Citations

For nearly a decade, researchers in the field of pediatric oncology have been using zebrafish as a model for understanding the contributions of genetic alternations to the pathogenesis of neuroblastoma (NB), and exploring the molecular and cellular mechanisms that underlie neuroblastoma initiation and metastasis. In this review, we will enumerate and illustrate the key advantages of using the zebrafish model in NB research, which allows researchers to: monitor tumor development in real-time; robustly manipulate gene expression (either transiently or stably); rapidly evaluate the cooperative interactions of multiple genetic alterations to disease pathogenesis; and provide a highly efficient and low-cost methodology to screen for effective pharmaceutical interventions (both alone and in combination with one another). This review will then list some of the common challenges of using the zebrafish model and provide strategies for overcoming these difficulties. We have also included visual diagram and figures to illustrate the workflow of cancer model development in zebrafish and provide a summary comparison of commonly used animal models in cancer research, as well as key findings of cooperative contributions between MYCN and diverse singling pathways in NB pathogenesis.

PurposeChannelized Hotelling observer (CHO) models have been implemented to assess imaging performance in x‐ray angiography systems. While current methods are appropriate for assessing unprocessed images of moving test objects upon uniform‐exposure backgrounds, they are inadequate for assessing conditions which more appropriately mimic clinical imaging conditions including the combination of moving test objects, complex anthropomorphic backgrounds, and image processing. In support of this broad goal, the purpose of this work was to develop theory and methods to automatically select a subset of task‐specific efficient Gabor channels from a task‐generic Gabor channel base set. Also, previously described theory and methods to manage detectability index (d′) bias due to nonrandom temporal variations in image electronic noise will be revisited herein.MethodsStarting with a base set of 96 Gabor channels, backward elimination of channels was used to automatically identify an “efficient” channel subset which reduced the number of channels retained in the subset while maintaining the magnitude of the d′ estimate. The concept of a pixelwise Hotelling observer (PHO) model was introduced and similarly implemented to assess the performance of the efficient‐channel CHO model. Bias in d′ estimates arising from temporally variable nonstationary noise was modeled as a bivariate probability density function for normal distributions, where one variable corresponds to the signal from the test object and the other variable corresponds to the signal from temporally variable nonstationary noise. Theory and methods were tested on uniform‐exposure unprocessed angiography images with detector target dose (DTD) of 6, 18, and 120 nGy containing static disk‐shaped test objects with diameter in the range of 0.5 to 4 mm.ResultsConsidering all DTD levels and test object sizes, the proposed method reduced the number of Gabor channels in the final subset by 63–82% compared to the original 96 Gabor channel base set, while maintaining a mean relative performance () of 95% 4% with respect to the reference PHO model. Experimental results demonstrated that the bivariate approach to account for bias due to temporally variable nonstationary noise resulted in improved correlation between the CHO and PHO models as compared to a previously proposed univariate approach.ConclusionsComputationally efficient backward elimination can be used to select an efficient subset of Gabor channels from an initial channel base set without substantially compromising the magnitude of the d′ estimate. Bias due to temporally variable nonstationary noise can be modeled through a bivariate approach leading to an improved unbiased estimate of d′.

