Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22.

Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. Changing CD28- to CD8-transmembrane design increased CAR persistence and expression in vitro. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansion in vitro, although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic.

Extended ischemic time (>15 hours) using controlled hypothermic storage in lung transplantation: A multicenter experience.

Static ice storage has long been the standard-of-care for lung preservation, although freezing injury limits ischemic time (IT). Controlled hypothermic storage (CHS) at elevated temperature could safely extend IT. This retrospective analysis assesses feasibility and safety of CHS with IT > 15 hours. Three lung transplant (LuTx) centers (April-October 2023) included demographics, storage details, IT, and short-term outcome from 13 LuTx recipients (8 male, 59 years old). Donor lungs were preserved in a portable CHS device at 7 (5-9.3)°C. Indication was overnight bridging and/or long-distance transport. IT of second-implanted lung was 17.3 (15.1-22) hours. LuTx were successful, 4/13 exhibited primary graft dysfunction grade 3 within 72 hours and 0/13 at 72 hours. Post-LuTx mechanical ventilation was 29 (7-442) hours. Intensive care unit stay was 9 (5-28) and hospital stay 30 (16-90) days. Four patients needed postoperative extracorporeal membrane oxygenation (ECMO). One patient died (day 7) following malpositioning of an ECMO cannula. This multicenter experience demonstrates the possibility of safely extending IT > 15 hours by CHS.

Experimental determination of magnetic field quality conversion factors for eleven ionization chambers in 1.5 T and 0.35 T MR-linac systems.

BACKGROUND: The static magnetic field present in magnetic resonance (MR)-guided radiotherapy systems can influence dose deposition and charged particle collection in air-filled ionization chambers. Thus, accurately quantifying the effect of the magnetic field on ionization chamber response is critical for output calibration. Formalisms for reference dosimetry in a magnetic field have been proposed, whereby a magnetic field quality conversion factor kB,Q is defined to account for the combined effects of the magnetic field on the radiation detector. Determination of kB,Q in the literature has focused on Monte Carlo simulation studies, with experimental validation limited to only a few ionization chamber models. PURPOSE: The purpose of this study is to experimentally measure kB,Q for 11 ionization chamber models in two commercially available MR-guided radiotherapy systems: Elekta Unity and ViewRay MRIdian. METHODS: Eleven ionization chamber models were characterized in this study: Exradin A12, A12S, A28, and A26, PTW T31010, T31021, and T31022, and IBA FC23-C, CC25, CC13, and CC08. The experimental method to measure kB,Q utilized cross-calibration against a reference Exradin A1SL chamber. Absorbed dose to water was measured for the reference A1SL chamber positioned parallel to the magnetic field with its centroid placed at the machine isocenter at a depth of 10 cm in water for a 10 × 10 cm2 field size at that depth. Output was subsequently measured with the test chamber at the same point of measurement. kB,Q for the test chamber was computed as the ratio of reference dose to test chamber output, with this procedure repeated for each chamber in each MR-guided radiotherapy system. For the high-field 1.5 T Elekta Unity system, the dependence of kB,Q on the chamber orientation relative to the magnetic field was quantified by rotating the chamber about the machine isocenter. RESULTS: Measured kB,Q values for our test dataset of ionization chamber models ranged from 0.991 to 1.002, and 0.995 to 1.004 for the Elekta Unity and ViewRay MRIdian, respectively, with kB,Q tending to increase as the chamber sensitive volume increased. Measured kB,Q values largely agreed within uncertainty to published Monte Carlo simulation data and available experimental data. kB,Q deviation from unity was minimized for ionization chamber orientation parallel or antiparallel to the magnetic field, with increased deviations observed at perpendicular orientations. Overall (k = 1) uncertainty in the experimental determination of the magnetic field quality conversion factor, kB,Q was 0.71% and 0.72% for the Elekta Unity and ViewRay MRIdian systems, respectively. CONCLUSIONS: For a high-field MR-linac, the characterization of ionization chamber performance as angular orientation varied relative to the magnetic field confirmed that the ideal orientation for output calibration is parallel. For most of these chamber models, this study represents the first experimental characterization of chamber performance in clinical MR-linac beams. This is a critical step toward accurate output calibration for MR-guided radiotherapy systems and the measured kB,Q values will be an important reference data source for forthcoming MR-linac reference dosimetry protocols.

