Brand ferumoxytol vs. generic ferumoxytol comparison across two dosing regimens: a cardiac MRI image quality study.

BACKGROUND: Ferumoxytol is becoming more widely used as an off-label blood-pool contrast agent for MR angiography (MRA) and four-dimensional (4D) flow imaging in pediatric cardiovascular disease. Brand and generic versions of ferumoxytol are available with no information on relative efficacy as a contrast agent and safety profiles. OBJECTIVE: This study evaluates patient safety and image quality of comparable dosages of generic ferumoxytol (GF) versus brand ferumoxytol (BF) with the following hypotheses: (1) Reducing the contrast dosage from 3 to 2 mg/kg will not affect imaging quality and diagnostic accuracy of MRA and four-dimensional 4D flow. (2) GF and BF have similar image quality. (3) GF and BF have similar patient safety profiles. MATERIALS AND METHODS: In an IRB-approved retrospective study, changes in vitals/clinical status between baseline, during infusion, and 30 min post-infusion were analyzed in 3 groups: group 1 (3 mg/kg BF, 216 patients, age: 19.29 ± 11.71 years ranging from 2 months to 62 years), group 2 (2 mg/kg BF, 47 patients, age: 15.35 ± 8.56 years ranging from 10 days to 41 years), and group 3 (2 mg/kg GF, 127 patients, age: 17.16 ± 12.18 years ranging from 6 days to 58 years). Both pediatric and adult patients with congenital heart disease (CHD) indications were included within the study. Adverse reactions were classified as mild, moderate, or severe. Quantitative analysis of MR image quality was performed with signal-to-noise ratio (SNR) on MRA and velocity-to-noise ratio (VNR) on 4D flow. Qualitative grading of imaging features was performed by 2 experienced observers. Two-way analysis of variance (ANOVA) and chi-square tests were used for comparison with a P value of ≤ 0.05 used for significance. RESULTS: No statistical difference was found in clinical status and vital signs (P>0.05). No severe reactions were reported. 7.9% of GF patients experienced an adverse reaction compared to 2.3% with 3 mg/kg BF and 8.4% with 2 mg/kg BF. There was no statistical difference in SNR between the 3 groups (P>0.05). For 4D flow, 2 mg/kg GF demonstrated an increase in VNR compared to 2 mg/kg BF (P = 0.005). The qualitative scores for MRA and 4D flow were high (≥ 3) across all 3 groups. CONCLUSIONS: No significant difference was identified between 2 mg/kg GF and BF in terms of safety profile and image quality. Given the small sample size of this study, further studies are required to confirm these results.

Longitudinal MRI brain volume changes over one year in children with mucopolysaccharidosis types IIIA and IIIB.

OBJECTIVE: To quantify changes in segmented brain volumes over 12 months in children with mucopolysaccharidosis types IIIA and IIIB (MPS IIIA and IIIB). METHODS: In order to establish suitable outcome measures for clinical trials, twenty-five children greater than 2 years of age were enrolled in a prospective natural history study of MPS IIIA and IIIB at Nationwide Children's Hospital. Data from sedated non-contrast brain 3 T MRIs and neuropsychological measures were reviewed from the baseline visit and at 12-month follow-up. No intervention beyond standard clinical care was provided. Age- and sex-matched controls were gathered from the National Institute of Mental Health Data Archive. Automated brain volume segmentation with longitudinal processing was performed using FreeSurfer. RESULTS: Of the 25 subjects enrolled with MPS III, 17 children (4 females, 13 males) completed at least one MRI with interpretable volumetric data. The ages ranged from 2.8 to 13.7 years old (average 7.2 years old) at enrollment, including 8 with MPS IIIA and 9 with MPS IIIB. At baseline, individuals with MPS III demonstrated reduced cerebral white matter and corpus callosum volumes, but greater volumes of the lateral ventricles, cerebellar cortex, and cerebellar white matter compared to controls. Among the 13 individuals with MPS III with two interpretable MRIs, there were annualized losses or plateaus in supratentorial brain tissue volumes (cerebral cortex -42.10 ± 18.52 cm3/year [mean ± SD], cerebral white matter -4.37 ± 11.82 cm3/year, subcortical gray matter -6.54 ± 3.63 cm3/year, corpus callosum -0.18 ± 0.62 cm3/yr) and in cerebellar cortex (-0.49 ± 12.57 cm3/year), with a compensatory increase in lateral ventricular volume (7.17 ± 6.79 cm3/year). Reductions in the cerebral cortex and subcortical gray matter were more striking in individuals younger than 8 years of age. Greater cerebral cortex volume was associated with higher fine and gross motor functioning on the Mullen Scales of Early Learning, while greater subcortical gray matter volume was associated with higher nonverbal functioning on the Leiter International Performance Scale. Larger cerebellar cortex was associated with higher receptive language performance on the Mullen, but greater cerebellar white matter correlated with worse adaptive functioning on the Vineland Adaptive Behavioral Scales and visual problem-solving on the Mullen. CONCLUSIONS: Loss or plateauing of supratentorial brain tissue volumes may serve as longitudinal biomarkers of MPS III age-related disease progression compared to age-related growth in typically developing controls. Abnormally increased cerebellar white matter in MPS III, and its association with worse performance on neuropsychological measures, suggest the possibility of pathophysiological mechanisms distinct from neurodegeneration-associated atrophy that warrant further investigation.

