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Purpose: Optimal head-and-neck cancer (HNC) treatment planning requires accurate and feasible planning goals to meet dosimetric constraints and generate robust online adaptive treatment plans. A new x-ray-based adaptive radiotherapy (ART) treatment planning system (TPS) version 2.0 emulator includes novel methods to drive the planning process including the revised intelligent optimization engine algorithm (IOE2). HNC is among the most challenging and complex sites and heavily depends on planner skill and experience to successfully generate a reference plan. Therefore, we evaluate the new TPS performance via conventionally accepted planning strategies with/without artificial intelligence (AI) and knowledge-based planning (KBP)., Methods: Our institution has a pre-clinical release of the Varian Ethos2.0 TPS emulator which includes several changes that may affect current planning strategies. Twenty definitive and post-operative HNC patients were retrospectively selected with a two or three-level simultaneous integrated boost (SIB) dosing scheme. Patients were replanned in the emulator using population-based, KBP-guided with/without human intervention and AI-guided planning goals. These planning strategies were compared both dosimetrically and for plan deliverability., Results: All strategies generally demonstrated acceptable plan quality with KBP- and AI-guided goals offering enhanced dosimetric sparing in organs-at-risk (OAR). The average contralateral parotid gland mean dose was 20.0 ± 6.1 Gy (p < 0.001) for population-based and 15.0 ± 6.1 Gy (p = n.s.) for KBP-with human intervention versus 15.1 ± 7.4 Gy for clinical plans. Target coverage, minimum dose, and plan hotspot were acceptable in all cases. KBP-enabled strategy demonstrated higher modulation and faster optimization time than both population-based and AI-guided strategies., Conclusion: Simply entering population, automatic KBP-enabled or AI-generated planning goals into the new Ethos2.0 TPS produced dosimetrically compliant plans, with AI-guided goals demonstrating the most OAR sparing. Several of these approaches are easy to translate to other treatment sites and will help lower the barrier to entry for x-ray-based online-ART., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

While chromosomal rearrangements are ubiquitous in all domains of life, very little is known about their evolutionary significance, mostly because, apart from a few specifically studied and well-documented mechanisms (interaction with recombination, gene duplication, etc.), very few models take them into account. As a consequence, we lack a general theory to account for their direct and indirect contributions to evolution. Here, we propose Aevol, a forward-in-time simulation platform specifically dedicated to unravelling the evolutionary significance of chromosomal rearrangements (CR) compared to local mutations (LM). Using the platform, we evolve populations of organisms in four conditions characterized by an increasing diversity of mutational operators-from substitutions alone to a mix of substitutions, InDels and CR-but with a constant global mutational rate. Despite being almost invisible in the phylogeny owing to the scarcity of their fixation in the lineages, we show that CR make a decisive contribution to the evolutionary dynamics by comparing the outcome in these four conditions. As expected, chromosomal rearrangements allow fast expansion of the gene repertoire through gene duplication, but they also reduce the effect of diminishing-returns epistasis, hence sustaining adaptation on the long-run. At last, we show that chromosomal rearrangements tightly regulate the size of the genome through indirect selection for reproductive robustness. Overall, these results confirm the need to improve our theoretical understanding of the contribution of chromosomal rearrangements to evolution and show that dedicated platforms like Aevol can efficiently contribute to this agenda., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Seed yield and vigor of hybrid maize determine the planting, yield, and quality of maize, and consequently affect food, nutrition, and livelihood security; however, the response of seed yield and vigor to climate change is still unclear. We established an optimization-simulation framework consisting of a water‑nitrogen crop production function, a seed vigor and a gridded process-based model to optimize irrigation and nitrogen fertilization management, and used it to evaluate seed yield and vigor in major seed production locations of China, the USA, and Mexico. This framework could reflect the influence of water and nitrogen inputs at different stages on seed yield and vigor considering the spatio-temporal variability of climate and soil properties. Projected seed yield and vigor decreased by 5.8-9.0 % without adaptation by the 2050s, due to the 1.3-5.8 % decrease in seed number and seed protein concentration. Seed yield was positively correlated with CO 2 and negatively correlated with temperature, while seed vigor depended on the response of components of seed vigor to climatic factors. Under optimized management, the direct positive effects of temperature on seed protein concentration and CO 2 on seed number were strengthened, and the direct negative effects of temperature on seed number and CO 2 on seed protein concentration were weakened, which mitigated the reductions in both seed yield and vigor. Elevated CO 2 was projected to exacerbate the 2.6 % seed vigor reduction and mitigate the 2.9 % seed yield loss without adaptation, while optimized management could increase seed yield by 4.1 % and mitigate the 2.2 % seed vigor reduction in the Hexi Corridor of China, and decrease the seed yield and vigor reduction by 2.4-5.8 % in the USA and Mexico. Optimized management can strengthen the positive and mitigate the negative effects of climate change on irrigated hybrid maize and inform high-yield and high-quality seed production globally., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Mutation-agnostic treatments such as airway gene therapy have the potential to treat any individual with cystic fibrosis (CF), irrespective of their CF transmembrane conductance regulator (CFTR) gene variants. The aim of this study was to employ two CF rat models, Phe508del and CFTR knockout (KO), to assess the comparative effectiveness of CFTR modulators and lentiviral (LV) vector-mediated gene therapy. Cells were isolated from the tracheas of rats and used to establish air-liquid interface (ALI) cultures. Phe508del rat ALIs were treated with the modulator combination, elexacaftor-tezacaftor-ivacaftor (ETI), and separate groups of Phe508del and KO tracheal epithelial cells were treated with LV-CFTR followed by differentiation at ALI. Ussing chamber measurements were performed to assess CFTR function. ETI-treated Phe508del ALI cultures demonstrated CFTR function that was 59% of wild-type level, while gene-addition therapy restored Phe508del to 68% and KO to 47% of wild-type level, respectively. Our findings show that rat Phe508del-CFTR protein can be successfully rescued with ETI treatment, and that CFTR gene-addition therapy provides significant CFTR correction in Phe508del and KO ALI cultures to levels that were comparable to ETI. These findings highlight the potential of an LV vector-based gene therapy for the treatment of CF lung disease., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Online adaptive radiation therapy (oART) has high resource costs especially for head and neck (H&N) cancer, which requires recontouring complex targets and numerous organs-at-risk (OARs). Adaptive radiation therapy systems provide autocontours to help. We aimed to explore the optimal level of editing automatic contours to maintain plan quality in a cone beam computed tomography-based oART system for H&N cancer. In this system, influencer OAR contours are generated and reviewed first, which then drives the autocontouring of the remaining OARs and targets., Methods and Materials: Three-hundred-forty-nine adapted fractions of 44 patients with H&N cancer were retrospectively analyzed, with physician-edited OARs and targets. These contours and associated online-adapted plans served as the gold standard for comparison. We simulated 3 contour editing workflows: (1) no editing of contours; (2) only editing the influencers; and (3) editing the influencers and targets. The geometric difference was quantified using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). The dosimetric differences in target coverage and OAR doses were calculated between the gold standard and these 3 simulated workflows., Results: Workflow 1 resulted in significantly inferior contour quality for all OARs (mean DSC, 0.85 ± 0.17 and HD95, 3.10 ± 5.80mm); hence, dosimetric data was not calculated for workflow 1. In workflow 2, the frequency of physician editing targets and remaining OARs were 80.8% to 95.7% and 2.3% (brachial plexus) to 67.7% (oral cavity), respectively, where the OAR differences were geometrically minor (mean DSC >0.95 with std ≤0.09). However, because of the unedited target contours of workflow 2 (mean DSC, 0.86-0.92 and mean HD95, 2.56-3.30 mm vs the ground-truth targets), plans were inadequate with insufficient coverage. In workflow 3, when both targets and influencers were edited (noninfluencer OARs were unedited), >95.5% of the adapted plans achieved the patient-specific dosimetry goals., Conclusions: The cone beam computed tomography-based H&N oART workflow can be meaningfully accelerated by only editing the influencers and targets while omitting the remaining OARs without compromising the quality of the adaptive plans., Competing Interests: Disclosures David Sher received a research grant from Varian Medical Systems for a phase 2 clinical trial of adaptive radiation therapy for head and neck cancer (DARTBOARD, NCT04883281). Mu-Han Lin and Justin Visak have a research agreement with Varian Medical Systems for an unrelated adaptive radiation therapy project., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Two cystic fibrosis (CF) rat models, one carrying the common Phe508del mutation and the other a nonsense cystic fibrosis transmembrane conductance regulator (CFTR) mutation (knockout) were previously characterised. Although relevant CFTR mRNA reductions were present in the lung, no overt CF lung disease was observed. This study used flexiVent lung mechanic assessment and regional ventilation assessment via X-ray velocimetry (XV) functional imaging to assess the lung phenotype in both models. To determine the sensitivity of XV regional ventilation imaging, the effect of a localised physical obstruction (delivery of agar beads to part of the lungs) on lung ventilation was examined. At baseline, Phe508del and knockout CF rats had a lower inspiratory capacity, total respiratory system compliance, and static compliance than wildtype rats. Following agar bead delivery all XV ventilation parameters were altered, with substantial increases in poorly ventilated regions and ventilation heterogeneity. XV ventilation maps accurately identified locations of bead-induced airflow changes. Despite unremarkable lung histopathology, this study indicated that CF rats display altered respiratory mechanics, with CF rats needing to exert additional effort to expand and deflate their lungs due to increased stiffness. This study demonstrated the utility of XV imaging providing spatial lung ventilation information., (© 2024. The Author(s).)

