SuPAR, biomarkers of inflammation, and severe outcomes in patients hospitalized for COVID-19: The International Study of Inflammation in COVID-19.

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19.

Revisiting fetal dose during radiation therapy: evaluating treatment techniques and a custom shield.

To create a comprehensive dataset of peripheral dose (PD) measurements from a new generation of linear accelerators with and without the presence of a newly designed fetal shield, PD measurements were performed to evaluate the effects of depth, field size, distance from the field edge, collimator angle, and beam modi-fiers for common treatment protocols and modalities. A custom fetal lead shield was designed and made for our department that allows external beam treatments from multiple angles while minimizing the need to adjust the shield during patient treatments. PD measurements were acquired for a comprehensive series of static fields on a stack of Solid Water. Additionally, PDs from various clinically relevant treatment scenarios for pregnant patients were measured using an anthropomorphic phantom that was abutted to a stack of Solid Water. As expected, the PD decreased as the distance from the field edge increased and the field size decreased. On aver-age, a PD reduction was observed when a 90° collimator rotation was applied and/or when the tertiary MLCs and jaws defined the field aperture. However, the effect of the collimator rotation (90° versus 0°) in PD reduction was not found to be clini-cally significant when the tertiary MLCs were used to define the field aperture. In the presence of both the MLCs and the fetal shield, the PD was reduced by 58% at a distance of 10 cm from the field edge. The newly designed fetal shield may effectively reduce fetal dose and is relatively easy to setup. Due to its design, we are able to use a broad range of treatment techniques and beam angles. We believe the acquired comprehensive PD dataset collected with and without the fetal shield will be useful for treatment teams to estimate fetal dose and help guide decisions on treat-ment techniques without the need to perform pretreatment phantom measurements.

Dosimetric measurements of Onyx embolization material for stereotactic radiosurgery.

PURPOSE: Arteriovenous malformations are often treated with a combination of embolization and stereotactic radiosurgery. Concern has been expressed in the past regarding the dosimetric properties of materials used in embolization and the effects that the introduction of these materials into the brain may have on the quality of the radiosurgery plan. To quantify these effects, the authors have taken large volumes of Onyx 34 and Onyx 18 (ethylene-vinyl alcohol copolymer doped with tantalum) and measured the attenuation and interface effects of these embolization materials. METHODS: The manufacturer provided large cured volumes (∼28 cc) of both Onyx materials. These samples were 8.5 cm in diameter with a nominal thickness of 5 mm. The samples were placed on a block tray above a stack of solid water with an Attix chamber at a depth of 5 cm within the stack. The Attix chamber was used to measure the attenuation. These measurements were made for both 6 and 16 MV beams. Placing the sample directly on the solid water stack and varying the thickness of solid water between the sample and the Attix chamber measured the interface effects. The computed tomography (CT) numbers for bulk material were measured in a phantom using a wide bore CT scanner. RESULTS: The transmission through the Onyx materials relative to solid water was approximately 98% and 97% for 16 and 6 MV beams, respectively. The interface effect shows an enhancement of approximately 2% and 1% downstream for 16 and 6 MV beams. CT numbers of approximately 2600-3000 were measured for both materials, which corresponded to an apparent relative electron density (RED) ρ(e) (w) to water of approximately 2.7-2.9 if calculated from the commissioning data of the CT scanner. CONCLUSIONS: We performed direct measurements of attenuation and interface effects of Onyx 34 and Onyx 18 embolization materials with large samples. The introduction of embolization materials affects the dose distribution of a MV therapeutic beam, but should be of negligible consequence for effective thicknesses of less than 8 mm. The measured interface effects are also small, particularly at 6 MV. Large areas of high-density artifacts and low-density artifacts can cause errors in dose calculations and need to be identified and resolved during planning.

Penalization of aperture complexity in inversely planned volumetric modulated arc therapy.