AbstractPurposeTo demonstrate that variation in chemical composition has a negligible effect on the mapping curve from relative electron density (RED) to proton stopping power ratio (SPR), and to establish the theoretical framework of using Megavoltage (MV) computed tomography (CT), instead of kilovoltage (kV) dual energy CT, to accurately estimate proton SPR.MethodsA simulation study was performed to evaluate the effect of chemical composition variation on kVCT number and proton SPR. The simulation study involved both reference and simulated human tissues. The reference human tissues, together with their physical densities and chemical compositions, came from the ICRP publication 23. The simulated human tissues were created from the reference human tissues assuming that elemental percentage weight followed a Gaussian distribution. For all tissues, kVCT number and proton SPR were obtained through (a) theoretical calculation from tissue’s physical density and chemical composition which served as the ground truth, and (b) estimation from RED using the calibration curves established from the stoichiometric method. Deviations of the estimated values from the calculated values were quantified as errors in using RED to estimate kVCT number and proton SPR.ResultsGiven a chemical composition variation of 5% (1σ) of the nominal percentage weights, the total estimation error of using RED to estimate kVCT number was 0.34%, 0.62%, and 0.77% and the total estimation error of using RED to estimate proton SPR was 0.30%, 0.22%, and 0.16% for fat tissues, non‐fat soft tissues and bone tissues, respectively.ConclusionChemical composition had a negligible effect on the method of using RED to determine proton SPR. RED itself is sufficient to accurately determine proton SPR. MVCT number maintains a superb linear relationship with RED because it is highly dominated by Compton scattering. Therefore, MVCT has great potential in reducing the proton range uncertainty.

Abstract One of the greatest barriers to curative treatment of neuroblastoma is its frequent metastatic outgrowth prior to diagnosis, especially in cases driven by amplification of the MYCN oncogene. However, only a limited number of regulatory proteins that contribute to this complex MYCN-mediated process have been elucidated. Here we show that the growth arrest-specific 7 (GAS7) gene, located at chromosome band 17p13.1, is preferentially deleted in high-risk MYCN-driven neuroblastoma. GAS7 expression was also suppressed in MYCN-amplified neuroblastoma lacking 17p deletion. GAS7 deficiency led to accelerated metastasis in both zebrafish and mammalian models of neuroblastoma with overexpression or amplification of MYCN. Analysis of expression profiles and the ultrastructure of zebrafish neuroblastoma tumors with MYCN overexpression identified that GAS7 deficiency led to (i) downregulation of genes involved in cell–cell interaction, (ii) loss of contact among tumor cells as critical determinants of accelerated metastasis, and (iii) increased levels of MYCN protein. These results provide the first genetic evidence that GAS7 depletion is a critical early step in the cascade of events culminating in neuroblastoma metastasis in the context of MYCN overexpression. Significance: Heterozygous deletion or MYCN-mediated repression of GAS7 in neuroblastoma releases an important brake on tumor cell dispersion and migration to distant sites, providing a novel mechanism underlying tumor metastasis in MYCN-driven neuroblastoma. See related commentary by Menard, p. 2815

Objective This study aims to determine if low iodine dynamic computed tomography angiography performed after a fixed delay or test bolus acquisition demonstrates high concordance with clinical computed tomography angiography (using a routine amount of iodinated contrast) to display lower extremity peripheral arterial disease. Methods After informed consent, low iodine dynamic computed tomography angiography examination (using either a fixed delay or test bolus) using 50 ml of iodine contrast media was performed. A subsequent clinical computed tomography angiography using standard iodine dose (115 or 145 ml) served as the reference standard. A vascular radiologist reviewed dynamic and clinical computed tomography angiography images to categorize the lumen into “not opacified”, “<50% stenosis”, “ 50 ̶70% stenosis”, “>70% stenosis”, and “occluded” for seven arterial segments in each lower extremity. Concordance between low iodine dynamic computed tomography angiography and the routine iodine reference standard was calculated. The clinical utility of 4D volume-rendered images was also evaluated. Results Sixty-eight patients (average age 66.1 ± 12.3 years, male; female = 49: 19) were enrolled, with 34 patients each undergoing low iodine dynamic computed tomography angiography using fixed delay and test bolus techniques, respectively. One patient assigned to the test bolus group did not undergo low iodine computed tomography angiography due to unavailable delayed time. The fixed delay was 13 s, with test bolus acquisition resulting in a mean variable delay prior to image acquisition of 19.5 s (range; 8–32 s). Run-off to the ankle was observed using low iodine dynamic computed tomography angiography following fixed delay and test bolus acquisition in 76.4% (26/34) and 100% (33/33) of patients, respectively ( p = 0.005). Considering extremities with run-off to the ankle and without severe artifact, the concordance rate between low iodine dynamic computed tomography angiography and the routine iodine reference standard was 86.8% (310/357) using fixed delay and 97.9% (425/434) using test bolus ( p < 0.001). 4D volume-rendered images using fixed delay and test bolus demonstrated asymmetric flow in 57.7% (15/26) and 58.1% (18/31) ( p = 0.978) of patients, and collateral blood flow in 11.5% (3/26) and 22.6% (7/31) of patients ( p = 0.319), respectively. Conclusion Low iodine dynamic computed tomography angiography with test bolus acquisition has a high concordance with routine peripheral computed tomography angiography performed with standard iodine dose, resulting in improved run-off to the ankle compared to dynamic computed tomography angiography performed after a fixed delay. This method is useful for minimizing iodine dose in patients at risk for contrast-induced nephropathy. 4D volume-rendered computed tomography angiography images provide useful dynamic information.