Pediatric Functional Neuroimaging: Practical Tips and Pearls.

OBJECTIVE. Functional MRI (fMRI) is clinically used for localization of eloquent cortex before surgical intervention, most commonly motor and language function in patients with tumors or epilepsy. In the pediatric population, special considerations for fMRI relate to limited examination tolerance, small head size, developing anatomy and physiology, and diverse potential abnormalities. In this article, we will highlight pearls and pitfalls of clinical pediatric fMRI including blood oxygenation level-dependent imaging principles, patient preparation, study acquisition, data postprocessing, and examination interpretation. CONCLUSION. Clinical fMRI is indicated for presurgical localization of eloquent cortex in patients with tumors, epilepsy, or other neurologic conditions and requires a solid understanding of technical considerations and data processing. In children, special approaches are needed for patient preparation as well as study design, acquisition, and interpretation. Radiologists should be cognizant of developmental neuroanatomy, causes of neuropathology, and capacity for neuroplasticity in the pediatric population.

Age-related differences in neural activation and functional connectivity during the processing of vocal prosody in adolescence.

The ability to recognize others' emotions based on vocal emotional prosody follows a protracted developmental trajectory during adolescence. However, little is known about the neural mechanisms supporting this maturation. The current study investigated age-related differences in neural activation during a vocal emotion recognition (ER) task. Listeners aged 8 to 19 years old completed the vocal ER task while undergoing functional magnetic resonance imaging. The task of categorizing vocal emotional prosody elicited activation primarily in temporal and frontal areas. Age was associated with a) greater activation in regions in the superior, middle, and inferior frontal gyri, b) greater functional connectivity between the left precentral and inferior frontal gyri and regions in the bilateral insula and temporo-parietal junction, and c) greater fractional anisotropy in the superior longitudinal fasciculus, which connects frontal areas to posterior temporo-parietal regions. Many of these age-related differences in brain activation and connectivity were associated with better performance on the ER task. Increased activation in, and connectivity between, areas typically involved in language processing and social cognition may facilitate the development of vocal ER skills in adolescence.

Virtual surgical planning and 3D printing in pediatric musculoskeletal oncological resections: a proof-of-concept description.

BACKGROUND AND OBJECTIVES: Patient-specific models may have a role in planning and executing complex surgical procedures. However, creating patient-specific models with virtual surgical planning (VSP) has many steps, from initial imaging to finally realizing the three-dimensional printed model (3DPM). This manuscript evaluated the feasibility and potential benefits of multimodal imaging and geometric VSP and 3DPM in pediatric orthopedic tumor resection and reconstruction. MATERIALS AND METHODS: Twelve children with Ewing's sarcoma, osteosarcoma, or chondrosarcoma were studied. Computed tomography (CT) and contrast-enhanced magnetic resonance imaging (MRI) were acquired as the standard-of-care. Bony and soft tissue components of the tumor and the adjacent bone were segmented to create a computer-generated 3D model of the region. VSP used the computer-generated 3D model. The Objet350 Stratasys™ polyjet printer printed the final physical model used for pre-surgical planning, intraoperative reference, and patient education. Clinical impact, the utility of the model, and its geometric accuracy were assessed. RESULTS: Subjectively, using the patient-specific model assisted in preoperative planning and intra-operative execution of the surgical plan. The mean difference between the models and the surgical resection was -0.09 mm (range: -0.29-0.45 mm). Pearson's correlation coefficient (r) of the cross-sectional area was -0.9994, linear regression r2 = 0.9989, and the Bland Altman plot at 95% confidence interval showed all data within boundaries. CONCLUSION: We studied the geometric accuracy, utility and clinical impact of VSP and 3DPM produced from multi-modal imaging studies and concluded 3DPM accurately represented the patients' tumor and proved very useful to the surgeon in both the preoperative surgical planning, patient and family education and operative phases. Future studies will be planned to evaluate surgery procedure duration and other outcomes.