Background: Molecular pathways contributing to Cystic Fibrosis pathogenesis remain poorly understood. Epithelial-mesenchymal transition (EMT) has been recently observed in CF lungs and certain CFTR mutation classes may be more susceptible than others. No investigations of EMT processes in CF animal models have been reported., Aim: The aim of this study was to assess the expression of EMT-related markers in Phe508del and knockout (CFTR-KO) rat lung tissue and tracheal-derived basal epithelial stem cells, to determine whether CFTR dysfunction can produce an EMT state., Method: The expression of EMT-related markers in lung tissue and cultured tracheal basal epithelial stem cells from wildtype (WT), Phe508del, and CFTR-KO rats were assessed using qPCR and Western blots. Cell responses were evaluated in the presence of Rho-associated protein kinase (ROCK) inhibitor Y27632, which blocks EMT-pathways, or after treatment with TGFβ1 to stimulate EMT., Results: Different gene expression profiles were observed between Phe508del and CFTR-KO rat models compared to wild type. There was lower expression of type 1 collagen in KO lungs and primary cell cultures, while Phe508del lungs and cells had higher expression, particularly when treated with TGFβ1. The addition of Y27632 rescued changes in EMT related genes in Phe508del cells but not in KO cells., Conclusion: Our findings show the first evidence of upregulated EMT pathways in the lungs and airway cells of any CF animal model. Differences in the regulation of the EMT genes and proteins in the Phe508del and CFTR-KO cells suggest that the signalling pathways underlying EMT are CFTR mutation dependent., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Online adaptive radiation therapy (oART) treatment planning requires evaluating the temporal robustness of reference plans and anticipating the potential changes during treatment courses that may even lead to risks unique to the adaptive workflow. This study conducted a risk analysis of the cone beam computed tomography guided adaptive workflow and is the first to assess an adaptive-specific reference planning review that mitigates risk in the planning process to prevent events and treatment deficiencies during adaptation., Methods and Materials: A quality management team of medical physicists, residents, physicians, and radiation therapists performed a fault tree analysis and failure mode and effects analysis. Fault trees were created for under/overdosing targets and treatment deficiencies and assisted in identifying failure modes for the failure mode and effects analysis. Treatment deficiency was defined as a nonideal oART plan resulting in treatment with a lower quality plan (either oART or scheduled plan), treatment delay, or canceling treatment for the day. A reference planning checklist was created to catch failure modes before reaching the patient. Risk priority numbers (RPNs = severity * detectability * occurrence) were scored with and without the reference planning checklist to quantify risk mitigation. A root cause analysis was conducted for an event where an adaptive plan failed to generate., Results: The reference planning checklist (with items covering patient background, contouring/planning robustness for anatomy variability, and machine limitations) reduced the RPN for all failure modes. Only 1 failure mode with an RPN > 150 occurred with the reference planning checklist compared with 29 failure modes without, including 14 adaptive-specific failure modes. Contouring, planning, setup, scheduling, and documentation errors were identified during the fault tree analysis. Twenty-nine of 70 errors were adaptive-specific. The reference planning checklist could address 23 of 33 errors for over- or underdosing and 28 of 37 errors for treatment deficiency. The root cause analysis highlighted the need to check the setup prior to adaptive plan delivery and the time-out checklist., Conclusions: The reference planning checklist improved the detection of the failure modes and improved the quality and robustness of the plans produced for oART. It is ideally performed before the physician plan review to prevent last-minute replan (before or after first adaptive treatment) and delay of patient start. The checklist presented can be modified based on failures specific to individual clinics and used at various planning steps based on available resources., Competing Interests: Dennis Stanley reports travel costs for attending conference meetings and presentations from Varian Medical Systems. Bin Cai reports speaker fees and travel costs from RefleXion Medical System and Varian Medical System as an invited speaker.

Background: Surface-guided imaging (SGI) is increasingly utilized to monitor patient motion during deep inspiration breath hold (DIBH) in radiotherapy. Understanding the association between surface and internal motion is crucial for effective monitoring., Purpose: To investigate the relation between motion detected by SGI using surface-guided radiotherapy (SGRT) and internal motion measured through diaphragm tracking on kV projections acquired with DIBH for online CBCT., Methods: Both SGI and kV were simultaneously acquired for ten patients over a total of 200 breath holds (BH). Diaphragm tracking was performed using second-degree polynomial curve fitting on the derivative images for each kV projection and high-pass filtering at 1/30 Hz to remove rotational effects. The superior-inferior (SI) and anterior-posterior (AP) motions of SGI were then compared to kV tracking using various statistical measures., Results: The correlation (individuals' median: -0.07 to 0.73) was a suboptimal metric for the BH data. The median and 95th percentile absolute differences between SGI-SI and kV were 0.73 mm and 3.46 mm, respectively, during DIBH. For SGI-AP, the corresponding values were 0.55 mm and 2.80 mm. For inter-BH measurements, the contingency table based on a 3 mm threshold indicated surface/diaphragm motion agreement for SGI-SI/kV and SGI-AP/kV was 61 % and 56 %, respectively., Conclusion: Both intra- and inter-BH measurements indicated a limited association between surface and diaphragm motion, with certain constraints noted due to kV tracking and DIBH data. These findings warrant further investigation into the association between surface and internal motion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Purpose: Real-time adaptation of thoracic radiation plans is compelling because offline adaptive experiences show that tumor volumes and lung anatomy can change during therapy. We present and analyze a novel adaptive-on-demand (AOD) workflow combining online adaptive radiation therapy (o-ART) on the ETHOS system with image guided radiation therapy delivery on a Halcyon unit for conventional fractionated radiation therapy of locally advanced lung cancer (LALC)., Methods and Materials: We analyzed 26 patients with LALC treated with the AOD workflow, adapting weekly. We timed segments of the workflow to evaluate efficiency in a real-world clinic. Target coverage and organ at risk (OAR) doses were compared between adaptive plans (ADP) and nonadaptive scheduled plans (SCH). Planning robustness was evaluated by the frequency of preplanning goals achieved in ADP plans, stratified by tumor volume change., Results: The AOD workflow was achievable within 30 minutes for most radiation fractions. Over the course of therapy, we observed an average 26.6% ± 23.3% reduction in internal target volume (ITV). Despite these changes, with o-ART, ITV and planning target volume (PTV) coverage (V100%) was 99.2% and 93.9% for all members of the cohort, respectively. This represented a 2.9% and 6.8% improvement over nonadaptive plans (P < .05), respectively. For tumors that grew >10%, V100% was 93.1% for o-ART and 76.4% for nonadaptive plans, representing a median 17.2% improvement in the PTV coverage (P < .05). In these plans, critical OAR constraints were met 94.1% of the time, whereas in nonadaptive plans, this figure was 81.9%. This represented reductions of 1.32 Gy, 1.34 Gy, or 1.75 Gy in the heart, esophagus, and lung, respectively. The effect was larger when tumors had shrunk more than 10%. Regardless of tumor volume alterations, the PTV/ITV coverage was achieved for all adaptive plans. Exceptional cases, where dose constraints were not met, were due to large initial tumor volumes or tumor growth., Conclusions: The AOD workflow is efficient and robust in responding to anatomic changes in LALC patients, providing dosimetric advantages over standard therapy. Weekly adaptation was adequate to keep pace with changes. This approach is a feasible alternative to conventional offline replanning workflows for managing anatomy changes in LALC radiation therapy., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