Technical note: The migration distance - a unidirectional distance metric for region-of-interest comparisons.

BACKGROUND: The radiotherapy process relies on several metrics in determining a notion of "distance" from one three-dimensional region-of-interest (ROI) to another. The majority are symmetric (or commutative) and do not contain information pertaining to directionality. Growth versus regression, for example, is not inherently distinguished by these metrics. PURPOSE: The purpose of this work was to formalize a unidirectional distance metric, motivated by radiotherapy margin concepts, which we term the migration distance. Informally, the migration distance from ROI X to Y is the minimum isotropic expansion of X such that Y is completely encompassed by the expansion. If Y is contained within X, the migration distance is negative with magnitude equal to the maximum isotropic contraction of X such that Y remains contained within contraction. The metric is demonstrated by quantifying glioblastoma interfraction target changes. METHODS: An explicit mathematical formulation of the migration distance is presented and contrasted with the related Hausdorff distance. The results are demonstrated for the gross tumor volume (GTV) dynamics of a glioblastoma cohort consisting of 111 patients that underwent standard chemoradiotherapy with offline MR imaging at planning, fraction 10, fraction 20, and 1-month post radiotherapy. RESULTS: The mean ± SD of the GTV migration distance relative to planning was 5.9 ± 3.9 mm at fraction 10, 6.2 ± 4.4 mm at fraction 20, and 7.9 ± 7.1 mm at 1-month post radiotherapy. The maximum GTV migration distance across all patients at the same timepoints was 20.4, 20.7, and 45.5 mm, respectively. CONCLUSIONS: We have proposed and demonstrated a unidirectional distance metric. The migration distance may have applications in the quantification of anatomical changes, planning target volume designs, and dosimetric radiotherapy plan assessment.

A simple Monte Carlo method for estimating power in multilevel designs.

Estimating power for multilevel models is complex because there are many moving parts, several sources of variation to consider, and unique sample sizes at Level 1 and Level 2. Monte Carlo computer simulation is a flexible tool that has received considerable attention in the literature. However, much of the work to date has focused on very simple models with one predictor at each level and one cross-level interaction effect, and approaches that do not share this limitation require users to specify a large set of population parameters. The goal of this tutorial is to describe a flexible Monte Carlo approach that accommodates a broad class of multilevel regression models with continuous outcomes. Our tutorial makes three important contributions. First, it allows any number of within-cluster effects, between-cluster effects, covariate effects at either level, cross-level interactions, and random coefficients. Moreover, we do not assume orthogonal effects, and predictors can correlate at either level. Second, our approach accommodates models with multiple interaction effects, and it does so with exact expressions for the variances and covariances of product random variables. Finally, our strategy for deriving hypothetical population parameters does not require pilot or comparable data. Instead, we use intuitive variance-explained effect size expressions to reverse-engineer solutions for the regression coefficients and variance components. We describe a new R package mlmpower that computes these solutions and automates the process of generating artificial data sets and summarizing the simulation results. The online supplemental materials provide detailed vignettes that annotate the R scripts and resulting output. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Comparing DIC and WAIC for multilevel models with missing data.

In Bayesian statistics, the most widely used criteria of Bayesian model assessment and comparison are Deviance Information Criterion (DIC) and Watanabe-Akaike Information Criterion (WAIC). We use a multilevel mediation model as an illustrative example to compare different types of DIC and WAIC. More specifically, we aim to compare the performance of conditional and marginal DICs and WAICs, and investigate their performance with missing data. We focus on two versions of DIC ([Formula: see text] and [Formula: see text]) and one version of WAIC. In addition, we explore whether it is necessary to include the nuisance models of incomplete exogenous variables in likelihood. Based on the simulation results, whether [Formula: see text] is better than [Formula: see text] and WAIC and whether we should include the nuisance models of exogenous variables in likelihood functions depend on whether we use marginal or conditional likelihoods. Overall, we find that the marginal likelihood based-[Formula: see text] that excludes the likelihood of covariate models generally had the highest true model selection rates.