PURPOSE: Apertures obtained during volumetric modulated arc therapy (VMAT) planning can be small and irregular, resulting in dosimetric inaccuracies during delivery. Our purpose is to develop and integrate an aperture-regularization objective function into the optimization process for VMAT, and to quantify the impact of using this objective function on dose delivery accuracy and optimized dose distributions. METHODS: An aperture-based metric ("edge penalty") was developed that penalizes complex aperture shapes based on the ratio of MLC side edge length and aperture area. To assess the utility of the metric, VMAT plans were created for example paraspinal, brain, and liver SBRT cases with and without incorporating the edge penalty in the cost function. To investigate the dose calculation accuracy, Gafchromic EBT2 film was used to measure the 15 highest weighted apertures individually and as a composite from each of two paraspinal plans: one with and one without the edge penalty applied. Films were analyzed using a triple-channel nonuniformity correction and measurements were compared directly to calculations. RESULTS: Apertures generated with the edge penalty were larger, more regularly shaped and required up to 30% fewer monitor units than those created without the edge penalty. Dose volume histogram analysis showed that the changes in doses to targets, organs at risk, and normal tissues were negligible. Edge penalty apertures that were measured with film for the paraspinal plan showed a notable decrease in the number of pixels disagreeing with calculation by more than 10%. For a 5% dose passing criterion, the number of pixels passing in the composite dose distributions for the non-edge penalty and edge penalty plans were 52% and 96%, respectively. Employing gamma with 3% dose/1 mm distance criteria resulted in a 79.5% (without penalty)/95.4% (with penalty) pass rate for the two plans. Gradient compensation of 3%/1 mm resulted in 83.3%/96.2% pass rates. CONCLUSIONS: The use of the edge penalty during optimization has the potential to markedly improve dose delivery accuracy for VMAT plans while still maintaining high quality optimized dose distributions. The penalty regularizes aperture shape and improves delivery efficiency.

A framework for automated and streamlined kV cone beam computed tomography image quality assurance: a multi-institutional study.

The purpose of this study was to develop and evaluate a framework to support automated standardized testing and analysis of Cone Beam Computed Tomography (CBCT) image quality QA across multiple institutions. A survey was conducted among the participating institutions to understand the variability of the CBCT QA practices. A commercial, automated software platform was validated by seven institutions participating in a consortium dedicated to automated quality assurance. The CBCT image analysis framework was used to compare periodic QA results among 23 linear accelerators (linacs) from seven institutions. The CBCT image quality metrics (geometric distortion, spatial resolution, contrast, HU constancy, uniformity and noise) data are plotted as a function of means with the upper and lower control limits compared to the linac acceptance criteria and AAPM recommendations. For example, mean geometric distortion and HU constancy metrics were found to be 0.13 mm (TG142 recommendation: ≤2 mm) and 13.4 respectively (manufacturer acceptance specification: ≤±50).Image upload and analysis process was fully automated using a MATLAB-based platform. This analysis enabled a quantitative, longitudinal assessment of the performance of quality metrics which were also compared across 23 linacs. For key CBCT parameters such as uniformity, contrast, and HU constancy, all seven institutions used stricter goals than what would be recommended based on the analysis of the upper and lower control limits. These institutional goals were also found to be stricter than that found in AAPM published guidance. This work provides a reference that could be used to machine-specific optimized tolerance of CBCT image maintenance via control charts to monitor performance we well as the sensitivity of different tests in support of a broader quality assurance program. To ensure the daily image quality needed for patient care, the optimized statistical QA metrics recommended to using along with risk-based QA.

Performance of a direct-detection active matrix flat panel dosimeter (AMFPD) for IMRT measurements.

The dosimetric performance of a direct-detection active matrix flat panel dosimeter (AMFPD) is reported for intensity modulated radiation therapy (IMRT) measurements. The AMFPD consists of a-Si : H photodiodes and thin-film transistors deposited on a glass substrate with no overlying scintillator screen or metal plate. The device is operated at 0.8 frames per second in a continuous acquisition or fluoroscopic mode. The effect of the applied bias voltage across the photodiodes on the response of the AMFPD was evaluated because this parameter affects dark signal, lag contributions, and pixel sensitivity. In addition, the AMPFD response was evaluated as a function of dose, dose rate, and energy, for static fields at 10 cm depth. In continuous acquisition mode, the AMFPD maintained a linear dose response (r2 > 0.99999) up to at least 1040 cGy. In order to obtain reliable integrated dose results for IMRT fields, the effects of lag on the radiation signal were minimized by operating the system at the highest frame rate and at an appropriate reverse bias voltage. Segmental MLC and dynamic MLC IMRT fields were measured with the AMFPD, and the results were compared to film, using standard methods for reliable film dosimetry. Both AMFPD and film measurements were independently converted to dose in cGy. Gamma and chi values were calculated as indices of agreement. The results from the AMFPD were in excellent agreement with those from film. When 2% of D(max) and 2 mm of distance to agreement were used as the criteria, 98% of the region of interest (defined as the region where dose is greater than 5% of D(max)) satisfied [chi] < or = 1 on average across the cases that were tested.