The coexistence of eosinophilic esophagitis (EoE) and Barrett's esophagus (BE) is rare despite the known association of gastroesophageal reflux disease with both conditions. Radiofrequency ablation is an effective endoscopic eradication therapy in patients with dysplastic BE. However, the efficacy and outcomes of radiofrequency ablation in patients with concomitant EoE and BE are not well known. We report a case of rapid eosinophilic infiltration of the neosquamous mucosa after the complete eradication of long-segment dysplastic BE in a patient with coexisting BE and EoE., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background and Purpose: Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated., Experimental Approach: Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg -1 ·day -1 elexacaftor + 3.5 mg·kg -1 ·day -1 tezacaftor + 25 mg·kg -1 ·day -1 ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed., Key Results: No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development., Conclusion and Implication: Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: Online adaptive radiotherapy relies on a high degree of automation to enable rapid planning procedures. The Varian Ethos intelligent optimization engine (IOE) was originally designed for conventional treatments so it is crucial to provide clear guidance for lung SAbR plans. This study investigates using the Ethos IOE together with adaptive-specific optimization tuning structures we designed and templated within Ethos to mitigate inter-planner variability in meeting RTOG metrics for both online-adaptive and offline SAbR plans., Methods: We developed a planning strategy to automate the generation of tuning structures and optimization. This was validated by retrospective analysis of 35 lung SAbR cases (total 105 fractions) treated on Ethos. The effectiveness of our planning strategy was evaluated by comparing plan quality with-and-without auto-generated tuning structures. Internal target volume (ITV) contour was compared between that drawn from CT simulation and from cone-beam CT (CBCT) at time of treatment to verify CBCT image quality and treatment effectiveness. Planning strategy robustness for lung SAbR was quantified by frequency of plans meeting reference plan RTOG constraints., Results: Our planning strategy creates a gradient within the ITV with maximum dose in the core and improves intermediate dose conformality on average by 2%. ITV size showed no significant difference between those contoured from CT simulation and first fraction, and also trended towards decreasing over course of treatment. Compared to non-adaptive plans, adaptive plans better meet reference plan goals (37% vs. 100% PTV coverage compliance, for scheduled and adapted plans) while improving plan quality (improved GI (gradient index) by 3.8%, CI (conformity index) by 1.7%)., Conclusion: We developed a robust and readily shareable planning strategy for the treatment of adaptive lung SAbR on the Ethos system. We validated that automatic online plan re-optimization along with the formulated adaptive tuning structures can ensure consistent plan quality. With the proposed planning strategy, highly ablative treatments are feasible on Ethos., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics is published by Wiley Periodicals, Inc. on behalf of The American Association of Physicists in Medicine.)

Objective: We explore the potential dosimetric benefits of reducing treatment volumes through daily adaptive radiation therapy for head and neck cancer (HNC) patients using the Ethos system/Intelligent Optimizer Engine (IOE). We hypothesize reducing treatment volumes afforded by daily adaption will significantly reduce the dose to adjacent organs at risk. We also explore the capability of the Ethos IOE to accommodate this highly conformal approach in HNC radiation therapy., Methods: Ten HNC patients from a phase II trial were chosen, and their cone-beam CT (CBCT) scans were uploaded to the adaptive RT (ART) emulator. A new initial reference plan was generated using both a 1 mm and 5 mm planning target volume (PTV) expansion. Daily adaptive ART plans (1 mm) were simulated from the clinical CBCT taken every fifth fraction. Additionally, using physician-modified ART contours the larger 5 mm plan was recalculated on this recontoured on daily anatomy. Changes in target and OAR contours were measured using Dice coefficients as a surrogate of clinician effort. PTV coverage and organ-at-risk (OAR) doses were statistically compared, and the robustness of each ART plan was evaluated at fractions 5 and 35 to observe if OAR doses were within 3 Gy of pre-plan., Results: This study involved six patients with oropharynx and four with larynx cancer, totaling 70 adaptive fractions. The primary and nodal gross tumor volumes (GTV) required the most adjustments, with median Dice scores of 0.88 (range: 0.80-0.93) and 0.83 (range: 0.66-0.91), respectively. For the 5th and 35th fraction plans, 80 % of structures met robustness criteria (quartile 1-3: 67-100 % and 70-90 %). Adaptive planning improved median PTV V100% coverage for doses of 70 Gy (96 % vs. 95.6 %), 66.5 Gy (98.5 % vs. 76.5 %), and 63 Gy (98.9 % vs. 74.9 %) (p < 0.03). Implementing ART with total volume reduction yielded median dose reductions of 7-12 Gy to key organs-at-risk (OARs) like submandibular glands, parotids, oral cavity, and constrictors (p < 0.05)., Conclusions: The IOE enables feasible daily ART treatments with reduced margins while enhancing target coverage and reducing OAR doses for HNC patients. A phase II trial recently finished accrual and forthcoming analysis will determine if these dosimetric improvements correlate with improved patient-reported outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: In radiation therapy (RT), accelerated partial breast irradiation (APBI) has emerged as an increasingly preferred treatment modality over conventional whole breast irradiation due to its targeted dose delivery and shorter course of treatment. APBI can be delivered through various modalities including Cobalt-60-based systems and linear accelerators with C-arm, O-ring, or robotic arm design. Each modality possesses distinct features, such as beam energy or the degrees of freedom in treatment planning, which influence their respective dose distributions. These modality-specific considerations emphasize the need for a quantitative approach in determining the optimal dose delivery modality on a patient-specific basis. However, manually generating treatment plans for each modality across every patient is time-consuming and clinically impractical., Purpose: We aim to develop an efficient and personalized approach for determining the optimal RT modality for APBI by training predictive models using two different deep learning-based convolutional neural networks. The baseline network performs a single-task (ST), predicting dose for a single modality. Our proposed multi-task (MT) network, which is capable of leveraging shared information among different tasks, can concurrently predict dose distributions for various RT modalities. Utilizing patient-specific input data, such as a patient's computed tomography (CT) scan and treatment protocol dosimetric goals, the MT model predicts patient-specific dose distributions across all trained modalities. These dose distributions provide patients and clinicians quantitative insights, facilitating informed and personalized modality comparison prior to treatment planning., Methods: The dataset, comprising 28 APBI patients and their 92 treatment plans, was partitioned into training, validation, and test subsets. Eight patients were dedicated to the test subset, leaving 68 treatment plans across 20 patients to divide between the training and validation subsets. ST models were trained for each modality, and one MT model was trained to predict doses for all modalities simultaneously. Model performance was evaluated across the test dataset in terms of Mean Absolute Percent Error (MAPE). We conducted statistical analysis of model performance using the two-tailed Wilcoxon signed-rank test., Results: Training times for five ST models ranged from 255 to 430 min per modality, totaling 1925 min, while the MT model required 2384 min. MT model prediction required an average of 1.82 s per patient, compared to ST model predictions at 0.93 s per modality. The MT model yielded MAPE of 1.1033 ± 0.3627% as opposed to the collective MAPE of 1.2386 ± 0.3872% from ST models, and the differences were statistically significant (p = 0.0003, 95% confidence interval = [-0.0865, -0.0712])., Conclusion: Our study highlights the potential benefits of a MT learning framework in predicting RT dose distributions across various modalities without notable compromises. This MT architecture approach offers several advantages, such as flexibility, scalability, and streamlined model management, making it an appealing solution for clinical deployment. With such a MT model, patients can make more informed treatment decisions, physicians gain more quantitative insight for pre-treatment decision-making, and clinics can better optimize resource allocation. With our proposed goal array and MT framework, we aim to expand this work to a site-agnostic dose prediction model, enhancing its generalizability and applicability., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Objective. Magnetic nanoparticles can be used as a targeted delivery vehicle for genetic therapies. Understanding how they can be manipulated within the complex environment of live airways is key to their application to cystic fibrosis and other respiratory diseases. Approach. Dark-field x-ray imaging provides sensitivity to scattering information, and allows the presence of structures smaller than the detector pixel size to be detected. In this study, ultra-fast directional dark-field synchrotron x-ray imaging was utlilised to understand how magnetic nanoparticles move within a live, anaesthetised, rat airway under the influence of static and moving magnetic fields. Main results. Magnetic nanoparticles emerging from an indwelling tracheal cannula were detectable during delivery, with dark-field imaging increasing the signal-to-noise ratio of this event by 3.5 times compared to the x-ray transmission signal. Particle movement as well as particle retention was evident. Dynamic magnetic fields could manipulate the magnetic particles in situ. Significance. This is the first evidence of the effectiveness of in vivo dark-field imaging operating at these spatial and temporal resolutions, used to detect magnetic nanoparticles. These findings provide the basis for further development toward the effective use of magnetic nanoparticles, and advance their potential as an effective delivery vehicle for genetic agents in the airways of live organisms., (Creative Commons Attribution license.)