Noncanonical mechanism of Nrf2 activation by diacylglycerol polyethylene glycol adducts in normal human epidermal keratinocytes.

Polyethylene glycol-23 glyceryl distearate (GDS-23), a diacylglycerol polyethylene glycol adduct, forms niosomes with a liposome-like structure and functions as an active ingredient in drug delivery systems. In addition, it upregulates antioxidant proteins such as heme oxygenase 1 and NAD(P)H-quinone dehydrogenase 1 in cells. However, the activation of nuclear factor E2-related factor-2 (Nrf2), which plays a role in inducing the expression of antioxidant proteins, and its protective effects induced by GDS-23 treatment against oxidative stress have not been elucidated. This study aimed at verifying the activation of Nrf2 by GDS-23 and clarifying its underlying mechanisms, and investigated whether GDS-23 protects against hydroquinone-induced cytotoxicity. Normal human epidermal keratinocytes were treated with GDS-23. Real-time reverse transcription-polymerase chain reaction, western blotting, and immunostaining were used to investigate the mechanism of Nrf2 activation, and neutral red assay was performed to evaluate cytotoxicity. GDS-23-treated cells showed an increase in antioxidant protein levels and stabilization of Nrf2 in the nucleus. During Nrf2 activation, p62, an autophagy-related adaptor protein, was phosphorylated at Ser349. Inhibition of the interaction between the phosphorylated p62 and Kelch-like ECH-associated protein 1 significantly suppressed the GDS-23-mediated induction of antioxidant protein expression. In addition, hydroquinone-induced cell toxicity was significantly attenuated by GDS-23. GDS-23 induced the intracellular antioxidant system by activating Nrf2 in a p62 phosphorylation-dependent manner without generating oxidative stress in the cells. GDS-23 may be applied as a multifunctional material for drug delivery system that enhances internal antioxidant systems.

Quantifying uncertainties associated with reference dosimetry in an MR-Linac.

BACKGROUND: Magnetic resonance (MR)-guided radiation therapy provides capabilities to utilize high-resolution and real-time MR imaging before and during treatment, which is critical for adaptive radiotherapy. This emerging modality has been promptly adopted in the clinic settings in advance of adaptations to reference dosimetry formalism that are needed to account for the presence of strong magnetic fields. In particular, the influence of magnetic field on the uncertainty of parameters in the reference dosimetry equation needs to be determined in order to fully characterize the uncertainty budget for reference dosimetry in MR-guided radiation therapy systems. PURPOSE: To identify and quantify key sources of uncertainty in the reference dosimetry of external high energy radiotherapy beams in the presence of a strong magnetic field. METHODS: In the absence of a formalized Task Group report for reference dosimetry in MR-integrated linacs, the currently suggested formalism follows the TG-51 protocol with the addition of a quality conversion factor kBQ accounting for the effects of the magnetic field on ionization chamber response. In this work, we quantify various sources of uncertainty that impact each of the parameters in the formalism, and evaluate their overall contribution to the final dose. Measurements are done in a 1.5 T MR-Linac (Unity, Elekta AB, Stockholm, Sweden) which integrates a 1.5 T Philips MR scanner and a 7 MVFFF linac. The responses of several reference-class small volume ionization chambers (Exradin:A1SL, IBA:CC13, PTW:Semiflex-3D) and Farmer type ionization chambers (Exradin:A19, IBA:FC65-G) were evaluated throughout this process. Long-term reproducibility and stability of beam quality, TPR 10 20 ${\mathrm{TPR}}_{10}^{20}$ , was also measured with an in-house built phantom. RESULTS: Relative to the conventional external high energy linacs, the uncertainty on overall reference dose in MR-linac is more significantly affected by the chamber setup: A translational displacement along y-axis of ± 3 mm results in dose variation of < |0.20| ± 0.02% (k = 1), while rotation of ± 5° in horizontal and vertical parallel planes relative to relative to the direction of magnetic field, did not exceed variation of < |0.44| ± 0.02% for all 5 ionization chambers. We measured a larger dose variation for xy-plane (horizontal) rotations (< |0.44| ± 0.02% (k = 1)) than for yz-plane (vertical) rotations (< ||0.28| ± 0.02% (k = 1)), which we associate with the gradient of kB,Q as a function of chamber orientation with respect to direction of the B0 -field. Uncertainty in Pion (for two depths), Ppol (with various sub-studies including effects of cable length, cable looping in the MRgRT bore, connector type in magnetic environment), and Prp were determined. Combined conversion factor kQ × kB,Q was provided for two reference depths at four cardinal angle orientations. Over a two-year period, beam quality was quite stable with TPR 10 20 ${\mathrm{TPR}}_{10}^{20}$ being 0.669 ± 0.01%. The actual magnitude of TPR 10 20 ${\mathrm{TPR}}_{10}^{20}$ was measured using identical equipment and compared between two different Elekta Unity MR-Linacs with results agreeing to within 0.21%. CONCLUSION: In this work, the uncertainty of a number of parameters influencing reference dosimetry was quantified. The results of this work can be used to identify best practice guidelines for reference dosimetry in the presence of magnetic fields, and to evaluate an uncertainty budget for future reference dosimetry protocols for MR-linac.

