields Gx (chemical species per 100 eV deposited) produced at neutral pH and 25 °C by short track-segments of charged particles were compared to published measurements. The LET range was 0.05-230 keV µm-1. The calculated Gx values for electrons satisfied the material balance equation within 0.3%, similar for protons albeit with long calculation time. A smaller geometry was used to speed up proton and alpha simulations, with an acceptable difference in the balance equation of 1.3%. Available experimental data of time-dependent G-values for [Formula: see text] agreed with simulated results within 7%  ±  8% over the entire time range; for [Formula: see text] over the full time range within 3%  ±  4%; for H2O2 from 49%  ±  7% at earliest stages and 3%  ±  12% at saturation. For the LET-dependent Gx, the mean ratios to the experimental data were 1.11  ±  0.98, 1.21  ±  1.11, 1.05  ±  0.52, 1.23  ±  0.59 and 1.49  ±  0.63 (1 standard deviation) for [Formula: see text], [Formula: see text], H2, H2O2 and [Formula: see text], respectively. In conclusion, radiolysis and subsequent chemistry with Geant4-DNA has been successfully incorporated in TOPAS-nBio. Results are in reasonable agreement with published measured and simulated data.

Modeling ionizing radiation interaction with biological matter is a major scientific challenge, especially for protons that are nowadays widely used in cancer treatment. That presupposes a sound understanding of the mechanisms that take place from the early events of the induction of DNA damage. Herein, we present results of irradiation-induced complex DNA damage measurements using plasmid pBR322 along a typical Proton Treatment Plan at the MedAustron proton and carbon beam therapy facility (energy 137–198 MeV and Linear Energy Transfer (LET) range 1–9 keV/μm), by means of Agarose Gel Electrophoresis and DNA fragmentation using Atomic Force Microscopy (AFM). The induction rate Mbp−1 Gy−1 for each type of damage, single strand breaks (SSBs), double-strand breaks (DSBs), base lesions and non-DSB clusters was measured after irradiations in solutions with varying scavenging capacity containing 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris) and coumarin-3-carboxylic acid (C3CA) as scavengers. Our combined results reveal the determining role of LET and Reactive Oxygen Species (ROS) in DNA fragmentation. Furthermore, AFM used to measure apparent DNA lengths provided us with insights into the role of increasing LET in the induction of highly complex DNA damage. [ABSTRACT FROM AUTHOR]

The authors present a review of new experimental data on the relative biological effectiveness (RBE) of the impact on the body of fast neutrons and accelerated multicharged ions (AMIs) in small, absorbed doses of 0.01–0.5 Gy, which are allowed by modern radiation safety standards for the career of astronauts to limit the risk of delayed adverse effects. According to new radiobiological data for low doses and their rates, the literature presents higher (2–3 times) maximum values of the RBE coefficients for cytogenetic disorders that persist in the long-term period; malignant transformation of cells and the risk of developing tumors of different tissues; reduction in life expectancy; disorders of neurons in the cerebral cortex and damage to individual organs; and the degree of clouding of the lens and the formation of cataracts. Based on the analysis performed, a new dependence of quality factors on linear energy transfer is presented, from which it follows that the estimated values of equivalent doses in relation to the effects of galactic cosmic rays and fast neutrons, as well as the calculated values of the total radiation risk during the life of astronauts, will increase significantly. [ABSTRACT FROM AUTHOR]

Real time radioluminescence fibre-based detectors were investigated for application in proton, helium, and carbon therapy dosimetry. The Al2O3:C probes are made of one single crystal (1 mm) and two droplets of micro powder in two sizes (38 μm and 4 μm) mixed with a water-equivalent binder. The fibres were irradiated behind different thicknesses of solid slabs, and the Bragg curves presented a quenching effect attributed to the nonlinear response of the radioluminescence (RL) signal as a function of linear energy transfer (LET). Experimental data and Monte Carlo simulations were utilised to acquire a quenching correction method, adapted from Birks' formulation, to restore the linear dose–response for particle therapy beams. The method for quenching correction was applied and yielded the best results for the '4 μm' optical fibre probe, with an agreement at the Bragg peak of 1.4% (160 MeV), and 1.5% (230 MeV) for proton-charged particles; 2.4% (150 MeV/u) for helium-charged particles and of 4.8% (290 MeV/u) and 2.9% (400 MeV/u) for the carbon-charged particles. The most substantial deviations for the '4 μm' optical fibre probe were found at the falloff regions, with ~3% (protons), ~5% (helium) and 6% (carbon). [ABSTRACT FROM AUTHOR]