Zero-TE MRI: Potential Applications in the Oral Cavity and Oropharynx.

ABSTRACT: Zero-echo time (ZTE) magnetic resonance imaging (MRI) is the newest in a family of MRI pulse sequences that involve ultrafast sequence readouts, permitting visualization of short-T2 tissues such as cortical bone. Inherent sequence properties enable rapid, high-resolution, quiet, and artifact-resistant imaging. ZTE can be performed as part of a "one-stop-shop" MRI examination for comprehensive evaluation of head and neck pathology. As a potential alternative to computed tomography for bone imaging, this approach could help reduce patient exposure to ionizing radiation and improve radiology resource utilization. Because ZTE is not yet widely used clinically, it is important to understand the technical limitations and pitfalls for diagnosis. Imaging cases are presented to demonstrate potential applications of ZTE for imaging of oral cavity, oropharynx, and jaw anatomy and pathology in adult and pediatric patients. Emerging studies indicate promise for future clinical implementation based on synthetic computed tomography image generation, 3D printing, and interventional applications.

Comparison of 2D BLADE Turbo Gradient- and Spin-Echo and 2D Spin-Echo Echo-Planar Diffusion-Weighted Brain MRI at 3 T: Preliminary Experience in Children.

RATIONALE AND OBJECTIVES: We describe our preliminary experience using a 2D turbo gradient- and spin-echo (TGSE) diffusion-weighted (DW) pulse sequence with non-Cartesian BLADE trajectory at 3 T in pediatric patients. We compared the TGSE BLADE to conventional DW spin-echo echo-planar imaging (SE-EPI) in pediatric brain imaging, assessing the presence of artifacts from signal pile-ups, geometric distortion, motion, susceptibility from air-tissue interface, shunts and orthodontia, and diagnostic image quality. MATERIALS AND METHODS: Data were acquired in 53 patients (10.4 ± 7.9 years). All DW imaging data were acquired precontrast, with SE-EPI first. A four-point scale for rating was used-1 (best) and 4 (worst). A neuroradiologist scored the two sequences and further noted whether the TGSE BLADE approach or SE-EPI was preferred in each case. Apparent diffusion coefficients were compared quantitatively between the two sequences in a subset of 16 patients, in 41 separate regions of interests including caudate nucleus, putamen, globus pallidus, thalamus, and pathological areas. RESULTS: In 43.4% of the cases, TGSE BLADE was preferred; in 49.1% of the cases, both sequences were preferred equally. Average scores for SE-EPI were 2.2 ± 0.8 versus TGSE's 1.2 ± 0.4 in assessing diagnostic quality (p < 0.05). Motion artifacts were minimal on both sequences in 92.5% of the cases. In the TGSE BLADE scores, no case received a "4" for significant artifacts with marginally acceptable image quality. Apparent diffusion coefficients values between the two sequences were statistically similar, with a linear regression slope of 0.92 (r2 = 0.97). CONCLUSION: TGSE BLADE DW imaging exhibited less geometric distortion in the brain and reduced signal pile-ups in areas of high susceptibility than conventional SE-EPI.

Multi-phase 3D arterial spin labeling brain MRI in assessing cerebral blood perfusion and arterial transit times in children at 3T.