A factored regression model for composite scores with item-level missing data.

Composite scores are an exceptionally important psychometric tool for behavioral science research applications. A prototypical example occurs with self-report data, where researchers routinely use questionnaires with multiple items that tap into different features of a target construct. Item-level missing data are endemic to composite score applications. Many studies have investigated this issue, and the near-universal theme is that item-level missing data treatment is superior because it maximizes precision and power. However, item-level missing data handling can be challenging because missing data models become very complex and suffer from the same "curse of dimensionality" problem that plagues the estimation of psychometric models. A good deal of recent missing data literature has focused on advancing factored regression specifications that use a sequence of regression models to represent the multivariate distribution of a set of incomplete variables. The purpose of this paper is to describe and evaluate a factored specification for composite scores with incomplete item responses. We used a series of computer simulations to compare the proposed approach to gold standard multiple imputation and latent variable modeling approaches. Overall, the simulation results suggest that this new approach can be very effective, even under extreme conditions where the number of items is very large (or even exceeds) the sample size. A real data analysis illustrates the application of the method using software available on the internet. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Reduced Community-acquired Respiratory Virus Infection, but Not Non-virus Infection, in Lung Transplant Recipients During Government-mandated Public Health Measures to Reduce COVID-19 Transmission.

Community-acquired respiratory viruses (CARVs) are an important cause of morbidity and mortality in lung transplant (LTx) recipients. Despite routine mask-wearing, LTx patients remain at a higher risk of CARV infection than the general population. In 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 and a novel CARV, emerged leading federal and state officials to implement public health nonpharmaceutical interventions (NPIs) to curb its spread. We hypothesized that NPI would be associated with the reduced spread of traditional CARVs. Methods: A single-center, retrospective cohort analysis comparing CARV infection before a statewide stay-at-home order, during the stay-at-home order and subsequent statewide mask mandate, and during 5 mo following the elimination of NPI was performed. All LTx recipients followed by and tested at our center were included. Data (multiplex respiratory viral panels; SARS-CoV-2 reverse transcription polymerase chain reaction; blood cytomegalovirus and Epstein Barr virus polymerase chain reaction; blood and bronchoalveolar lavage bacterial and fungal cultures) were collected from the medical record. Chi-square or Fisher exact tests were utilized for categorical variables. A mixed-effect model was used for continuous variables. Results: Incidence of non-COVID CARV infection was significantly lower during the MASK period than during the PRE period. No difference was noted in airway or bloodstream bacterial or fungal infections, but cytomegalovirus bloodborne viral infections increased. Conclusions: Reductions in respiratory viral infections, but not bloodborne viral infections nor nonviral respiratory, bloodborne, or urinary infections, were observed in the setting of public health COVID-19 mitigation strategies, suggesting the effectiveness of NPI in preventing general respiratory virus transmission.

An Investigation of Factored Regression Missing Data Methods for Multilevel Models with Cross-Level Interactions.