Currently, our knowledge of how different cell types in a tissue microenvironment respond to low and high linear energy transfer (LET) radiation is highly restricted. In this study, a comparative analysis was performed on γ-ray-induced DNA damage and repair in primary human melanocytes and keratinocytes isolated from 3 donors. Our study demonstrates a modest interindividual variability in both melanocytes and keratinocytes in terms of both spontaneous and ionizing radiation (IR)-induced 53BP1 foci formation and persistence. Melanocytes, in general, showed a slightly elevated (1.66–2.79 folds more) 53BP1 foci induction relative to keratinocytes after exposure to different doses of γ-rays (0.1–2.5 Gy) radiation. To verify the influence of ATM kinase on IR-induced 53BP1 foci formation, melanocytes and keratinocytes were treated with a specific ATM kinase inhibitor (KU55993, 10 μM) for 1 h prior to radiation. ATM kinase inhibition resulted in the reduction of both spontaneous and IR-induced 53BP1 foci by 17–42% in both melanocytes and keratinocytes of all the 3 donors. Increased persistence of IR-induced 53BP1 foci number was observed in ATM-inhibited melanocytes and keratinocytes after different post exposure times (6 h and 24 h). Taken together, our study suggests that interindividual variations exist in the induction and repair of DNA double-strand breaks (DSBs) in melanocytes and keratinocytes and that ATM is crucial for an optimal DSB repair efficiency in both human skin cell types. [ABSTRACT FROM AUTHOR]

Purpose: Challenges in proton therapy include identifying patients most likely to benefit; ensuring consistent, high‐quality plans as its adoption becomes more widespread; and recognizing biological uncertainties that may be related to increased relative biologic effectiveness driven by linear energy transfer (LET). Knowledge‐based planning (KBP) is a domain that may help to address all three. Methods: Artificial neural networks were trained using 117 unique treatment plans and associated dose and dose‐weighted LET (LETD) distributions. The data set was split into training (n = 82), validation (n = 17), and test (n = 18) sets. Model performance was evaluated on the test set using dose‐ and LETD‐volume metrics in the clinical target volume (CTV) and nearby organs at risk and Dice similarity coefficients (DSC) comparing predicted and planned isodose lines at 50%, 75%, and 95% of the prescription dose. Results: Dose‐volume metrics significantly differed (α = 0.05) between predicted and planned dose distributions in only one dose‐volume metric, D2% to the CTV. The maximum observed root mean square (RMS) difference between corresponding metrics was 4.3 GyRBE (8% of prescription) for D1cc to optic chiasm. DSC were 0.90, 0.93, and 0.88 for the 50%, 75%, and 95% isodose lines, respectively. LETD‐volume metrics significantly differed in all but one metric, L0.1cc of the brainstem. The maximum observed difference in RMS differences for LETD metrics was 1.0 keV/μm for L0.1cc to brainstem. Conclusions: We have devised the first three‐dimensional dose and LETD‐prediction model for cranial proton radiation therapy has been developed. Dose accuracy compared favorably with that of previously published models in other treatment sites. The agreement in LETD supports future investigations with biological doses in mind to enable the full potential of KBP in proton therapy. [ABSTRACT FROM AUTHOR]

Background: Parallel‐opposed lateral beams are the conventional beam arrangements in proton therapy for prostate cancer. However, when considering linear energy transfer (LET) and RBE effects, alternative beam arrangements should be investigated. Purpose: To investigate the dose and dose averaged LET (LETd) impact of using new beam arrangements rotating beams 5°–15° posteriorly to the laterals in prostate cancer treated with pencil‐beam‐scanning (PBS) proton therapy. Methods: Twenty patients with localized prostate cancer were included in this study. Four proton treatment plans for each patient were generated utilizing 0°, 5°, 10°, and 15° posterior oblique beam pairs relative to parallel‐opposed lateral beams. Dose‐volume histograms (DVHs) from posterior oblique beams were analyzed. Dose‐LETd‐volume histogram (DLVH) was employed to study the difference in dose and LETd with each beam arrangement. DLVH indices, V(d,l)$V({d,l})$, defined as the cumulative absolute volume that has a dose of at least d (Gy[RBE]) and a LETd of at least l (keV/µm), were calculated for both the rectum and bladder to the whole group of patients and two‐sub groups with and without hydrogel spacer. These metrics were tested using Wilcoxon signed‐rank test. Results: Rotating beam angles from laterals to slightly posterior by 5°–15° reduced high LETd volumes while it increased the dose volume in the rectum and increased LETd in bladders. Beam angles rotated five degrees posteriorly from laterals (i.e., gantry in 95° and 265°) are proposed since they achieved the optimal balance of better LETd sparing and minimal dose increase in the rectum. A reduction of V(50 Gy[RBE], 2.6 keV/µm) from 7.41 to 3.96 cc (p < 0.01), and a slight increase of V(50 Gy[RBE], 0 keV/µm) from 20.1 to 21.6 cc (p < 0.01) were observed for the group without hydrogel spacer. The LETd sparing was less effective for the group with hydrogel spacer, which achieved the reduction of V(50 Gy[RBE], 2.6 keV/µm) from 4.28 to 2.10 cc (p < 0.01). Conclusions: Posterior oblique angle plans improved LETd sparing of the rectum while sacrificing LETd sparing in the bladder in the treatment of prostate cancer with PBS. Beam angle modification from laterals to slightly posterior may be a strategy to redistribute LETd and perhaps reduce rectal toxicity risks in prostate cancer patients treated with PBS. However, the effect is reduced for patients with hydrogel spacer. [ABSTRACT FROM AUTHOR]