Introduction: Phe508del is the most common cystic fibrosis transmembrane conductance regulator (CFTR) gene variant that results in the recessive genetic disorder cystic fibrosis (CF). The recent development of highly effective CFTR modulator therapies has led to significant health improvements in individuals with this mutation. While numerous animal models of CF exist, few have a CFTR mutation that is amenable to the triple combination therapy elexacaftor-tezacaftor-ivacaftor (ETI). Methods: To determine the responsiveness of Phe508del rats to ETI, a baseline nasal potential difference was measured. Subsequently, they received ETI daily for 14 days, after which post-treatment nasal potential difference, lung mechanics (via flexiVent) and lung ventilation (via X-ray Velocimetry) were assessed. Results: Chloride ion transport in nasal airways was restored in Phe508del rats treated with ETI, but neither lung mechanics nor ventilation were significantly altered. Discussion: These findings validate the usefulness of this rat model for future investigations of modulator therapy in CF., Competing Interests: Authors NE and PP were employed by 4DMedical. Authors MD and DP were involved in the research development and validation of the XV technology and have personally purchased shares in 4DMedical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Reyne, Cmielewski, McCarron, Smith, Eikelis, Pirakalathanan, Parsons and Donnelley.)

This article focuses on various aspects of breast radiation treatment planning, from simulation to field design. It covers the most common techniques including tangents, mono isocentric, dual isocentric, electron-photon match, and VMAT. This can serve as a guide for radiation oncology residents and medical students to advance their understanding of key aspects of breast radiation treatment and planning processes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Introduction: Cystic fibrosis (CF) is a life-limiting autosomal recessive genetic condition. It is caused by mutations in the gene that encodes for a chloride and bicarbonate conducting transmembrane channel. X-ray velocimetry (XV) is a novel form of X-ray imaging that can generate lung ventilation data through the breathing cycle. XV technology has been validated in multiple animal models, including the β-ENaC mouse model of CF lung disease. It has since been assessed in early-phase clinical trials in adult human subjects; however, there is a paucity of data in the paediatric cohort, including in CF. The aim of this pilot study was to investigate the feasibility of performing a single-centre cohort study in paediatric patients with CF and in those with normal lungs to demonstrate the appropriateness of proceeding with further studies of XV in these cohorts., Methods and Analysis: This is a cross-sectional, single-centre, pilot study. It will recruit children aged 3-18 years to have XV lung imaging performed, as well as paired pulmonary function testing. The study will aim to recruit 20 children without CF with normal lungs and 20 children with CF. The primary outcome will be the feasibility of recruiting children and performing XV testing. Secondary outcomes will include comparisons between XV and current assessments of pulmonary function and structure., Ethics and Dissemination: This project has ethical approval granted by The Women's and Children's Hospital Human Research Ethics Committee (HREC ID 2021/HRE00396). Findings will be disseminated through peer-reviewed publication and conferences., Trial Registration Number: ACTRN12623000109606., Competing Interests: Competing interests: DP has received renumeration for research advice from 4DMedical. DP and MD have both purchased shares in 4DMedical Ltd., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The potential effects of the very effective cystic fibrosis triple combination drug, Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pregnancy on prenatal development of offspring remain largely unknown., Research Question: We aimed to investigate the fetal tissue distribution pattern of maternally administered ETI by placental transfer in the rat fetuses., Study Design and Methods: Sprague Dawley pregnant rats were administered ETI (6.7 mg/kg/d elexacaftor + 3.5 mg/kg/d tezacaftor + 25 mg/kg/d ivacaftor) traced with [ 3 H ]-ivacaftor in single dose acute experiments (intraperitoneal injection) or treated orally with ETI (the same dose) for 7 days in sub-chronic experiments. Fetal tissue samples were collected at embryonic day (E) 19 and analyzed using liquid scintillation counting for acute experiments or liquid chromatography-mass spectrometry for sub-chronic experiments., Results: On day E19, after acute exposure, the entry of ivacaftor into fetal brain (brain/plasma concentration ratios <50%) was significantly lower than to other tissues (>100%). However, after sub-chronic exposure, the entry of all 3 components into the developing brain was comparably extensive as into other tissues (tissue/plasma ratios, 260 - 1000%). Each component of ETI accumulated in different fetal tissues to approximately equal extent. Inter-litter differences on fetal drug distribution were found in cortex for ivacaftor, muscle for tezacaftor and cortex and mid/hindbrain for elexacaftor. Fetal plasma concentrations of ETI (ng/mL) were variable between litters. The entry of ivacaftor and tezacaftor into adult brain appeared to be restricted (<100%)., Interpretation: Fetal rats are exposed to maternally ingested ETI after sub-chronic exposure, potentially impacting fetal development. The brain entry data highlights the need for attention be paid to any long-term potential effects ETI exposure could have on normal brain development., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This study explored the feasibility of on-couch intensity modulated radiotherapy (IMRT) planning for prostate cancer (PCa) on a cone-beam CT (CBCT)-based online adaptive RT platform without an individualized pre-treatment plan and contours. Ten patients with PCa previously treated with image-guided IMRT (60 Gy/20 fractions) were selected. In contrast to the routine online adaptive RT workflow, a novel approach was employed in which the same preplan that was optimized on one reference patient was adapted to generate individual on-couch/initial plans for the other nine test patients using Ethos emulator. Simulation CTs of the test patients were used as simulated online CBCT (sCBCT) for emulation. Quality assessments were conducted on synthetic CTs (sCT). Dosimetric comparisons were performed between on-couch plans, on-couch plans recomputed on the sCBCT and individually optimized plans for test patients. The median value of mean absolute difference between sCT and sCBCT was 74.7 HU (range 69.5-91.5 HU). The average CTV/PTV coverage by prescription dose was 100.0%/94.7%, and normal tissue constraints were met for the nine test patients in on-couch plans on sCT. Recalculating on-couch plans on the sCBCT showed about 0.7% reduction of PTV coverage and a 0.6% increasing of hotspot, and the dose difference of the OARs was negligible (<0.5 Gy). Hence, initial IMRT plans for new patients can be generated by adapting a reference patient's preplan with online contours, which had similar qualities to the conventional approach of individually optimized plan on the simulation CT. Further study is needed to identify selection criteria for patient anatomy most amenable to this workflow., (© 2024 IOP Publishing Ltd.)

The authors review the role of endoscopic ultrasound (EUS) in the staging of cancers throughout the gastrointestinal tract. EUS offers an advantage over cross-sectional imaging in locoregional tumor staging but is less sensitive in identifying distant metastasis. The addition of FNA increases diagnostic accuracy and provides a tissue diagnosis. EUS combined with cross-sectional imaging is important in accurately staging GI tumors and thereby reducing unnecessary procedures and health care costs., Competing Interests: Disclosure The authors have no financial or commercial interests to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Study Design: Prospective experimental study., Objective: To compare the accuracy of O-Arm-acquired radiographic and computed tomography (CT) evaluation of thoracic pedicle screw placement with open laminectomy in a simulation laboratory., Summary of Background Data: Improving surgical safety and procedural efficiency during thoracic posterior spine instrumentation is essential for decreasing complication rates and possible related risks. The most common way of verifying the position of pedicle screws during the surgical procedure and immediately postoperatively is to acquire intraoperative fluoroscopic images and plain radiographs of the spine, respectively. Laboratory simulated surgery is a valuable tool to evaluate the accuracy of those exams., Methods: Twenty simulation models of scoliosis from T3 to T7 were instrumented by five spine fellows (total of 200 pedicle screws), followed by radiographic and CT images acquired with the assistance of the O-Arm which were evaluated by three independent raters. A fellowship-trained spine neurosurgeon performed laminectomies on the instrumented levels and assessed pedicle integrity (gold standard)., Results: Forty-eight breaches were identified in the axial direct view after laminectomy. Of those, eighteen breaches were classified as unacceptable. Regarding the sagittal direct view, four breaches were observed, three of which were classified as unacceptable. Overall, both O-arm radiographic and CT evaluations had a significantly high negative predicted value but a low positive predicted value to identify unacceptable breaches, especially in the sagittal plane. The frequency of missed breaches by all three examiners was high, particularly in the sagittal plane., Conclusion: Postoperative evaluation of pedicle screws using O-arm-acquired radiographic or CT images may underdiagnose the presence of breaches. In our study, sagittal breaches were more difficult to diagnose than axial breaches. Although most breaches do not have clinical repercussions, this study suggests that this modality of postoperative radiographic assessment may be inaccurate., Level of Evidence: 4., Competing Interests: The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Small animal physiology studies are often complicated, but the level of complexity is greatly increased when performing live-animal X-ray imaging studies at synchrotron radiation facilities. This is because these facilities are typically not designed specifically for biomedical research, and the animals and image detectors are located away from the researchers in a radiation enclosure. In respiratory X-ray imaging studies one challenge is the detection of respiration in free-breathing anaesthetised rodents, to enable images to be acquired at specific phases of the breath and for detecting changes in respiratory rate. We have previously used a Philtec RC60 sensor interfaced to a PowerLab data acquisition system and custom-designed timing hub to perform this task. Here we evaluated the Panasonic HL-G108 for respiratory sensing. The performance of the two sensors for accurate and reliable breath detection was directly compared using a single anesthetized rat. We also assessed how an infrared heat lamp used to maintain body temperature affected sensor performance. Based on positive results from these comparisons, the HL-G108 sensor was then used for respiratory motion detection in tracheal X-ray imaging studies of 21 rats at the SPring-8 Synchrotron, including its use for gated image acquisition. The results of that test were compared to a similar imaging study that used the RC60 for respiratory detection in 19 rats. Finally, the HL-G108 sensor was tested on 5 mice to determine its effectiveness on smaller species. The results showed that the HL-G108 is much more robust and easier to configure than the RC60 sensor and produces an analog signal that is amenable to stable peak detection. Furthermore, gated image acquisition produced sequences with substantially reduced motion artefacts, enabling the additional benefit of reduced radiation dose through the application of shuttering. Finally, the mouse experiments showed that the HL-G108 is equally capable of detecting respiration in this smaller species.

