Long-term organ damage accrual and safety in patients with SLE treated with belimumab plus standard of care.

OBJECTIVE: To examine long-term organ damage and safety following treatment with belimumab plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE). METHODS: Pooled data were examined from two ongoing open-label studies that enrolled patients who completed BLISS-52 or BLISS-76. Patients received belimumab every four weeks plus SoC. SLICC Damage Index (SDI) values were assessed every 48 weeks (study years) following belimumab initiation (baseline). The primary endpoint was change in SDI from baseline at study years 5-6. Incidences of adverse events (AEs) were reported for the entire study period. RESULTS: The modified intent-to-treat (MITT) population comprised 998 patients. At baseline, 940 (94.2%) were female, mean (SD) age was 38.7 (11.49) years, and disease duration was 6.7 (6.24) years. The mean (SD) SELENA-SLEDAI and SDI scores were 8.2 (4.18) and 0.7 (1.19), respectively; 411 (41.2%) patients had organ damage (SDI = 1: 235 (23.5%); SDI ≥ 2: 176 (17.6%)) prior to belimumab. A total of 427 (42.8%) patients withdrew overall; the most common reasons were patient request (16.8%) and AEs (8.5%).The mean (SD) change in SDI was +0.2 (0.48) at study years 5-6 (n = 403); 343 (85.1%) patients had no change from baseline in SDI score (SDI +1: 46 (11.4%), SDI +2: 13 (3.2%), SDI +3: 1 (0.2%)). Of patients without organ damage at baseline, 211/241 (87.6%) had no change in SDI and the mean change (SD) in SDI was +0.2 (0.44). Of patients with organ damage at baseline, 132/162 (81.5%) had no change in SDI and the mean (SD) change in SDI was +0.2 (0.53). The probability of not having a worsening in SDI score was 0.88 (95% CI: 0.85, 0.91) and 0.75 (0.67, 0.81) in those without and with baseline damage, respectively (post hoc analysis).Drug-related AEs were reported for 433 (43.4%) patients; infections/infestations (282, 28.3%) and gastrointestinal disorders (139, 13.9%) were the most common. CONCLUSION: Patients with SLE treated with long-term belimumab plus SoC had a low incidence of organ damage accrual and no unexpected AEs. High-risk patients with pre-existing organ damage also had low accrual, suggesting a favorable effect on future damage development.

Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract.

Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross-species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro- and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat and human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles.

Evaluation of a clinically intuitive quality assurance method.

There is a pressing need for clinically intuitive quality assurance methods that report metrics of relevance to the likely impact on tumor control of normal tissue injury. This paper presents a preliminary investigation into the accuracy of a novel "transform method" which enables a clinically relevant analysis through dose-volume-histograms (DVHs) and dose overlays on the patient's CT data. The transform method was tested by inducing a series of known mechanical and delivery errors onto simulated 3D dosimetry measurements of six different head-and-neck IMRT treatment plans. Accuracy was then examined through the comparison of the transformed patient dose distributions and the known actual patient dose distributions through dose-volume histograms and normalized dose difference analysis. Through these metrics, the transform method was found to be highly accurate in predicting measured patient dose distributions for these types of errors.

Investigating the reproducibility of a complex multifocal radiosurgery treatment.

Stereotactic radiosurgery has become a widely used technique to treat solid tumors and secondary metastases of the brain. Multiple targets can be simultaneously treated with a single isocenter in order to reduce the set-up time to improve patient comfort and workflow. In this study, a 5-arc multifocal RapidArc treatment was delivered to multiple PRESAGE® dosimeters in order to explore the repeatability of the treatment. The three delivery measurements agreed well with each other, with less than 3% standard deviation of dose in the target. The deliveries also agreed well with the treatment plan, with gamma passing rates greater than 90% (5% dose-difference, and 2 mm distance-to-agreement criteria). The optical-CT PRESAGE® system provided a reproducible measurement for treatment verification, provided measurements were made immediately following treatment.

Customising PRESAGE® for diverse applications.