• We assessed the prognostic factors for sacrum insufficiency fractures (SIFs) in carbon-ion RT. • Median RBE-weighted dose to the sacrum was a risk factor for SIF. • Neither LET nor physical dose parameters were significant risk factors for SIF. The correlation between dose-averaged linear energy transfer (LETd) and its therapeutic or adverse effects, especially in carbon-ion radiotherapy (CIRT), remains controversial. This study aimed to investigate the effects of LETd and dose on pelvic insufficiency fractures after CIRT. Among patients who underwent CIRT for uterine carcinoma, 101 who were followed up for > 6 months without any other therapy were retrospectively analyzed. The sacrum insufficiency fractures (SIFs) were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity criteria. The correlations between the relative biological effectiveness (RBE)-weighted dose, LETd, physical dose, clinical factors, and SIFs were evaluated. In addition, we analyzed the association of SIF with LETd, physical dose, and clinical factors in cases where the sacrum D50% RBE-weighted dose was above the median dose. At the last follow-up, 19 patients developed SIFs. Receiver operating characteristic curve analysis revealed that the sacrum D50% RBE-weighted dose was a valuable predictor of SIF. Univariate analyses suggested that LETd V10 keV/µm, physical dose V5 Gy, and smoking status were associated with SIF. Cox regression analysis in patients over 50 years of age validated that current smoking habit was the sole risk factor for SIF. Therefore, LETd or physical dose parameters were not associated with SIF prediction. The sacrum D50% RBE-weighted dose was identified as a risk factor for SIF. Additionally, neither LETd nor physical dose parameters were associated with SIF prediction. [ABSTRACT FROM AUTHOR]

The accurate measurement of the beam range in the frame of quality assurance (QA) is a requirement for clinical use of a proton therapy machine. Conventionally used detectors mostly estimate the range by measuring the depth dose distribution of the protons. In this paper, we use pixel detectors designed for individual particle tracking in the high-radiation environment of the ATLAS experiment at LHC. The detector measures the deposited energy in the sensor for individual protons. Due to the limited dynamic energy range of the readout chip, several ways to measure the proton energy or range are examined. A staircase phantom is placed on the detector to perform an energy calibration relative to the NIST PSTAR stopping power database. In addition, track length measurements are performed using the detector aligned parallel with the beam axis to investigate the Linear Energy Transfer (LET) per pixel along the trajectory of individual protons. In this proof-of-principle study, we show that this radiation hardness detector can successfully be used to determine the initial proton energy for protons impinging on the sensor with an energy below 44 MeV after the range shifters. It becomes clear that an improvement of the energy resolution of the readout chip is required for clinical use. [ABSTRACT FROM AUTHOR]

Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results: Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radioresistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 mm vasculature spacing and 18.9 mM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion: We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments. [ABSTRACT FROM AUTHOR]