We compiled a sampling of the treatment techniques of intensity-modulated total body irradiation, total marrow irradiation and total marrow and lymphoid irradiation utilized by several centers across North America and Europe. This manuscript does not serve as a consensus guideline, but rather is meant to serve as a convenient reference for centers that are considering starting an intensity-modulated program., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Lentiviral vectors are attractive delivery vehicles for cystic fibrosis gene therapy owing to their low immunogenicity and ability to integrate into the host cell genome, thereby producing long-term, stable gene expression. Nonetheless, repeat dosing may be required to increase initial expression levels, and/or boost levels when they wane. The primary aim of this study was to determine if repeat dosing of a VSV-G pseudotyped LV vector delivered into mouse lungs is more effective than a single dose. C57Bl/6 mouse lungs were conditioned with lysophosphatidylcholine, followed one-hour later by a LV vector carrying the luciferase reporter gene, using six different short-term (≤1 wk) and long-term (>1 wk) dosing schedules. Luciferase expression was quantified using bioluminescence imaging over 12 months. Most dosing schedules produced detectable bioluminescence over the 12-month period, but the shorter intervals (≤1 wk) produced higher levels of flux than the longest interval (five doses at least 1-month apart). Ex vivo lung analysis at 12 months showed that the estimated mean flux for the group that received two doses 1-week apart was significantly greater than the single dose group and the two groups that received doses over a period greater than 1-week. These results suggest that early consecutive multiple doses are more effective at improving gene expression in mouse lungs at 12 months, than longer repeat dosing intervals., (© 2023. The Author(s).)

Purpose: Varian Ethos utilizes novel intelligent-optimization-engine (IOE) designed to automate the planning. However, this introduced a black box approach to plan optimization and challenge for planners to improve plan quality. This study aims to evaluate machine-learning-guided initial reference plan generation approaches for head & neck (H&N) adaptive radiotherapy (ART)., Methods: Twenty previously treated patients treated on C-arm/Ring-mounted were retroactively re-planned in the Ethos planning system using a fixed 18-beam intensity-modulated radiotherapy (IMRT) template. Clinical goals for IOE input were generated using (1) in-house deep-learning 3D-dose predictor (AI-Guided) (2) commercial knowledge-based planning (KBP) model with universal RTOG-based population criteria (KBP-RTOG) and (3) an RTOG-based constraint template only (RTOG) for in-depth analysis of IOE sensitivity. Similar training data was utilized for both models. Plans were optimized until their respective criteria were achieved or DVH-estimation band was satisfied. Plans were normalized such that the highest PTV dose level received 95% coverage. Target coverage, high-impact organs-at-risk (OAR) and plan deliverability was assessed in comparison to clinical (benchmark) plans. Statistical significance was evaluated using a paired two-tailed student t-test., Results: AI-guided plans were superior to both KBP-RTOG and RTOG-only plans with respect to clinical benchmark cases. Overall, OAR doses were comparable or improved with AI-guided plans versus benchmark, while they increased with KBP-RTOG and RTOG plans. However, all plans generally satisfied the RTOG criteria. Heterogeneity Index (HI) was on average <1.07 for all plans. Average modulation factor was 12.2 ± 1.9 (p = n.s), 13.1 ± 1.4 (p = <0.001), 11.5 ± 1.3 (p = n.s.) and 12.2 ± 1.9 for KBP-RTOG, AI-Guided, RTOG and benchmark plans, respectively., Conclusion: AI-guided plans were the highest quality. Both KBP-enabled and RTOG-only plans are feasible approaches as clinics adopt ART workflows. Similar to constrained optimization, the IOE is sensitive to clinical input goals and we recommend comparable input to an institution's planning directive dosimetric criteria., (© 2023 University of Texas Southwestern Medical Center. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Gene-based therapeutics are actively being pursued for the treatment of lung diseases. While promising advances have been made over the last decades, the absence of clinically available lung-directed genetic therapies highlights the difficulties associated with this effort. Largely, progress has been hindered by the presence of inherent physical and physiological airway barriers that significantly reduce the efficacy of gene transfer. These barriers include surface mucus, mucociliary action, cell-to-cell tight junctions, and the basolateral cell membrane location of viral receptors for many commonly used gene vectors. Accordingly, airway surface preparation methods have been developed to disrupt these barriers, creating a more conducive environment for gene uptake into the target airway cells. The two major approaches have been chemical and physical methods. Both have proven effective for increasing viral-mediated gene transfer pre-clinically, although with variable effect depending on the specific strategy employed. While such methods have been explored extensively in experimental settings, they have not been used clinically. This review covers the airway surface preparation strategies reported in the literature, the advantages and disadvantages of each method, as well as a discussion about applying this concept in the clinic., (© 2022. The Author(s).)

Introduction: Radiotherapy deliveries with dynamic couch motions that shorten the source-to-axis distance (SAD) on a C-arm linac have the potential to increase treatment efficiency through the increase of the effective dose rate. In this investigation, we convert clinically deliverable volumetric modulated arc therapy (VMAT) and dynamic conformal arc (DCA) plans for cranial radiosurgery into virtual isocenter plans through implementation of couch trajectories that maintain the target at a shortened but variable SAD throughout treatment., Materials and Methods: A randomly sampled population of patients treated with cranial radiosurgery from within the last three years were separated into groups with one, two, and three lesions. All plans had a single isocenter (regardless of number of targets), and a single prescription dose. Patient treatment plans were converted from their original delivery at a standard isocenter to a dynamic virtual isocenter in MATLAB. The virtual isocenter plan featured a variable isocenter position based upon the closest achievable source-to-target distance (referred to herein as a virtual source-to-axis distance [vSAD]) which avoided collision zones on a TrueBeam STx platform. Apertures were magnified according to the vSAD and monitor units at a given control point were scaled based on the inverse square law. Doses were calculated for the plans with a virtual isocenter in the Eclipse (v13.6.23) treatment planning system (TPS) and were compared with the clinical plans. Plan metrics (MU, Paddick conformity index, gradient index, and the volume receiving 12 Gy or more), normal brain dose-volume differences, as well as maximum doses received by organs at risk (OARs) were assessed. The values were compared between standard and virtual isocenter plans with Wilcoxon Sign Ranked tests to determine significance. A subset of the plans were mapped to the MAX-HD anthropomorphic phantom which contained an insert housing EBT3 GafChromic film and a PTW 31010 microion chamber for dose verification on a linac., Results: Delivering plans at a virtual isocenter resulted in an average reduction of 20.9% (p = 3×10 -6 ) and 20.6% (p = 3.0×10 -6 ) of MUs across all VMAT and all DCA plans, respectively. There was no significant change in OAR max doses received by plans delivered at a virtual isocenter. The low dose wash (1.0-2.0 Gy or 5-11% of the prescription dose) was increased (by approximately 20 cc) for plans with three lesions. This was equivalent to a 2.7%-3.8% volumetric increase in normal tissue receiving the respective dose level when comparing the plan with a virtual isocenter to a plan with a standard isocenter. Gamma pass rates with a 5%/1mm analysis criteria were 96.40% ± 2.90% and 95.07% ± 3.10% for deliveries at standard and virtual isocenter, respectively. Absolute point dose agreements were within -0.36% ± 3.45% and -0.55% ± 3.39% for deliveries at a standard and virtual isocenter, respectively. Potential time savings per arc were found to have linear relationship with the monitor units delivered per arc (savings of 0.009 s/MU with an r 2 = 0.866 when fit to plans with a single lesion)., Conclusions: Converting clinical plans at standard isocenter to a virtual isocenter design did not show any losses to plan quality while simultaneously improving treatment efficiency through MU reductions., (© 2023 American Association of Physicists in Medicine.)