PRESAGE® is a solid radiochromic dosimeter consisting of a polyurethane matrix, a triarylmethane leuco dye, and a trihalomethane initiator. Varying the composition and/or relative amounts of these constituents can affect the dose sensitivity, post-irradiation stability, and physical properties of the dosimeter. This allows customisation of PRESAGE® to meet application-specific requirements, such as low sensitivity for high dose applications, stability for remote dosimetry, optical clearing for reusability, and tissue-like elasticity for deformable dosimetry. This study evaluates five hard, non-deformable PRESAGE® formulations and six deformable PRESAGE® formulations and characterizes them for dose sensitivity and stability. Results demonstrated sensitivities in the range of 0.0029 - 0.0467 ΔOD/(Gy·cm) for hard formulations and 0.0003 - 0.0056 ΔOD/(Gy·cm) for deformable formulations. Exceptional stability was seen in both standard and low sensitivity non-deformable formulations, with promising applications for remote dosimetry. Deformable formulations exhibited potential for reusability with strong post-irradiation optical clearing. Tensile compression testing of the deformable formulations showed elastic response consistent with soft tissues, with further testing required for direct comparison. These results demonstrate that PRESAGE® dosimeters have the flexibility to be adapted for a wide spectrum of clinical applications.

Comprehensive quality assurance for base of skull IMRT.

Six base of skull IMRT treatment plans were delivered to Presage dosimeters within the RPC Head and Neck Phantom for quality assurance (QA) verification. Isotropic 2mm 3D data were acquired by optical-CT scanning with the DLOS system (Duke Large Optical-CT Scanner) and compared to the Eclipse (Varian) treatment plan. Normalized Dose Distribution (NDD) pass rates were obtained for a number of criteria. High quality 3D dosimetry data was observed from the DLOS system, illustrated here through colormaps, isodose lines, and profiles. Excellent agreement with the planned dose distributions was also observed with NDD analysis revealing > 90% pass rates (with criteria 3%, 2mm), and noise < 0.5%. The results comprehensively confirm the high accuracy of base-of-skull IMRT treatment in our clinic.

How accurate is image guided radiation therapy (IGRT) delivered with a micro-irradiator?

There is significant interest in delivering precisely targeted small-volume radiation treatments, in the pre-clinical setting, to study dose-volume relationships with tumor control and normal tissue damage. In this work we investigate the IGRT targeting accuracy of the XRad225Cx system from Precision x-Ray using high resolution 3D dosimetry techniques. Initial results revealed a significant targeting error of about 2.4mm. This error was reduced to within 0.5mm after the IGRT hardware and software had been recalibrated. The facility for 3D dosimetry was essential to gain a comprehensive understanding of the targeting error in 3D.

Preliminary investigation and application of a novel deformable PRESAGE® dosimeter.

Deformable 3D dosimeters have potential applications in validating deformable dose mapping algorithms. This study evaluates a novel deformable PRESAGE® dosimeter and its application toward validating the deformable algorithm employed by VelocityAI. The deformable PRESAGE® dosimeter exhibited a linear dose response with a sensitivity of 0.0032 ΔOD/(Gy/cm). Comparison of an experimental dosimeter irradiated with an MLC pencilbeam checkerboard pattern under lateral compression up to 27% to a non-deformed control dosimeter irradiated with the same pattern verified dose tracking under deformation. CTs of the experimental dosimeter prior to and during compression were exported into VelocityAI and used to map an Eclipse dose distribution calculated on the compressed dosimeter to its original shape. A comparison between the VelocityAI dose distribution and the distribution from the dosimeter showed field displacements up to 7.3 mm and up to a 175% difference in field dimensions. These results highlight the need for validating deformable dose mapping algorithms to ensure patient safety and quality of care.

The effect of motion on IMRT - looking at interplay with 3D measurements.

Six base of skull IMRT treatment plans were delivered to 3D dosimeters within the RPC Head and Neck Phantom for QA verification. Isotropic 2mm 3D data was obtained using the DLOS-PRESAGE system and compared to an Eclipse (Varian) treatment plan. Normalized Dose Distribution pass rates were obtained for a number of criteria. High quality 3D dosimetry data was observed from the DLOS system, illustrated here through colormaps, isodose lines, profiles, and NDD 3D maps. Excellent agreement with the planned dose distributions was also observed with NDD analysis revealing > 90% NDD pass rates [3%, 2mm], noise < 0.5%. This paper focuses on a detailed exploration of the quality and use of 3D dosimetry data obtained with the DLOS-PRESAGE system.

Towards comprehensive characterization of Cs-137 Seeds using PRESAGE® dosimetry with optical tomography.