The purpose of this work is to investigate collimating individual proton beamlets from a dosimetric perspective and to introduce a new device concept, the spot scanning aperture (SSA). The SSA consists of a thin aperture with a small cylindrical opening attached to a robotics system, which allows the aperture to follow and align with individual beamlets during spot delivery. Additionally, a range shifter is incorporated (source-side) for treating shallow depths. Since the SSA trims beamlets spot by spot, the patientfacing portion of the device only needs to be large enough to trim a single proton beamlet. The SSA has been modelled in an open-source Monte-Carlobased dose engine (MCsquare) to characterize its dosimetric properties in water at depths between 0 and 10 cm while varying the following parameters: the aperture material, thickness, distance to the water phantom, distance between the aperture and attached range shifter, and the aperture opening radius. Overall, the SSA greatly reduced spot sizes for all the aperture opening radii that were tested (1 - 4 mm), especially in comparison with the extended range shifter (ranger shifter placed at 30 cm from patient); greater than 50% when placed less than 10 cm away from the patient at depths in water less than 50 mm. The peak to entrance dose ratio and linear energy transfer was found to depend on the thickness of the aperture and therefore the aperture material. Neutron production rates were also investigated and discussed. [ABSTRACT FROM AUTHOR]

FinFET, with narrow silicon fin, and high k /metal gate stacked combined with SOI technology brings benefits to radiation effects. Single event transient (SET) of SOI FinFET at 14 nm technology node is simulated by TCAD. The device model is calibrated by the experiment data. The effects of ion strike locations and linear energy transfer (LET) on SET are analyzed. The trends of the transient current peak, the collected charge, the deposited charge and the bipolar amplification are discussed. The results indicate that the most sensitive area of FinFET to SET is the gate-drain junction of fin. With LET increasing, the transient current peak and the collected charge increase while the bipolar amplification decreases. [ABSTRACT FROM AUTHOR]

In this study, a model „ADM606M Portable Multifunction Ratemeter /Scalar“ (Gamma GP110 Detector) was used to estimate the effective dose rate in (µSv.h-1). The data were analyzed for three specified hours per day (9:00 a.m., 11:00 a.m., and 1:00 p.m.) from January 2009 to June 2016. In July 2019, the gamma scout radiation meter (dosimeter) was used to measure the outdoor gamma effective dose rate (µSv.h-1) for the same building every minute for three hours, from 10 a.m. to 1 p.m., at 1m above the second floor of the building. The average effective dose rate and average Annual Effective Dose Rate were 0.158±0.013 µSv.h-1 and 0.2614145 mSv.y-1, respectively, within acceptable limits. The excess lifetime cancer risk (ELCR) value was also assessed to be (0.91495x10-3), which was found to be greater than the UNSCEAR, 2000 stated world average (0.29x10-3). The risks of cancer morbidity and mortality for specific organs and tissues from external sources of low linear energy transfer (LET) radiation were also assessed. They showed biological effects associated with the potential long-term exposure of Dohuk city residents to natural background radiation. [ABSTRACT FROM AUTHOR]

Single-event transient (SET) due to heavy-ion strike is a serious reliability concern for devices operated in radiation environment. Due to technology scaling, nodal capacitance decreases which increases the SET vulnerability. In this paper, the sensitivity of SET pulse width in 45nm bulk and SOI MOSFET to linear energy transfer (LET), heavy-ion track length, angle of strike, characteristic radius, and characteristic time of the track is analysed. The modification of SET pulse width while propagating through 45nm bulk-and SOI-based CMOS chain of inverters and its dependence on aforementioned radiation parameters is also analysed. The results show that all the pulses produced in SOI-based inverter chain get attenuated during propagation and do not reach the last stage. However, in the case of bulk, any SET having pulse width greater than 37 ps (measured using full width at half maximum) propagates and reaches the last stage of the inverter chain. Thus, the SOI devices are more immune to SET compared to the bulk, for different heavy-ion track parameters. [ABSTRACT FROM AUTHOR]

Lung is one of the high-risk organs for radiation-induced carcinogenesis, but the risk of secondary lung-cancer development after particle-beam therapy and the underlying mechanism(s) remain to be elucidated. To investigate the effects of particle-beam radiation on adjacent normal tissues during cancer therapy, 7-week-old male and female B6C3F1 mice were irradiated with 0.2–4 Gy of gamma rays (for comparison), carbon ions (290 MeV/u, linear energy transfer 13 keV/µm), or fast neutrons (0.05–1 Gy, mean energy, ∼2 MeV), and lung-tumor development was assessed by histopathology. Mice irradiated with ≥2 Gy of carbon ions or ≥0.2 Gy of neutrons developed lung adenocarcinoma (AC) significantly sooner than did non-irradiated mice. The relative biological effectiveness values for carbon ions for lung AC development were 1.07 for male mice and 2.59 for females, and the corresponding values for neutrons were 4.63 and 4.57. Genomic analysis of lung ACs revealed alterations in genes involved in Egfr signaling. Hyperphosphorylation of Erk and a frequent nuclear abnormality (i.e., nuclear groove) were observed in lung ACs of mice irradiated with carbon ions or neutrons compared with ACs from non-irradiated or gamma-ray-irradiated groups. Our data indicate that the induction of lung AC by carbon ions occurred at a rate similar to that for gamma rays in males and approximately 2-to 3-fold greater than that for gamma rays in females. In contrast, the effect of neutrons on lung AC development was approximately 4- to 5-fold greater than that of gamma rays. Our results provide valuable information concerning risk assessment of radiation-induced lung tumors after particle-beam therapy and increase our understanding of the molecular basis of tumor development. [ABSTRACT FROM AUTHOR]