Purpose: Deep inspiration breath-hold (DIBH) is crucial in reducing the lung and cardiac dose for treatment of left-sided breast cancer. We compared the stability and reproducibility of two DIBH techniques: Active Breathing Coordinator (ABC) and VisionRT (VRT)., Materials and Methods: We examined intra- and inter-fraction positional variation of the left lung. Eight left-sided breast cancer patients were monitored with electronic portal imaging during breath-hold (BH) at every fraction. For each patient, half of the fractions were treated using ABC and the other half with VRT, with an equal amount starting with either ABC or VRT. The lung in each portal image was delineated, and the variation of its area was evaluated. Intrafraction stability was evaluated as the mean coefficient of variation (CV) of the lung area for the supraclavicular (SCV) and left lateral (LLat) field over the course of treatment. Reproducibility was the CV for the first image of each fraction. Daily session time and total imaging monitor units (MU) used in patient positioning were recorded., Results: The mean intrafraction stability across all patients for the LLat field was 1.3 ± 0.7% and 1.5 ± 0.9% for VRT and ABC, respectively. Similarly, this was 1.5 ± 0.7% and 1.6 ± 0.8% for VRT and ABC, respectively, for the SCV field. The mean interfraction reproducibility for the LLat field was 11.0 ± 3.4% and 14.9 ± 6.0% for VRT and ABC, respectively. Similarly, this was 13.0 ± 2.5% and 14.8 ± 9% for VRT and ABC, respectively, for the SCV. No difference was observed in the number of verification images required for either technique., Conclusions: The stability and reproducibility were found to be comparable between ABC and VRT. ABC can have larger interfractional variation with less feedback to the treating therapist compared to VRT as shown in the increase in geometric misses at the matchline., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Cystic fibrosis (CF), the result of mutations in the CF transmembrane conductance regulator (CFTR), causes essential fatty acid deficiency. The aim of this study was to characterize fatty acid handling in two rodent models of CF; one strain which harbors the loss of phenylalanine at position 508 (Phe508del) in CFTR and the other lacks functional CFTR (510X). Fatty acid concentrations were determined using gas chromatography in serum from Phe508del and 510X rats. The relative expression of genes responsible for fatty acid transport and metabolism were quantified using real-time PCR. Ileal tissue morphology was assessed histologically. There was an age-dependent decrease in eicosapentaenoic acid and the linoleic acid:α-linolenic acid ratio, a genotype-dependent decrease in docosapentaenoic acid (n-3) and an increase in the arachidonic acid:docosahexaenoic acid ratio in Phe508del rat serum, which was not observed in 510X rats. In the ileum, Cftr mRNA was increased in Phe508del rats but decreased in 510X rats. Further, Elvol2 , Slc27a1 , Slc27a2 and Got2 mRNA were increased in Phe508del rats only. As assessed by Sirius Red staining, collagen was increased in Phe508del and 510X ileum. Thus, CF rat models exhibit alterations in the concentration of circulating fatty acids, which may be due to altered transport and metabolism, in addition to fibrosis and microscopic structural changes in the ileum.

Purpose: Ethos CBCT-based adaptive radiotherapy (ART) system can generate an online adaptive plan by re-optimizing the initial reference plan based on the patient anatomy at the treatment. The optimization process is fully automated without any room for human intervention. Due to the change in anatomy, the ART plan can be significantly different from the initial plan in terms of plan parameters such as the aperture shapes and number of monitor units (MUs). In this study, we investigated the feasibility of using calculation-based patient specific QA for ART plans in conjunction with measurement-based and calculation-based QA for initial plans to establish an action level for the online ART patient-specific QA., Methods: A cohort of 98 cases treated on CBCT-based ART system were collected for this study. We performed measurement-based QA using ArcCheck and calculation-based QA using Mobius for both the initial plan and the ART plan for analysis. For online the ART plan, Mobius calculation was conducted prior to the delivery, while ArcCheck measurement was delivered on the same day after the treatment. We first investigated the modulation factors (MFs) and MU numbers of the initial plans and ART plans, respectively. The γ passing rates of initial and ART plan QA were analyzed. Then action limits were derived for QA calculation and measurement for both initial and online ART plans, respectively, from 30 randomly selected patient cases, and were evaluated using the other 68 patient cases., Results: The difference in MF between initial plan and ART-plan was 12.9% ± 12.7% which demonstrates their significant difference in plan parameters. Based on the patient QA results, pre-treatment calculation and measurement results are generally well aligned with ArcCheck measurement results for online ART plans, illustrating their feasibility as an indicator of failure in online ART QA measurements. Furthermore, using 30 randomly selected patient cases, the γ analysis action limit derived for initial plans and ART plans are 89.6% and 90.4% in ArcCheck QA (2%/2 mm) and are 92.4% and 93.6% in Mobius QA(3%/2 mm), respectively. According to the calculated action limits, the ArcCheck measurements for all the initial and ART plans passed QA successfully while the Mobius calculation action limits flagged seven and four failure cases respectively for initial plans and ART plans, respectively., Conclusion: An ART plan can be substantially different from the initial plan, and therefore a separate session of ART plan QA is needed to ensure treatment safety and quality. The pre-treatment QA calculation via Mobius can serve as a reliable indicator of failure in online ART plan QA. However, given that Ethos ART system is still relatively new, ArcCheck measurement of initial plan is still in practice. It may be skipped as we gain more experience and have better understanding of the system., (© 2023 University of Texas Southwestern Medical Center. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of American Association of Physicists in Medicine.)

Cystic fibrosis (CF) lung disease is characterised by recurring bacterial infections resulting in inflammation, lung damage and ultimately respiratory failure. Pseudomonas aeruginosa is considered one of the most important lung pathogens in those with cystic fibrosis. While multiple cystic fibrosis animal models have been developed, many fail to mirror the cystic fibrosis lung disease of humans, including the colonisation by opportunistic environmental pathogens. Delivering bacteria to the lungs of animals in different forms is a way to model cystic fibrosis bacterial lung infections and disease. This review presents an overview of previous models, and factors to consider when generating a new P. aeruginosa lung infection model. The future development and application of lung infection models that more accurately reflect human cystic fibrosis lung disease has the potential to assist in understanding the pathophysiology of cystic fibrosis lung disease and for developing treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Reyne, McCarron, Cmielewski, Parsons and Donnelley.)