We describe a method to directly measure the radial dose and anisotropy functions of brachytherapy sources using polyurethane based dosimeters read out with optical CT. We measured the radial dose and anisotropy functions for a Cs-137 source using a PRESAGE® dosimeter (9.5cm diameter, 9.2cm height) with a 0.35cm channel drilled for source placement. The dosimeter was immersed in water and irradiated to 5.3Gy at 1cm. Pre- and post-irradiation optical CT scans were acquired with the Duke Large field of view Optical CT Scanner (DLOS) and dose was reconstructed with 0.5mm isotropic voxel size. The measured radial dose factor matched the published fit to within 3% for radii between 0.5-3.0cm, and the anisotropy function matched to within 4% except for θ near 0° and 180° and radii >3cm. Further improvements in measurement accuracy may be achieved by optimizing dose, using the high dynamic range scanning capability of DLOS, and irradiating multiple dosimeters. Initial simulations indicate an 8 fold increase in dose is possible while still allowing sufficient light transmission during optical CT. A more comprehensive measurement may be achieved by increasing dosimeter size and flipping the source orientation between irradiations.

Locating, quantifying and characterising radiation hazards in contaminated nuclear facilities using a novel passive non-electrical polymer based radiation imaging device.

This paper provides a summary of recent trials which took place at the US Department of Energy Oak Ridge National Laboratory (ORNL) during December 2010. The overall objective for the trials was to demonstrate that a newly developed technology could be used to locate, quantify and characterise the radiological hazards within two separate ORNL hot cells (B and C). The technology used, known as RadBall(®), is a novel, passive, non-electrical polymer based radiation detection device which provides a 3D visualisation of radiation from areas where effective measurements have not been previously possible due to lack of access. This is particularly useful in the nuclear industry prior to the decommissioning of facilities where the quantity, location and type of contamination are often unknown. For hot cell B, the primary objective of demonstrating that the technology could be used to locate, quantify and characterise three radiological sources was met with 100% success. Despite more challenging conditions in hot cell C, two sources were detected and accurately located. To summarise, the technology performed extremely well with regards to detecting and locating radiation sources and, despite the challenging conditions, moderately well when assessing the relative energy and intensity of those sources. Due to the technology's unique deployability, non-electrical nature and its directional awareness the technology shows significant promise for the future characterisation of radiation hazards prior to and during the decommissioning of contaminated nuclear facilities.

Evaluation of a method to measure fluorescent cell burden in complex culture systems.

Purpose. This work introduces and evaluates a method for accurate in-vitro measurement of fluorescent cell burden in complex 3D-culture conditions.Methods.The Fluorescent Cell Burden (FCB) method was developed to analyze the burden of 4T1 mCherry-expressing cells grown in an organotypic co-culture model of brain metastasis using 400µm rat brain slices. As a first step, representative simulated image-data accurately reflecting the 4T1 experimental data, but with known ground truth burden, were created. The FCB method was then developed in the CellProfiler software to measure the integrated intensity and area of the colonies in the simulated image data. Parameters in the pipeline were varied to span the experimentally observed range (e.g. of cell colony size) and the result compared with simulation ground truth to evaluate and optimize FCB performance. The optimized CellProfiler pipeline was then applied to the original 4T1 tumor cell images to determine colony growth with time, and re-applied with upper and lower bound parameters to determine uncertainty estimates.Results.The FCB method measured integrated intensity across 10 simulated images with an accuracy of 99.23% ± 0.75%. When colony density was increased by increasing colony number to 450, 600, and 750, the FCB measurement was 98.68%, 100.9%, 97.6% and 113.5% of the true value respectively. For the increasing number of cells plated on the rat brain slices, the integrated intensity increased nearly linearly with cell count except for at high cell counts, where it is hypothesized that shadowing from clumped cells causes a sub-linear relationship.Conclusion. The FCB method accurately measured an integrated fluorescent light intensity to within 5% of ground truth for a wide range of simulated image data spanning the range of observed variability in experimental data. The method is readily customizable to in-vitro studies requiring estimation of fluorescent tumor cell burden.

Fit-for-purpose characterization of air-liquid-interface (ALI) in vitro exposure systems for e-vapor aerosol.