The III-V binary compound semiconductor is considered to be an appealing candidate for future complementary metal oxide semiconductor applications and the most promising silicon substitute in terms of high electron mobility. In this study, the authors used the Monte Carlo simulation software Geant4 and the data analysis tool Python to comprehensively examine the interaction between protons with a wide range of energy and III-V binary compound semiconductors. This work focus on the radiation responses of 11 kinds of III-V materials—AlAs, AlP, AlSb, GaAs, GaN, GaP, GaSb, InAs, InN, InP, and InSb—with silicon as a reference. Energy straggling, secondary ion generation, and energy distribution in the sensitive layer were represented in each simulation of the incident protons. Information about the distributions of the linear energy transfer of the secondary ions and energy deposition was acquired through data analysis. Finally, the impact of the material species on the single-event upset responses triggered by the direct ionization and the nuclear reaction mechanisms at different critical charges were investigated. [ABSTRACT FROM AUTHOR]

Cancer develops in a multi-step process where environmental carcinogenic exposure is a primary etiological component, and where cell–cell communication governs the biological activities of tissues. Identifying the molecular genes that regulate this process is essential to targeting metastatic breast cancer. Ionizing radiation can modify and damage DNA, RNA, and cell membrane components such as lipids and proteins by direct ionization. Comparing differential gene expression can help to determine the effect of radiation and estrogens on cell adhesion. An in vitro experimental breast cancer model was developed by exposure of the immortalized human breast epithelial cell line MCF-10F to low doses of high linear energy transfer α particle radiation and subsequent growth in the presence of 17β-estradiol. The MCF-10F cell line was analyzed in different stages of transformation that showed gradual phenotypic changes including altered morphology, increase in cell proliferation relative to the control, anchorage-independent growth, and invasive capability before becoming tumorigenic in nude mice. This model was used to determine genes associated with cell adhesion and communication such as E-cadherin, the desmocollin 3, the gap junction protein alpha 1, the Integrin alpha 6, the Integrin beta 6, the Keratin 14, Keratin 16, Keratin 17, Keratin 6B, and the laminin beta 3. Results indicated that most genes had greater expression in the tumorigenic cell line Tumor2 derived from the athymic animal than the Alpha3, a non-tumorigenic cell line exposed only to radiation, indicating that altered expression levels of adhesion molecules depended on estrogen. There is a significant need for experimental model systems that facilitate the study of cell plasticity to assess the importance of estrogens in modulating the biology of cancer cells. [ABSTRACT FROM AUTHOR]

Plasmid DNA is useful for investigating the DNA damaging effects of ionizing radiation. In this study, we have explored the feasibility of plasmid DNA-based detectors to assess the DNA damaging effectiveness of two radiotherapy X-ray beam qualities after undergoing return shipment of ~8000 km between two institutions. The detectors consisted of 18   μ L of pBR322 DNA enclosed with an aluminum seal in nine cylindrical cavities drilled into polycarbonate blocks. We shipped them to Toronto, Canada for irradiation with either 100   kVp   or 6   MV   X-ray beams to doses of 10, 20, and 30 Gy in triplicate before being shipped back to San Diego, USA. The Toronto return shipment also included non-irradiated controls and we kept a separate set of controls in San Diego. In San Diego, we quantified DNA single strand breaks (SSBs), double strand breaks (DSBs), and applied Nth and Fpg enzymes to quantify oxidized base damage. The rate of DSBs/Gy/plasmid was 2.8 ± 0.7   greater for the 100 kVp than the 6 MV irradiation. The 100   kVp irradiation also resulted in 5 ± 2 times more DSBs/SSB than the 6   MV beam, demonstrating that the detector is sensitive enough to quantify relative DNA damage effectiveness, even after shipment over thousands of kilometers. [ABSTRACT FROM AUTHOR]