A growing body of literature has focused on missing data methods that factorize the joint distribution into a part representing the analysis model of interest and a part representing the distributions of the incomplete predictors. Relatively little is known about the utility of this method for multilevel models with interactive effects. This study presents a series of Monte Carlo computer simulations that investigates Bayesian and multiple imputation strategies based on factored regressions. When the model's distributional assumptions are satisfied, these methods generally produce nearly unbiased estimates and good coverage, with few exceptions. Severe misspecifications that arise from substantially non-normal distributions can introduce biased estimates and poor coverage. Follow-up simulations suggest that a Yeo-Johnson transformation can mitigate these biases. A real data example illustrates the methodology, and the paper suggests several avenues for future research.

Empirical planning target volume modeling for high precision MRI guided intracranial radiotherapy.

Purpose: Magnetic resonance image-guided radiotherapy for intracranial indications is a promising advance; however, uncertainties remain for both target localization after translation-only MR setup and intrafraction motion. This investigation quantified these uncertainties and developed a population-based planning target volume (PTV) model to explore target and organ-at-risk (OAR) volumetric coverage tradeoffs. Methods: Sixty-six patients, 49 with a primary brain tumor and 17 with a post-surgical resection cavity, treated on a 1.5T-based MR-linac across 1329 fractions were included. At each fraction, patients were setup by translation-only fusion of the online T1 MRI to the planning image. Each fusion was independently repeated offline accounting for rotations. The six degree-of-freedom difference between fusions was applied to transform the planning CTV at each fraction (CTVfx). A PTV model parameterized by volumetric CTVfx coverage, proportion of fractions, and proportion of patients was developed. Intrafraction motion was quantified in a 412 fraction subset as the fusion difference between post- and pre-irradiation T1 MRIs. Results: For the left-right/anterior-posterior/superior-inferior axes, mean ± SD of the rotational fusion differences were 0.1 ± 0.8/0.1 ± 0.8/-0.2 ± 0.9°. Covering 98 % of the CTVfx in 95 % of fractions in 95 % of patients required a 3 mm PTV margin. Margin reduction decreased PTV-OAR overlap; for example, the proportion of optic chiasm overlapped by the PTV was reduced up to 23.5 % by margin reduction from 4 mm to 3 mm. Conclusions: An evidence-based PTV model was developed for brain cancer patients treated on the MR-linac. Informed by this model, we have clinically adopted a 3 mm PTV margin for conventionally fractionated intracranial patients.

Donor and Recipient Hepatitis C Status Does Not Affect Rejection in Thoracic Transplantation.

BACKGROUND: Donors with hepatitis C virus (HCV) have expanded the donor pool for heart and lung transplantation, but concerns have arisen about rejection. We examined the incidence of rejection after heart and lung transplantation in recipients of HCV-positive donors as well as HCV-positive recipients. METHODS: Adults undergoing heart and lung transplantation from March 31, 2015 to December 31, 2019 were identified in the United Network for Organ Sharing/Organ Transplantation and Procurement Network Standard Transplant Analysis and Research file. Patients were stratified as donor-recipient HCV negative, donor positive, and recipient positive. Comparative statistics and a multilevel logistic regression model were used. RESULTS: Meeting the criteria were 10 624 heart transplant recipients. Donor-positive recipients were significantly associated with older age, blood group O, and shorter waitlist time. No significant differences existed with regards to treatment for rejection in the first year (negative, 19.5%; donor positive, 22.3%; recipient positive, 19.5%; P = .45) or other outcomes. On regression analysis HCV status was not associated with treated rejection; however center variability was significantly associated with treated rejection (median odds ratio, 2.18). Similarly, 9917 lung transplant recipients were identified. Donor-positive recipients were more commonly White and had obstructive disease and lower lung allocation scores. Both unadjusted (negative, 22.1%; donor positive, 23.0%; recipient positive, 18.6%; P = .43) and adjusted analyses failed to demonstrate a significant association between HCV status and treatment for rejection, whereas center variability remained significantly associated with treatment for rejection (median odds ratio, 2.41). CONCLUSIONS: Use of HCV donors has expanded the donor pool for heart and lung transplantation. HCV donor status was not associated with treatment for rejection in the first year, but center variability played a role in the incidence and treatment of rejection.

Thoracic retransplantation: Does time to retransplantation matter?