Air-liquid-interface (ALI) exposure systems deliver aerosol to the apical surface of cells which mimics the in vivo inhalation exposure conditions. It is necessary, however, to quantify the delivered amount of aerosol for ALI-based in vitro toxicity assessment. In this study, we evaluated two commercially available ALI exposure systems, a Vitrocell® Ames 48 (Ames 48) and a Vitrocell® 24/48 (VC 24/48), and the Vitrocell® VC1/7 smoking machine using a cig-a-like cartridge-based e-vapor device with a prototype formulation (containing 4% nicotine by weight). We characterized aerosol particle-size distribution, aerosol mass, and major chemical components (nicotine, propylene glycol, and glycerol) at the generation source and verified the repeatability of the aerosol generation. We determined aerosol delivery at the ALI by gravimetric analysis of mass collected on Cambridge filter pads and analytical quantitation of the buffer medium which showed that both aerosol mass and nicotine to an exposure insert linearly increased up to 400 puffs. The delivered aerosol mass covered a wide range of 0.8-3.4 mg per insert in the Ames 48 with variability (relative standard deviation, RSD) up to 12% and 1.1-6.4 mg per insert in the VC 24/48 with variability up to 15%. The delivered nicotine ranged approximately up to 200 µg per insert in both exposure systems. These results provided operation and aerosol delivery information of these ALI exposure systems for subsequent in vitro testing of e-vapor aerosols.

Preliminary Investigation of the Dosimetric Properties of 'RadGel'

A preliminary investigation into the efficacy of a new 3D dosimetry material, RadGel™, for verification of radiation therapy dose distributions is presented. Small volumes of RadGel™ were found to exhibit a linear, reproducible response to dose. A gradual increase in optical-density (OD) with time was observed, suggesting scanning should be completed within 18 hours to keep a linear correlation of R(2) > 0.99. A larger 10 cm diameter volume of RadGel™ was irradiated with a rotationally symmetric "spoke" plan designed to rigorously evaluate scanner/dosimeter combined performance. The dosimeter was imaged with the Duke Mid-sized Optical-CT Scanner (DMOS). Promising OD and corresponding dose maps were obtained. Edge artefacts were observed and are suspected to be exacerbated by the particular container used in this early study. Further studies will evaluate new containers and methods for refractive matching at the gel-container-fluid interface.

Machine intelligence identifies soluble TNFa as a therapeutic target for spinal cord injury.

Traumatic spinal cord injury (SCI) produces a complex syndrome that is expressed across multiple endpoints ranging from molecular and cellular changes to functional behavioral deficits. Effective therapeutic strategies for CNS injury are therefore likely to manifest multi-factorial effects across a broad range of biological and functional outcome measures. Thus, multivariate analytic approaches are needed to capture the linkage between biological and neurobehavioral outcomes. Injury-induced neuroinflammation (NI) presents a particularly challenging therapeutic target, since NI is involved in both degeneration and repair. Here, we used big-data integration and large-scale analytics to examine a large dataset of preclinical efficacy tests combining five different blinded, fully counter-balanced treatment trials for different acute anti-inflammatory treatments for cervical spinal cord injury in rats. Multi-dimensional discovery, using topological data analysis (TDA) and principal components analysis (PCA) revealed that only one showed consistent multidimensional syndromic benefit: intrathecal application of recombinant soluble TNFα receptor 1 (sTNFR1), which showed an inverse-U dose response efficacy. Using the optimal acute dose, we showed that clinically-relevant 90 min delayed treatment profoundly affected multiple biological indices of NI in the first 48 h after injury, including reduction in pro-inflammatory cytokines and gene expression of a coherent complex of acute inflammatory mediators and receptors. Further, a 90 min delayed bolus dose of sTNFR1 reduced the expression of NI markers in the chronic perilesional spinal cord, and consistently improved neurological function over 6 weeks post SCI. These results provide validation of a novel strategy for precision preclinical drug discovery that is likely to improve translation in the difficult landscape of CNS trauma, and confirm the importance of TNFα signaling as a therapeutic target.

Fast, large field-of-view, telecentric optical-CT scanning system for 3D radiochromic dosimetry.

We describe initial experiences with an in-house, fast, large field-of-view optical-CT telecentric scanner (the Duke Large field of view Optical-CT Scanner (DLOS)). The DLOS system is designed to enable telecentric optical-CT imaging of dosimeters up to 24 cm in diameter with a spatial resolution of 1 mm(3), in approximately 10 minutes. These capabilities render the DLOS system a unique device at present. The system is a scaled up version of early prototypes in our lab. This scaling introduces several challenges, including the accurate measurement of a greatly increased range of light attenuation within the dosimeter, and the need to reduce even minor reflections and scattered light within the imaging chain. We present several corrections and techniques that enable accurate, low noise, 3D dosimetery with the DLOS system.

Preliminary commissioning investigations with the DMOS-RPC optical-CT Scanner.