Carbon‐ions are charged particles with a high linear energy transfer, and therefore, they make a better dose distribution with greater biological effects on the tumors compared with photons and protons. Since prostate cancer, renal cell carcinoma, and retroperitoneal sarcomas such as liposarcoma and leiomyosarcoma are known to be radioresistant tumors, carbon‐ion radiotherapy, which provides the advantageous radiobiological properties such as an increasing relative biological effectiveness toward the Bragg peak, a reduced oxygen enhancement ratio, and a reduced dependence on fractionation and cell‐cycle stage, has been tested for these urological tumors at the National Institute for Radiological Sciences since 1994. To promote carbon‐ion radiotherapy as a standard cancer therapy, the Japan Carbon‐ion Radiation Oncology Study Group was established in 2015 to create a registry of all treated patients and conduct multi‐institutional prospective studies in cooperation with all the Japanese institutes. Based on accumulating evidence of the efficacy and feasibility of carbon‐ion therapy for prostate cancer and retroperitoneal sarcoma, it is now covered by the Japanese health insurance system. On the other hand, carbon‐ion radiotherapy for renal cell cancer is not still covered by the insurance system, although the two previous studies showed the efficacy. In this review, we introduce the characteristics, clinical outcomes, and perspectives of carbon‐ion radiotherapy and our efforts to disseminate the use of this new technology worldwide. [ABSTRACT FROM AUTHOR]

Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry. [ABSTRACT FROM AUTHOR]

Purpose: To present biological dose optimization for particle arc therapy using helium and carbon ions.Methods and Materials: Treatment planning and optimization procedures were developed for spot-scanning hadron arc (SHArc) delivery using the RayStation treatment planning system and FRoG dose engine. The SHArc optimization algorithm is applicable for charged particle beams and determines angle dependencies for spot and energy selection with three main initiatives: (i) achieve standard clinical optimization goals and constraints for target and organs at risk (OARs), (ii) target dose robustness, and (iii) increase linear energy transfer (LET) in the target volume. Three patient cases previously treated at the Heidelberg Ion-beam Therapy Center (HIT) were selected for evaluation of conventional versus arc delivery for the two clinical particle beams (helium [4He] and carbon [12C] ions): glioblastoma, prostate adenocarcinoma, and skull-base chordoma. Biological dose and dose-averaged LET (LETd) distributions for SHArc were evaluated against conventional planning techniques (volumetric modulated arc therapy [VMAT] and 2-field intensity modulated particle therapy) applying the modified microdosimetric kinetic model with (α/β)x = 2 Gy. Clinical viability and deliverability were assessed via evaluation of plan quality, robustness, and irradiation time.Results: For all investigated patient cases, SHArc treatment optimizations met planning goals and constraints for target coverage and OARs, exhibiting acceptable target coverage and reduced normal tissue volumes, with effective dose >10-GyRBE compared with conventional 2F planning. For carbon ions, LETd was increased in the target volume from ∼40-60 to ∼80-140 keV/µm for SHArc compared with conventional treatments. Favorable LETd distributions were possible with the SHArc approach, with maximum LETd in clinical target volume/gross tumor volume and potential reductions of high-LET regions in normal tissues and OARs. Compared with VMAT, SHArc affords substantial reductions in normal tissue dose (40%-70%).Conclusions: SHArc therapy offers potential treatment benefits such as increased normal tissue sparing from higher doses >10-GyRBE, enhanced target LETd, and potential reduction in high-LET components in OARs. Findings justify further development of robust SHArc treatment planning toward potential clinical translation. [ABSTRACT FROM AUTHOR]

• Many clinical studies have analysed patient toxicities/image changes to investigate proton RBE. • Clinical evidence for variable proton RBE remains statistically weak. • Expert statistical advice should be sought during study planning. • Proton centres should collaborate on follow-up, enabling larger patient cohorts to be considered. Recently, a number of clinical studies have explored links between possible Relative Biological Effectiveness (RBE) elevations and patient toxicities and/or image changes following proton therapy. Our objective was to perform a systematic review of such studies. We applied a "Problem [RBE], Intervention [Protons], Population [Patients], Outcome [Side effect]" search strategy to the PubMed database. From our search, we retrieved studies which: (a) performed novel voxel-wise analyses of patient effects versus physical dose and LET (n = 13), and (b) compared image changes between proton and photon cohorts with regard to proton RBE (n = 9). For each retrieved study, we extracted data regarding: primary tumour type; size of patient cohort; type of image change studied; image-registration method (deformable or rigid); LET calculation method, and statistical methodology. We compared and contrasted their methods in order to discuss the weight of clinical evidence for variable proton RBE. We concluded that clinical evidence for variable proton RBE remains statistically weak at present. Our principal recommendation is that proton centres and clinical trial teams collaborate to standardize follow-up protocols and statistical analysis methods, so that larger patient cohorts can ultimately be considered for RBE analyses. [ABSTRACT FROM AUTHOR]