OBJECTIVE: For some individuals, chronic allograft failure is best treated with retransplantation. We sought to determine if time to retransplantation impacts short- and long-term outcomes for heart or lung retransplant recipients with a time to retransplantation more than 1 year. METHODS: The United Network for Organ Sharing/Organ Procurement and Transplantation Network STAR file was queried for all adult, first-time heart (June 1, 2006, to September 30, 2020) and lung (May 1, 2005, to September 30, 2020) retransplantations with a time to retransplantation of at least 1 year. Patients were grouped according to the tertile of time to retransplantation (tertile 1: 1-7.7 years, tertile 2: 7.7-14.7 years, tertile 3: 14.7+ years; lung: tertile 1: 1-2.8 years, tertile 2: 2.8-5.6 years, tertile 3: 5.6+ years). The primary outcome was survival after retransplantation. Comparative statistics identified differences in groups, and Kaplan-Meier methods and a Cox proportional hazard model were used for survival analysis. RESULTS: After selection, 908 heart and 871 lung retransplants were identified. Among heart retransplant recipients, tertile 1 was associated with male sex, smoking history, higher listing status, and increased mechanical support pretransplant. Tertile 3 had the highest rate of concomitant kidney transplant; however, the incidence of morbidity and in-hospital mortality was similar among the groups. Unadjusted and adjusted analyses revealed no survival difference among all groups. Regarding lung retransplant recipients, tertile 1 was associated with increased lung allocation score, pretransplant hospitalization, and mechanical support. Unadjusted and adjusted survival analyses revealed decreased survival in tertile 1. CONCLUSIONS: Time to retransplant does not appear to affect heart recipients with a time to retransplantation of more than 1 year; however, shorter time to retransplantation for prior lung recipients is associated with decreased survival. Potential lung retransplant candidates with a time to retransplantation of less than 2.8 years should be carefully evaluated before retransplantation.

Molecular Pathogenesis of Penile Squamous Cell Carcinoma: Current Understanding and Potential Treatment Implications.

CONTEXT.­: Penile squamous cell carcinomas (PSCCs) are divided into tumors that are human papillomavirus (HPV) associated and those that are non-HPV associated. HPV and non-HPV PSCCs each display unique pathogenic mechanisms, histologic subtypes, and clinical behaviors. Treatment of localized PSCC tumors is linked to significant physical and psychological morbidity, and management of advanced disease is often treatment refractory. The identification of novel actionable mutations is of critical importance so that translational scientists and clinicians alike can pursue additional therapeutic options. OBJECTIVE.­: To provide an update on the molecular pathogenesis associated with PSCC. A special emphasis is placed on next-generation sequencing data and its role in identifying potential therapeutic targets. DATA SOURCES.­: A literature review using the PubMed search engine to access peer-reviewed literature published on PSCC. CONCLUSIONS.­: Our understanding of the genetic and molecular mechanisms that underlie PSCC pathogenesis continues to evolve. PSCC tumorigenesis is mediated by multiple pathways, and mutations of oncogenic significance have been identified that may represent targets for personalized therapy. Preliminary results of treatment with immune checkpoint inhibition and tyrosine kinase inhibitors have produced variable clinical results. Further insight into the pathogenesis of PSCC will help guide clinical trials and develop additional precision medicine approaches.

High grade glioma radiation therapy on a high field 1.5 Tesla MR-Linac - workflow and initial experience with daily adapt-to-position (ATP) MR guidance: A first report.

Purpose: This study reports the workflow and initial clinical experience of high grade glioma (HGG) radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow. Materials and methods: Ten HGG patients treated with radiation within the first year of the MRL's clinical operation, between October 2019 and August 2020, were identified from a prospective database. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the relative FHR volumes (n = 281 contours) and migration distances (maximum linear displacement of the volume). Research mpMRIs were acquired on the MRL during radiation and changes in selected functional parameters were investigated within the FHR. Results: All patients completed radiotherapy to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction with or without post-beam research imaging was 42.9 minutes (range, 25.0-69.0 minutes) and 37.3 minutes (range, 24.0-51.0 minutes), respectively. Three patients (30%) required re-planning between fractions 9 to 12 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30-day post-first fraction time points 3, 3, and 4 patients, respectively, had a FHR volume that changed by at least 20% relative to the first fraction. Research mpMRIs were successfully acquired on the MRL. The median apparent diffusion coefficient (ADC) within the FHR and the volumes of FLAIR were significantly correlated when data from all patients and time points were pooled (R=0.68, p<.001). Conclusion: We report the first clinical series of HGG patients treated with radiotherapy on the MRL. The ATP workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of mpMRIs was feasible on the MRL during routine treatment workflow. Prospective clinical outcomes data is anticipated from the ongoing UNITED phase 2 trial to further refine the role of MR-guided adaptive radiotherapy.