Purpose: Describe an early-adopting institution's experience with online adaptive radiation for stereotactic partial breast irradiation., Methods and Materials: Retrospective review of 22 women treated between May 2021 and March 2022 with adaptive stereotactic partial breast irradiation. A total of 106 of 110 fractions were evaluated for dosimetric changes in target coverage and organ-at-risk (OAR) dose. Patient set up with stereotactic wooden frame and adapted per fraction. Treatment and planning times were collected prospectively by radiation therapists., Results: Scheduled PTV 30 Gy was <95% in 72.1% and <90% in 38.5% of fractions, and both PTV and CTV coverage were improved significantly after adaption, and 83.7% of fractions were delivered as adapted per physician choice. There was no difference in OAR coverage. Average adaptive treatment planning took 15 min and average time-on-couch was 34.4 min., Conclusions: Adaptive stereotactic breast irradiation resulted in improved target coverage with equivalent dosing to OARs in an efficient and tolerated treatment time. Improved target coverage allowed for decreased PTV margins compared to prior trial protocols that may improve acute and late toxicities., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background: Active breathing coordinator (ABC)-assisted deep inspiration breath hold (DIBH) is an important organ sparing radiation therapy (RT) technique for left-sided breast cancer patients. Patients with advanced breast cancer undergoing chest wall and regional nodal irradiation often require a field matching technique. While field matching has been demonstrated to be safe and effective in free breathing patients, its safety and accuracy in DIBH/ABC use has not been previously reported., Purpose: To report the accuracy, feasibility, and safety of field matching with ABC/DIBH for patients receiving breast/chest wall irradiation with nodal irradiation using a three-field technique., Methods: From December 2012 to May 2018, breast cancer patients undergoing ABC/DIBH-based RT at a single institution were reviewed. For each fraction, the amount of overlap/gap between the supraclavicular and the tangential field were measured and recorded. Patient characteristics, including acute and delayed skin toxicities, were analyzed., Results: A total of 202 patients utilized ABC/DIBH and 4973 fractions had gap/overlap measurements available for analysis. The average gap/overlap measured at junction was 0.28 mm ± 0.99 mm. A total of 72% of fractions had no measurable gap/overlap (0 mm), while 5.6% had an overlap and 22.7% a gap. There was no significant trend for worsening or improvement of gap/overlap measurements with increasing fraction number per patient. OSLD measurements were compared to the planned dose. The median dose 1 cm above the junction was 106% ± 7% of planned dose (range 94%-116%). One centimeter below the junction, the median dose was 114% ± 11% of planned dose (range 95%-131%). At the junction, the median dose was 106% ± 16.3% of planned dose (range 86%-131%). Acute skin toxicity was similar to historically reported values (grade 3, 5.4%, grade 4, 0%)., Conclusion: ABC-assisted DIBH is a safe and technically feasible method of delivering RT in the setting of complex matching field technique for breast and regional nodal treatments., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background: Airway gene therapy could produce lasting benefit for cystic fibrosis (CF) lung disease, however patient and public support is critical for successful adoption., Research Design and Methods: Two separate quantitative online surveys were conducted to examine perceptions towards airway gene therapy for CF among people with CF, their families, and members of the public. Data was collected from a total of 213 participants across both studies, with 43 having a diagnosis of CF, 122 having a family member with CF, and 135 knowing someone with CF., Results: Participants in both studies displayed positive perceptions towards gene therapy and were supportive of involvement in CF gene therapy trials. Around 50% hoped gene therapy could provide a cure. In Study 1 gene therapy was the most important research area, but in Study 2 this was new daily drugs. Almost all thought gene therapy was still required even if modulators already improved quality of life., Conclusion: The factors that influence acceptance, whether trials would be positively viewed, and whether individuals with CF are receptive to gene therapy, are essential to determine prior to clinical trials. Our findings indicate people have positive opinions about airway gene therapy for CF, but further education is vital.

Objectives . The purpose of this study is to present data from the clinical commissioning of an Xstrahl 150 x-ray unit used for superficial radiotherapy, Methods . Commissioning tasks included vendor acceptance tests, timer reproducibility, linearity and end-effect measurements, half-value layer (HVL) measurements, inverse square law verification, head-leakage measurements, and beam output calibration. In addition, percent depth dose (PDD) curves were determined for different combinations of filter/kV settings and applicators. Automated PDD water phantom scans were performed utilizing four contemporary detectors: a microDiamond detector, a microSilicon detector, an EDGE detector, and a PinPoint ionization chamber. The measured PDD data were compared to the published values in BJR Supplement 25, Results . The x-ray unit's mechanical, safety, and radiation characteristics were within vendor-stated specifications. Across sixty commissioned x-ray beams, the PDDs determined in water using solid state detectors were in excellent agreement with the BJR 25 data. For the lower (<100 kVp) and medium-energy (≥100 kVp) superficial beams the average agreement was within [-3.6,+0.4]% and [-3.7,+1.4]% range, respectively. For the high-energy superficial (low-energy orthovoltage) x-rays at 150 kVp, the average difference for the largest 20 × 20 cm 2 collimator was (-0.7 ± 1.0)%, Conclusions . This study presents machine characterization data collected for clinical use of a superficial x-ray unit. Special focus was placed on utilizing contemporary detectors and techniques for the relative PDD measurements using a motorized water phantom. The results in this study confirm that the aggregate values published in the BJR 25 report still serve as a valid benchmark when comparing data from site-specific measurements, or the reference data for clinical utilization without such measurements, Advances in knowledge . This paper presents comprehensive data from the acceptance and commissioning of a modern kilovoltage superficial x-ray radiotherapy machine. Comparisons between the PDD data measured in this study using different detectors and BJR 25 data are highlighted., (Creative Commons Attribution license.)

Adequate intake of nutrients such as essential fatty acids (EFA) are critical in cystic fibrosis (CF). The clinical course of deterioration of lung function in people with CF has been shown to relate to nutrition. Independent of the higher energy consumption and malabsorption due to pancreatic insufficiency, EFA deficiency is closely associated with the risk of pulmonary infection, the most significant pathology in CF. This review will focus on the EFA deficiency identified in people with CF, as well as the limited progress made in deciphering the exact metabolic pathways that are dysfunctional in CF. Specifically, people with CF are deficient in linoleic acid, an omega 6 fatty acid, and the ratio of arachidonic acid (omega 6 metabolite) and docosahexaenoic acid (omega 3 metabolite) is increased. Analysis of the molecular pathways in bronchial cells has identified changes in the enzymes that metabolise EFA. However, fatty acid metabolism primarily occurs in the liver, with EFA metabolism in CF liver not yet investigated, indicating that further research is required. Despite limited understanding in this area, it is well known that adequate EFA concentrations are critical to normal membrane structure and function, and thus are important to consider in disease processes. Novel insights into the relationship between CF genotype and EFA phenotype will be discussed, in addition to sex differences in EFA concentrations in people with CF. Collectively, investigating the specific effects of genotype and sex on fatty acid metabolism may provide support for the management of people with CF via personalised genotype- and sex-specific nutritional therapies.

Purpose: To automate the generation of region-of-interest (ROI) apertures for use with megavoltage imaging for online positional corrections during cranial stereotactic radiosurgery., Materials and Methods: Digitally reconstructed radiographs (DRRs) were created for a 3D-printed skull phantom at 5 degree gantry angle increments for a three-arc beam arrangement. At each angle, 3000 random rectangular apertures were generated, and 100 shifts on a grid were applied to the anatomy within the frame. For all shifts, the mutual information (MI) between the shifted and unshifted DRR was calculated to derive an average MI gradient. The top 10% of apertures that minimized registration errors were overlaid and discretely thresholded to generate imaging plans. Imaging was acquired with the skull while implementing simulated patient motion on a linac. Control point-specific couch motions were derived to align the skull to its planned positioning., Results: Apertures with a range of repositioning errors less than 0.1 mm possessed a 42% larger average MI gradient when compared with apertures with a range greater than 1 mm. Dose calculations with Monte Carlo exhibited an 84% reduction in the dose received by 50% of the skull with the 50% thresholded plan when compared to a constant 22 × 22 cm 2 imaging plan. For all different imaging plans (with and without motion), the calculated median 3D-errors with respect to the tracking of a metal-BB fiducial positioned at isocenter in the skull were sub-mm except for the 80% thresholded plan., Conclusions: Sub-mm positional errors are achievable with couch motions derived from control point-specific ROI imaging. Smaller apertures that conform to an anatomical ROI can be utilized to minimize the imaging dose incurred at the expense of larger errors., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Natural airway defenses currently impede the efficacy of viral vector-mediated airway gene therapy. Conditioning airways before vector delivery can disrupt these barriers, improving viral vector access to target receptors and airway stem cells. This study aimed to assess and quantify the in vivo histological and gene transfer effects of physical perturbation devices to identify effective conditioning approaches. A range of flexible wire baskets with varying configurations, a Brush, biopsy forceps, and a balloon catheter were examined. We first evaluated the histological effects of physical perturbation devices in rat tracheas that were excised 10 min after conditioning. Based on the histological findings, a selection of devices was used to condition rat tracheas in vivo before delivering a lentiviral vector containing the LacZ reporter gene. After 7 days, excised tracheas were X-gal processed and examined en face to quantify the area of LacZ staining. Histological observations 10 min after conditioning found that physical perturbation dislodged cells from the basement membrane to varying degrees, with some producing significant levels of epithelial cell removal. When a subset of devices was assessed for their ability to enhance gene transfer, only the NGage ® wire basket (Cook Medical) produced a significant increase in the proportion of X-gal-stained area when compared with unconditioned tracheas (eightfold, p  = 0.00025). These results suggest that a range of factors contribute to perturbation-enhanced gene transfer. Overall, this study supports existing evidence that physical perturbation can assist airway gene transfer and will help to identify the characteristics of an effective device for airway gene therapy.