• A trend towards higher LET were seen in patients with brainstem toxicity. • Observed differences were systematic but minor and statistically insignificant. • The elevated LET could be a minor contributor to the observed brainstem toxicity. • Variable RBE-weighted dose was marginally elevated for cases vs controls. A fixed relative biological effectiveness (RBE) of 1.1 (RBE 1.1) is used clinically in proton therapy even though the RBE varies with properties such as dose level and linear energy transfer (LET). We therefore investigated if symptomatic brainstem toxicity in pediatric brain tumor patients treated with proton therapy could be associated with a variable LET and RBE. 36 patients treated with passive scattering proton therapy were selected for a case-control study from a cohort of 954 pediatric brain tumor patients. Nine children with symptomatic brainstem toxicity were each matched to three controls based on age, diagnosis, adjuvant therapy, and brainstem RBE 1.1 dose characteristics. Differences across cases and controls related to the dose-averaged LET (LET d) and variable RBE-weighted dose from two RBE models were analyzed in the high-dose region. LET d metrics were marginally higher for cases vs. controls for the majority of dose levels and brainstem substructures. Considering areas with doses above 54 Gy(RBE 1.1), we found a moderate trend of 13% higher median LET d in the brainstem for cases compared to controls (P =.08), while the difference in the median variable RBE-weighted dose for the same structure was only 2% (P =.6). Trends towards higher LET d for cases compared to controls were noticeable across structures and LET d metrics for this patient cohort. While case-control differences were minor, an association with the observed symptomatic brainstem toxicity cannot be ruled out. [ABSTRACT FROM AUTHOR]

The BepiColombo Environment Radiation Monitor (BERM) on board the European Space Agency's Mercury Planetary Orbiter (MPO), is designed to measure the radiation environment encountered by BepiColombo. The instrument measures electrons with energies from ∼ 150 keV to ∼ 10 MeV , protons with energies from ∼ 1.5 MeV to ∼ 100 MeV , and heavy ions with Linear Energy Transfer from 1 to 50 MeV ⋅ mg − 1 ⋅ cm 2 . BERM is operated continuously, being responsible for monitoring the radiation levels during all phases of the mission, including the cruise, the planetary flybys of Earth, Venus and Mercury, and the Hermean environment. In this paper, we describe the scientific objectives, instrument design and calibration, and the in-flight scientific performance of BERM. Moreover, we provide the first scientific results obtained by BERM during the BepiColombo flyby of Earth in April 2020, and after the impact of a solar energetic particle event during the cruise phase in May 2021. We also discuss the future plans of the instrument including synergies with other instruments on the BepiColombo and on other missions. [ABSTRACT FROM AUTHOR]

The aim of the study was to upgrade the Horia Hulubei National Institute for Physics and Nuclear Engineering existing facility - a 3 MV TandetronTM accelerator - to be used in radiobiology experiments. Irradiations were performed with 1.95 MeV protons (beam with uniform distribution over a 30 mm2). Particle fluence was determined with plastic track detectors and live monitored using Rutherford Backscattering Spectrometry technique. Absolute and relative dose (Advanced Markus ion chamber) and the lateral quality of the irradiation spot (radiochromic film) were measured. The dosimetric measurements were confirmed by Geant4 simulations of the dose averaged Linear Energy Transfer, the Bragg peak profile and the beam lateral energy distribution. A complete setup for exposing in vitro cell cultures to the particle beams was constructed from scratch. Preliminary data of survival rate of V79 fibroblast cells are reported. The obtained results are similarly with data reported using other proton beam facilities. [ABSTRACT FROM AUTHOR]