Comparison of Prospectively Generated Glioma Treatment Plans Clinically Delivered on Magnetic Resonance Imaging (MRI)-Linear Accelerator (MR-Linac) Versus Conventional Linac: Predicted and Measured Skin Dose.

Introduction: Magnetic resonance imaging-linear accelerator radiotherapy is an innovative technology that requires special consideration for secondary electron interactions within the magnetic field, which can alter dose deposition at air-tissue interfaces. As part of ongoing quality assurance and quality improvement of new radiotherapy technologies, the purpose of this study was to evaluate skin dose modelled from the treatment planning systems of a magnetic resonance imaging-linear accelerator and a conventional linear accelerator, and then correlate with in vivo measurements of delivered skin dose from each linear accelerator. Methods: In this prospective cohort study, 37 consecutive glioma patients had treatment planning completed and approved prior to radiotherapy initiation using commercial treatment planning systems: a Monte Carlo-based algorithm for magnetic resonance imaging-linear accelerator or a convolution-based algorithm for conventional linear accelerator. In vivo skin dose was measured using an optically stimulated luminescent dosimeter. Results: Monte Carlo-based magnetic resonance imaging-linear accelerator plans and convolution-based conventional linear accelerator plans had similar dosimetric parameters for target volumes and organs-at-risk. However, magnetic resonance imaging-linear accelerator plans had 1.52 Gy higher mean dose to air cavities (P < .0001) and 1.10 Gy higher mean dose to skin (P < .0001). In vivo skin dose was 14.5% greater for magnetic resonance imaging-linear accelerator treatments (P = .0027), and was more accurately predicted by Monte Carlo-based calculation (ρ = 0.95, P < .0001) versus convolution-based (ρ = 0.80, P = .0096). Conclusion: This is the first prospective dosimetric comparison of glioma patients clinically treated on both magnetic resonance imaging-linear accelerator and conventional linear accelerator. Our findings suggest that skin doses were significantly greater with magnetic resonance imaging-linear accelerator plans but correlated better with in vivo measurements of actual skin dose from delivered treatments. Future magnetic resonance imaging-linear accelerator planning processes are being designed to account for skin dosimetry and treatment delivery.

Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy.

Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or "cancer-killing" viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.

Trends in Donation After Circulatory Death in Lung Transplantation in the United States: Impact Of Era.

Background: Use of lungs donated after circulatory death (DCD) has expanded, but changes in donor/recipient characteristics and comparison to brain dead donors (DBD) has not been studied. We examined the evolution of the use of DCD lungs for transplantation and compare outcomes to DBD lungs. Methods: The SRTR database was used to construct three 5-year intervals. Perioperative variables and survival were compared by era and for DCD vs. DBD. Geographic variation was estimated using recipient permanent address. Results: 728 DCD and 27,205 DBD lung transplants were identified. DCD volume increased from Era 1 (n = 73) to Era 3 (n = 528), representing 1.1% and 4.2% of lung transplants. Proportionally more DCD recipients were in ICU or on ECMO pre-transplant, and had shorter waitlist times. DCD donors were older, had lower PaO2/FiO2 ratios compared to DBD, more likely to be bilateral, had longer ischemic time, length of stay, post-op dialysis, and increased use of lung perfusion. There was no difference in overall survival. Geographically, use was heterogeneous. Conclusion: DCD utilization is low but increasing. Despite increasing ischemic time and transplantation into sicker patients, survival is similar, which supports further DCD use in lung transplantation. DCD lung transplantation presents an opportunity to continue to expand the donor pool.