AbstractPurposeAn increasing number of implantable or external devices can impact whether patients can receive radiological imaging examinations. This study examines and tests the Neulasta (pegfilgrastim) Onpro on‐body injector in multiple imaging environments.MethodsThe injector was analyzed for four imaging modalities with testing protocols and strategies developed for each modality. In x‐ray and computed tomography (CT), scans with much higher exposure than clinical protocols were performed with the device attached to an anthropomorphic phantom. The device was monitored until the completion of drug delivery. For magnetic resonance imaging (MRI), the device was assessed using a hand‐held magnet and underwent the magnetically induced displacement testing in a 1.5T clinical MRI scanner room. For ultrasound, magnetic field changes were measured around an ultrasound scanner system with three transducers.ResultsFor x‐ray and CT no sign of device error was identified during or after the high radiation exposure scans. Drug delivery was completed at expected timing with expected volume. For MRI the device showed significant attractive force towards the hand‐held magnet and a 50‐degree deflection angle at 50 cm from the opening of the scanner bore. No further assessment from the gradient or radiofrequency field was deemed necessary. For ultrasound the maximum magnetic field change from baseline was measured to be +11.7 μT in comparison to +74.2 μT at 4 inches from a working microwave.ConclusionsNo device performance issue was identified under the extreme test conditions in x‐ray or CT. The device was found to be MR Unsafe. Magnetic field changes around an ultrasound system met the limitation set by manufacture. Patient ultrasound scanning is considered safe as long as the transducers do not inadvertently loosen the device.

PurposeTalbot‐Lau grating interferometry enables the use of polychromatic x‐ray sources, extending the range of potential applications amenable to phase contrast imaging. However, these sources introduce beam hardening effects not only from the samples but also from the gratings. As a result, grating inhomogeneities due to manufacturing imperfections can cause spectral nonuniformity artifacts when used with polychromatic sources. Consequently, the different energy dependencies of absorption, phase, and visibility contrasts impose challenges that so far have limited the achievable image quality. The purpose of this work was to develop and validate a correction strategy for grating‐based x‐ray imaging that accounts for beam hardening generated from both the imaged object and the gratings.MethodsThe proposed two‐variable polynomial expansion strategy was inspired by work performed to address beam hardening from a primary modulator. To account for the multicontrast nature of grating interferometry, this approach was extended to each contrast to obtain three sets of correction coefficients, which were determined empirically from a calibration scan. The method’s feasibility was demonstrated using a tabletop Talbot‐Lau grating interferometer micro‐computed tomography (CT) system using CT acquisitions of a water sample and a silicon sample, representing low and high atomic number materials. Spectral artifacts such as cupping and ring artifacts were quantified using mean squared error (MSE) from the beam‐hardening‐free target image and standard deviation within a reconstructed image of the sample. Finally, the model developed using the water sample was applied to a fixated murine lung sample to demonstrate robustness for similar materials.ResultsThe water sample’s absorption CT image was most impacted by spectral artifacts, but following correction to decrease ring artifacts, an 80% reduction in MSE and 57% reduction in standard deviation was observed. The silicon sample created severe artifacts in all contrasts, but following correction, MSE was reduced by 94% in absorption, 96% in phase, and 90% in visibility images. These improvements were due to the removal of ring artifacts for all contrasts and reduced cupping in absorption and phase images and reduced capping in visibility images. When the water calibration coefficients were applied to the lung sample, ring artifacts most prominent in the absorption contrast were eliminated.ConclusionsThe described method, which was developed to remove artifacts in absorption, phase, and normalized visibility micro‐CT images due to beam hardening in the system gratings and imaged object, reduced the MSE by up to 96%. The method depends on calibrations that can be performed on any system and does not require detailed knowledge of the x‐ray spectrum, detector energy response, grating attenuation properties and imperfections, or the geometry and composition of the imaged object.