Background: Malignancies of the head and neck region, encompassing cutaneous, mucosal, and sarcomatous histologies, are complex entities to manage, comprising of coordination between surgery, radiation therapy, and systemic therapy. Malignancies of the posterior scalp are particular challenging to treat with radiation therapy, given its irregular contours and anatomy as well as the superficial location of the target volume. Bolus material is commonly used in radiation therapy to ensure that the dose to the skin and subcutaneous tissue is appropriate and adequate, accounting for the buildup effect of megavoltage photon treatment. The use of commercially available bolus material on the posterior scalp potentially creates air gaps between the bolus and posterior scalp., Case Presentations: In this report, we created and utilized a custom 3D-printed integrated bolus and headrest for 5 patients to irradiate malignancies involving the posterior scalp, including those with cutaneous squamous cell carcinoma, melanoma, malignant peripheral nerve sheath tumor, and dermal sarcoma. Treatment setup was consistently reproducible, and patients tolerated treatment well without any unexpected adverse effects., Conclusions: We found that the use of this custom 3D-printed integrated bolus/headrest allowed for comfortable, consistent, and reproducible treatment set up while minimizing the risk of creating significant air gaps and should be considered in the radiotherapeutic management of patients with posterior scalp malignancies., (© 2022. The Author(s).)

Gene vectors to treat cystic fibrosis lung disease should be targeted to the conducting airways, as peripheral lung transduction does not offer therapeutic benefit. Viral transduction efficiency is directly related to the vector residence time. However, delivered fluids such as gene vectors naturally spread to the alveoli during inspiration, and therapeutic particles of any form are rapidly cleared via mucociliary transit. Extending gene vector residence time within the conducting airways is important, but hard to achieve. Gene vector conjugated magnetic particles that can be guided to the conducting airway surfaces could improve regional targeting. Due to the challenges of in-vivo visualisation, the behaviour of such small magnetic particles on the airway surface in the presence of an applied magnetic field is poorly understood. The aim of this study was to use synchrotron imaging to visualise the in-vivo motion of a range of magnetic particles in the trachea of anaesthetised rats to examine the dynamics and patterns of individual and bulk particle behaviour in-vivo. We also then assessed whether lentiviral-magnetic particle delivery in the presence of a magnetic field increases transduction efficiency in the rat trachea. Synchrotron X-ray imaging revealed the behaviour of magnetic particles in stationary and moving magnetic fields, both in-vitro and in-vivo. Particles could not easily be dragged along the live airway surface with the magnet, but during delivery deposition was focussed within the field of view where the magnetic field was the strongest. Transduction efficiency was also improved six-fold when the lentiviral-magnetic particles were delivered in the presence of a magnetic field. Together these results show that lentiviral-magnetic particles and magnetic fields may be a valuable approach for improving gene vector targeting and increasing transduction levels in the conducting airways in-vivo., (© 2022. The Author(s).)

In 2019, our institution became the second in the world to go live with GammaPod (Xcision Medical Systems, LLC, Columbia, MD), a device dedicated for stereotactic radiation therapy of breast cancer, with breast immobilization, real-time imaging, and highly-conformal dosimetry. At our institution, GammaPod is used for 5-fraction adjuvant partial breast irradiation, single-fraction tumor cavity boost before whole-breast irradiation, single-fraction preoperative radiation, and (in poor surgical candidates), single-fraction definitive radiation. Here, we describe our workflow, observed procedure step times, and homegrown techniques for improved efficiency in our institutional experience of 93 patients treated between 2019 and 2021., (Published by Elsevier Inc.)

Total body irradiation is an important part of the conditioning regimens frequently used to prepare patients for allogeneic hematopoietic stem cell transplantation (SCT). Volumetric-modulated arc therapy enabled total body irradiation (VMAT-TBI), an alternative to conventional TBI (cTBI), is a novel radiotherapy treatment technique that has been implemented and investigated in our institution. The purpose of this study is to (1) report our six-year clinical experience in terms of treatment planning strategy and delivery time and (2) evaluate the clinical outcomes and toxicities in our cohort of patients treated with VMAT-TBI. This is a retrospective single center study. Forty-four patients at our institution received VMAT-TBI and chemotherapy conditioning followed by allogeneic SCT between 2014 and 2020. Thirty-two patients (73%) received standard-dose TBI (12-13.2 Gy in 6-8 fractions twice daily), whereas 12 (27%) received low-dose TBI (2-4 Gy in one fraction). Treatment planning, delivery, and treatment outcome data including overall survival (OS), relapse-free survival (RFS), and toxicities were analyzed. The developed VMAT-TBI planning strategy consistently generated plans satisfying our dose constraints, with planning target volume coverage >90%, mean lung dose ∼50% to 75% of prescription dose, and minimal hotspots in critical organs. Most of the treatment deliveries were <100 minutes (range 33-147, mean 72). The median follow-up was 26 months. At the last follow-up, 34 of 44 (77%) of patients were alive, with 1- and 2-year OS of 90% and 79% and RFS of 88% and 71%, respectively. The most common grade 3+ toxicities observed were mucositis (31 patients [71%]) and nephrotoxicity (6 patients [13%]), both of which were deemed multifactorial in cause. Four patients (9%) in standard-dose cohort developed grade 3+ pneumonitis, with 3 cases in the setting of documented respiratory infection and only 1 (2%) deemed likely related to radiation alone. VMAT-TBI provides a safe alternative to cTBI. The dose modulation capability of VMAT-TBI may lead to new treatment strategies, such as simultaneous boost and further critical organ sparing, for better malignant cell eradication, immune suppression, and lower toxicities., (Published by Elsevier Inc.)

Background: Administering allergens in increasing doses can temporarily suppress IgE-mediated allergy and anaphylaxis by desensitizing mast cells and basophils; however, allergen administration during desensitization therapy can itself induce allergic responses. Several small molecule drugs and nutraceuticals have been used clinically and experimentally to suppress these allergic responses., Objectives: This study sought to optimize drug inhibition of IgE-mediated anaphylaxis., Methods: Several agents were tested individually and in combination for ability to suppress IgE-mediated anaphylaxis in conventional mice, FcεRIα-humanized mice, and reconstituted immunodeficient mice that have human mast cells and basophils. Hypothermia was the readout for anaphylaxis; therapeutic efficacy was measured by degree of inhibition of hypothermia. Serum mouse mast cell protease 1 level was used to measure extent of mast cell degranulation., Results: Histamine receptor 1 (HR1) antagonists, β-adrenergic agonists, and a spleen tyrosine kinase (Syk) inhibitor were best at individually inhibiting IgE-mediated anaphylaxis. A Bruton's tyrosine kinase (BTK) inhibitor, administered alone, only inhibited hypothermia when FcεRI signaling was suboptimal. Combinations of these agents could completely or nearly completely inhibit IgE-mediated hypothermia in these models. Both Syk and BTK inhibition decreased mast cell degranulation, but only Syk inhibition also blocked desensitization. Many other agents that are used clinically and experimentally had little or no beneficial effect., Conclusions: Combinations of an HR1 antagonist, a β-adrenergic agonist, and a Syk or a BTK inhibitor protect best against IgE-mediated anaphylaxis, while an HR1 antagonist plus a β-adrenergic agonist ± a BTK antagonist is optimal for inhibiting IgE-mediated anaphylaxis without suppressing desensitization., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Essential fatty acid deficiency has been observed in most patients with Cystic Fibrosis (CF); however, pancreatic supplementation does not restore the deficiency, suggesting a different pathology independent of the pancreas. At this time, the underlying pathological mechanisms are largely unknown. Essential fatty acids are obtained from the diet and processed by organs including the liver and intestine, two organs significantly impacted by mutations in the cystic fibrosis transmembrane conductance regulator gene (Cftr). There are several CF animal models in a variety of species that have been developed to investigate molecular mechanisms associated with the CF phenotype. Specifically, global and systemic mutations in Cftr which mimic genotypic changes identified in CF patients have been generated in mice, rats, sheep, pigs and ferrets. These mutations produce CFTR proteins with a gating defect, trafficking defect, or an absent or inactive CFTR channel. Essential fatty acids are critical to CFTR function, with a bidirectional relationship between CFTR and essential fatty acids proposed. Currently, there are limited analyses on the essential fatty acid status in most of these animal models. Of interest, in the mouse model, essential fatty acid status is dependent on the genotype and resultant phenotype of the mouse. Future investigations should identify an optimal animal model that has most of the phenotypic changes associated with CF including the essential fatty acid deficiencies, which can be used in the development of therapeutics., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)