A midsized broad beam Optical-CT scanner is being developed for collaborative research between Duke and the Radiological Physics Center (RPC). The Duke Midsized Optical-CT Scanner (DMOS-RPC) is designed to be compatible with several of the RPC phantoms, including the head and neck, stereotactic SRS, and lung phantoms. Preliminary data investigating the basic performance of the scanner is described. Two 10 cm PRESAGE cylinders were irradiated with simple test plans. Projections of ~80 µm resolution of each dosimeter were collected at 1 degree intervals over a full 360 degrees both before and after irradiation. 3 dimensional reconstructions of attenuation coefficients throughout the dosimeter were computed with 1 mm(3) resolution. Scans were normalized to the calculated dose distribution and a 3D comparison was made with a commissioned treatment planning system. Initial results indicate DMOS-RPC can produce accurate relative dose distributions with high spatial resolution (up to 1 mm(3) in 3D) in less than 30 minutes (acquisition and reconstruction). A maximum dose of ~3.6Gy was delivered in these tests, and observed noise was ~2% for 1 mm(3) reconstructions. Good agreement is observed with the planning system in these simple distributions, indicating promising potential for this scanner.

Achieving accurate radiochromic optical-CT imaging when using a polychromatic light source.

Optical-CT performed with a broad spectrum light source can lead to inaccurate reconstructed attenuation coefficients (and hence dose) due to 'spectral warping' as the beam passes through the dosimeter. Some wavelengths will be attenuated more strongly than others depending on the absorption spectrum of the radiochromic dosimeter. A simulation was run to characterize the error introduced by the spectrum warping phenomena. Simulations of a typical dosimeter and delivered dose (6cm diameter, 2 Gy irradiation) showed reconstructed attenuation coefficients can be in error by >12% when compared to those obtained from a monochromatic scan. A method to correct for these errors is presented and preliminary data suggests that with the correction, polychromatic imaging can yield imaging results equal in accuracy to those of monochromatic imaging. The advantage is that polychromatic imaging may be less sensitive to prominent schlerring artefacts that are often observed in telecentric optical-CT scanning systems with tight bandwidth filters applied.

A 'quad-phantom' film dosimeter for use as a multi-planar verification tool for PRESAGE/optical-CT.

INTRODUCTION: To develop and characterize the accuracy and reproducibility of a quad-phantom dosimeter which will serve as an independent verification tool during commissioning of a PRESAGE/optical-CT 3D dosimetry system. METHODS: A 16cm × 12cm cylindrical quad-phantom was constructed from four pieces of solid polyurethane mimicking the PRESAGE material. Films were placed and anchored in orthogonal planes and the quad-phantom was fastened tightly together and placed in a water-filled Styrofoam container for irradiation. A simple, two-field plan consisting of 6×6cm anterior-posterior and right-lateral 6MV photon beams (400cGy) was delivered three times (fresh films inserted for each) with a Varian Clinac 600C. Image registration was performed in the Computational Environment for Radiological Research (CERR) and dose profiles and gamma analysis was performed in CERR and MATLAB. RESULTS #ENTITYSTARTX00026; DISCUSSION: Excellent reproducibility was observed during the irradiations, with ~2.3% standard deviation between all pixels. Using a 3%, 3mm gamma criteria, excellent dosimetric accuracy was observed, with 98.8% and 96.3% passing rates in the sagittal and axial planes, respectively. CONCLUSION: The preliminary results indicate that the quad-phantom can serve as a reproducible and accurate system for high resolution dosimetry in orthogonal planes and should serve as an effective verification tool for PRESAGE/optical-CT in more challenging clinical scenarios.

On the Feasibility of Verification of 3D Dosimetry Near Brachytherapy Sources Using PRESAGE/Optical-CT.

PURPOSE: The feasibility of using the PRESAGE/Optical-CT system for 3D dosimetry verification around a brachytherapy source is investigated. METHOD AND MATERIALS: Brachytherapy dose distributions were obtained by irradiation of cylindrical PRESAGE volumes 6cm in diameter by 8cm height with a GammaMed 12i Ir-192 HDR unit (Varian Medical Systems). A narrow channel on the central axis was created by setting a steel catheter in the Presage during manufacture, enabling measurements close to the source (~3mm). RESULTS: Comparison of dose line profiles shows good agreement between PRESAGE and verified calculated dose calculation, in both high and low dose regions. CONCLUSION: The PRESAGE/Optical-CT shows good potential in verification of 3D dose distributions around brachytherapy sources.