Chondrosarcomas are particularly difficult to treat due to their resistance to chemotherapy and radiotherapy. However, particle therapy can enhance local control and patient survival rates. To improve our understanding of the basic cellular radiation response, as a function of dose and linear energy transfer (LET), we developed a novel water phantom-based setup for cell culture experiments and characterized it dosimetrically. In a direct comparison, human chondrosarcoma cell lines were analyzed with regard to their viability, cell proliferation, cell cycle, and DNA repair behavior after irradiation with X-ray, proton, and carbon ions. Our results clearly showed that cell viability and proliferation were inhibited according to the increasing ionization density, i.e., LET, of the irradiation modes. Furthermore, a prominent G2/M arrest was shown. Gene expression profiling proved the upregulation of the senescence genes CDKN1A (p21), CDKN2A (p16NK4a), BMI1, and FOXO4 after particle irradiation. Both proton or C-ion irradiation caused a positive regulation of the repair genes ATM, NBN, ATXR, and XPC, and a highly significant increase in XRCC1/2/3, ERCC1, XPC, and PCNA expression, with C-ions appearing to activate DNA repair mechanisms more effectively. The link between the physical data and the cellular responses is an important contribution to the improvement of the treatment system. [ABSTRACT FROM AUTHOR]

Proton irradiations are highly sensitive to spatial variations, mainly due to their high linear energy transfer (LET) and densely ionizing nature. In realistic clinical applications, the targets of ionizing radiation are inhomogeneous in terms of geometry and chemical composition (i.e., organs in the human body). One of the main methods for proton range monitoring is to utilize the production of proton induced positron emitting radionuclides; these could be measured precisely with positron emission tomography (PET) systems. One main positron emitting radionuclide that could be used for proton range monitoring and verification was found to be 13N that produces a peak close to the Bragg peak. In the present work, we have employed the Monte Carlo method and Spectral Analysis (SA) technique to investigate the feasibility of utilizing the 13N peak for proton range monitoring and verification in inhomogeneous targets. Two different phantom types, namely, (1) ordinary slab and (2) MIRD anthropomorphic phantoms, were used. We have found that the generated 13N peak in such highly inhomogeneous targets (ordinary slab and human phantom) is close to the actual Bragg peak, when irradiated by incident proton beam. The feasibility of using the SA technique to estimate the distribution of positron emitter was also investigated. The current findings and the developed tools in the present work would be helpful in proton range monitoring and verification in realistic clinical radiation therapy using proton beams. [ABSTRACT FROM AUTHOR]

Exposure to ionizing radiation can occur during medical treatments, from naturally occurring sources in the environment, or as the result of a nuclear accident or thermonuclear war. The severity of cellular damage from ionizing radiation exposure is dependent upon a number of factors including the absorbed radiation dose of the exposure (energy absorbed per unit mass of the exposure), dose rate, area and volume of tissue exposed, type of radiation (e.g., X-rays, high-energy gamma rays, protons, or neutrons) and linear energy transfer. While the dose, the dose rate, and dose distribution in tissue are aspects of a radiation exposure that can be varied experimentally or in medical treatments, the LET and eV are inherent characteristics of the type of radiation. High-LET radiation deposits a higher concentration of energy in a shorter distance when traversing tissue compared with low-LET radiation. The different biological effects of high and low LET with similar energies have been documented in vivo in animal models and in cultured cells. High-LET results in intense macromolecular damage and more cell death. Findings indicate that while both low- and high-LET radiation activate non-homologous end-joining DNA repair activity, efficient repair of high-LET radiation requires the homologous recombination repair pathway. Low- and high-LET radiation activate p53 transcription factor activity in most cells, but high LET activates NF-kB transcription factor at lower radiation doses than low-LET radiation. Here we review the development, uses, and current understanding of the cellular effects of low- and high-LET radiation exposure. [ABSTRACT FROM AUTHOR]

The research on energy conversion and transportation of fuels at a microscopic level is of great significance to the development of industry. As a new alternative fuel, alcohols are widely used in industry and daily life, so it is necessary to investigate the thermophysical properties of them. In this work, seven species of pure liquid alcohols were performed to investigate the microscopic mechanisms of thermal energy transfer by non-equilibrium molecular dynamic (NEMD) method. Firstly, the thermal conductivity of alcohols was calculated and was found to be consistent with the experimental data. Then, the influence of temperature on energy transfer is investigated, the results show that the contribution of convection energy transfer increases and both the inter- and intramolecular terms decrease with the increase of temperature. Finally, the influence of molecular length on energy transfer was investigated at the same temperature, and it is concluded that the contribution of the convective term decreases and the interactive term increases to the total heat flux with increasing the length of the chain. It is worth mentioning that the contribution of intramolecular energy transfer gradually becomes a dominant part of the total energy transfer as the linear chain molecule increases to a certain length and the number of carbon atoms at the intersection point of inter- and intramolecular energy transfer is similar to the turning point of thermal conductivity. [ABSTRACT FROM AUTHOR]