An Active Matrix Flat Panel Dosimeter (AMFPD) for in-phantom dosimetric measurements.

An a-Si Active Matrix Flat Panel Imager (AMFPI) prototype developed in-house has been modified to function as an in-phantom dosimetry system providing high resolution two-dimensional (2-D) data. This Active Matrix Flat Panel Dosimeter (AMFPD) system can be used as a replacement device for standard in-phantom dosimeters, such as scanning ion chambers in water, or film in solid water. The initial characterization of the device demonstrates a wide dynamic range (up to 160 cGy), a stable calibration curve (less than 1.5% variation over 1 year), dose rate independence (less than 1%), and excellent agreement of output factors with ion chamber measurements for a range of field sizes (less than 2%). The device also compares well to film for 2-D planar dose distributions. It is expected that the AMFPD system will be useful for beam commissioning, algorithm verification test data, and routine IMRT quality assurance dosimetry.

Dosimetric measurements of an n-butyl cyanoacrylate embolization material for arteriovenous malformations.

PURPOSE: The therapeutic regimen for cranial arteriovenous malformations often involves both stereotactic radiosurgery and endovascular embolization. Embolization agents may contain tantalum or other contrast agents to assist the neurointerventionalists, leading to concerns regarding the dosimetric effects of these agents. This study investigated dosimetric properties of n-butyl cyanoacrylate (n-BCA) plus lipiodol with and without tantalum powder. METHODS: The embolization agents were provided cured from the manufacturer with and without added tantalum. Attenuation measurements were made for the samples and compared to the attenuation of a solid water substitute using a 6 MV photon beam. Effective linear attenuation coefficients (ELAC) were derived from attenuation measurements made using a portal imager and derived sample thickness maps projected in an identical geometry. Probable dosimetric errors for calculations in which the embolized regions are overridden with the properties of water were calculated using the ELAC values. Interface effects were investigated using a parallel plate ion chamber placed at set distances below fixed samples. Finally, Hounsfield units (HU) were measured using a stereotactic radiosurgery CT protocol, and more appropriate HU values were derived from the ELAC results and the CT scanner's HU calibration curve. RESULTS: The ELAC was 0.0516 ± 0.0063 cm(-1) and 0.0580 ± 0.0091 cm(-1) for n-BCA without and with tantalum, respectively, compared to 0.0487 ± 0.0009 cm(-1) for the water substitute. Dose calculations with the embolized region set to be water equivalent in the treatment planning system would result in errors of -0.29% and -0.93% per cm thickness of n-BCA without and with tantalum, respectively. Interface effects compared to water were small in magnitude and limited in distance for both embolization materials. CT values at 120 kVp were 2082 and 2358 HU for n-BCA without and with tantalum, respectively; dosimetrically appropriate HU values were estimated to be 79 and 199 HU, respectively. CONCLUSIONS: The dosimetric properties of the embolization agents are very close to those of water for a 6 MV beam. Therefore, treating the entire intracranial space as uniform in composition will result in less than 1% dosimetric error for n-BCA emboli smaller than 3.4 cm without added tantalum and n-BCA emboli smaller than 1.1 cm with added tantalum. Furthermore, when effective embolization can be achieved by the neurointerventionalist using n-BCA without tantalum, the dosimetric impact of overriding material properties will be lessened. However, due to the high attenuation of embolization agents with and without added tantalum for diagnostic energies, artifacts may occur that necessitate additional imaging to accurately identify the spatial extent of the region to be treated.