BACKGROUND: 3D pseudocontinuous arterial spin labeling (pCASL) with a single post-labeling delay time is commonly used to measure cerebral blood flow (CBF). Multi-phase pCASL has been developed to simultaneously estimate CBF and arterial transit time (ATT). PURPOSE: To evaluate the clinical feasibility of multi-phase 3D pCASL in pediatric patients, and to compare the estimation of ATT and CBF via linear weighted-delay and traditional non-linear iterative curve-fitting routines. MATERIAL & METHODS: Forty patients (average age: 8.6 y, 5 d-22.4 y) referred for routine brain MRI underwent additional 5-7 min of pCASL scans at 3T using 5 PLDs between 300 and 2300 ms. Data were post-processed by two algorithms for estimating CBF and ATT. Average CBF and ATT values were computed for vascular territories including the anterior, middle and posterior cerebral arteries as well as regions based on the Alberta Stroke Program Early CT Score template. Pearson correlation coefficients and linear regression were used for statistical analysis. The clinical value of multi-phase CASL was evaluated by a neuroradiologist based on asymmetric CBF and ATT maps in patients. RESULTS: All pCASL scans were successfully completed, generating diagnostic results. CBF computed from weighted-delay and curve-fitting methods agreed strongly, with Pearson correlation coefficients ranging from 0.97-0.99 across the measured regions (p < 0.05). Correlation coefficients for ATT ranged from 0.87-0.96 (p < 0.05). CBF and ATT maps were found to add valuable information to clinical diagnosis in 17 of 40 pediatric patients. CONCLUSION: Our preliminary results demonstrate the feasibility and potential clinical utility of multi-phase pCASL for simultaneous CBF and ATT quantification in pediatric patients.

Identification of a novel, putative cataract-causing allele in CRYAA (G98R) in an Indian family.

PURPOSE: The aim of the present study was to investigate the molecular basis underlying a nonsyndromic presenile autosomal dominant cataract in a three-generation pedigree. The phenotype was progressive from a peripheral ring-like opacity to a total cataract with advancing age from teenage to adulthood. The visual impairment started as problem in distant vision at the age of 16 years, to diminishing vision by the age of 24. METHODS: Clinical interventions included complete ophthalmological examination, a collection of case history, and pedigree details. Blood samples were collected from available family members irrespective of their clinical status. A functional candidate gene approach was employed for PCR screening and sequencing of the exons and their flanking regions of CRYGC, CRYGD, and CRYAA genes. For structural consequences of the mutated alphaA-crystallin we used the bioinformatics tool of the ExPASy server. RESULTS: Sequence analysis of CRYGC and CRYGD genes excluded possible causative mutations but identified known polymorphisms. Sequencing of the exons of the CRYAA gene identified a sequence variation in exon 2 (292 G->A) with a substitution of Gly to Arg at position 98. All three affected members revealed this change but it was not observed in the unaffected father or sister. The putative mutation obliterated a restriction site for the enzyme BstDSI. The same was checked in controls representing the general population of the same ethnicity (n=30) and of randomly selected DNA samples from ophthalmologically normal individuals from the population-based KORA S4 study (n=96). Moreover, the Gly at position 98 is highly conserved throughout the animal kingdom. For the mutant protein, the isoelectric point was raised from pH 5.77 to 5.96. Moreover, an extended alpha-helical structure is predicted in this region. CONCLUSIONS: The G98R mutation segregates only in affected family members and is not seen in representative controls. It represents very likely the fourth dominant cataract-causing allele in CRYAA. In all reported alleles the basic amino acid Arg is involved, suggesting the major importance of the net charge of the alphaA-crystallin for functional integrity in the lens.

Targeted Integration of Single-Copy Transgenes in Drosophila melanogaster Tissue-Culture Cells Using Recombination-Mediated Cassette Exchange.

Transfection of transgenes into Drosophila cultured cells is a standard approach for studying gene function. However, the number of transgenes present in the cell following transient transfection or stable random integration varies, and the resulting differences in expression level affect interpretation. Here we developed a system for Drosophila cell lines that allows selection of cells with a single-copy transgene inserted at a specific genomic site using recombination-mediated cassette exchange (RMCE). We used the φC31 integrase and its target sites attP and attB for RMCE. Cell lines with an attP-flanked genomic cassette were transfected with donor plasmids containing a transgene of interest (UAS-x), a dihydrofolate reductase (UAS-DHFR) gene flanked by attB sequences, and a thymidine kinase (UAS-TK) gene in the plasmid backbone outside the attB sequences. In cells undergoing RMCE, UAS-x and UAS-DHFR were exchanged for the attP-flanked genomic cassette, and UAS-TK was excluded. These cells were selected using methotrexate, which requires DHFR expression, and ganciclovir, which causes death in cells expressing TK. Pure populations of cells with one copy of a stably integrated transgene were efficiently selected by cloning or mass culture in ∼6 weeks. Our results show that RMCE avoids the problems associated with current methods, where transgene number is not controlled, and facilitates the rapid generation of Drosophila cell lines in which expression from a single transgene can be studied.