Purpose To determine the accuracy of CT number and calcium score of a kV‐independent technique based on an artificial 120 kV reconstruction, and its potential to reduce radiation dose. Methods Anthropomorphic chest phantoms were scanned on a third‐generation dual‐source CT system equipped with the artificial 120 kV reconstruction. First, a phantom module containing a 20‐mm diameter hydroxyapatite (HA) insert was scanned inside the chest phantoms at different tube potentials (70–140 kV) to evaluate calcium CT number accuracy. Next, three small HA inserts (diameter/length = 5 mm) were inserted into a pork steak and scanned inside the phantoms to evaluate calcium score accuracy at different kVs. Finally, the same setup was scanned using automatic exposure control (AEC) at 120 kV, and then with automatic kV selection (auto‐kV). Phantoms were also scanned at 120 kV using a size‐dependent mA chart. CT numbers of soft tissue and calcium were measured from different kV images. Calcium score of each small HA insert was measured using commercial software. Results The CT number difference from 120 kV was small with tube potentials from 90 to 140 kV for both soft tissue and calcium (maximal difference of 4/5 HU, respectively). Consistent calcium scores were obtained from images of different kVs compared to 120 kV, with a relative difference <8%. Auto‐kV provided a 25–34% dose reduction compared to AEC alone. Conclusion A kV‐independent calcium scoring technique can produce artificial 120 kV images with consistent soft tissue and calcium CT numbers compared to standard 120 kV examinations. When coupled with auto‐kV, this technique can reduce radiation by 25–34% compared to that with AEC alone, while providing consistent calcium scores as that of standard 120 kV examinations.

SummaryIn sickle cell disease (SCD), cerebral oxygen delivery is dependent on the cerebral vasculature's ability to increase blood flow and volume through relaxation of the smooth muscle that lines intracranial arteries. We hypothesised that anaemia extent and/or circulating markers of inflammation lead to concentric macrovascular arterial wall thickening, visible on intracranial vessel wall magnetic resonance imaging (VW‐MRI). Adult and pediatric SCD (n = 69; age = 19.9 ± 8.6 years) participants and age‐ and sex‐matched control participants (n = 38; age = 22.2 ± 8.9 years) underwent 3‐Tesla VW‐MRI; two raters measured basilar and bilateral supraclinoid internal carotid artery (ICA) wall thickness independently. Mean wall thickness was compared with demographic, cerebrovascular and haematological variables. Mean vessel wall thickness was elevated (P < 0·001) in SCD (1·07 ± 0·19 mm) compared to controls (0·97 ± 0·07 mm) after controlling for age and sex. Vessel wall thickness was higher in participants on chronic transfusions (P = 0·013). No significant relationship between vessel wall thickness and flow velocity, haematocrit, white blood cell count or platelet count was observed; however, trends (P < 0·10) for wall thickness increasing with decreasing haematocrit and increasing white blood cell count were noted. Findings are discussed in the context of how anaemia and circulating inflammatory markers may impact arterial wall morphology.