Introduction

Left atrial (LA) tissue characteristics may play an important role in atrial fibrillation (AF) induction and perpetuation. Although frequently used in clinical practice, computed tomography (CT) has not been employed to describe differences in LA wall properties between AF patients and controls. We sought to noninvasively characterize AF-associated differences in LA tissue using CT.

Methods

CT images of the LA were obtained in 98 consecutive patients undergoing AF ablation and in 89 controls. A custom software algorithm was used to measure wall thickness and density in four prespecified regions of the LA.

Results

On average, LA walls were thinner (-15.5%, 95% confidence interval [CI] -23.2 to -7.8%, P < 0.001) and demonstrated significantly lower density (-19.7 Hounsfield Units [HU], 95% CI -27.0 to -12.5 HU, P < 0.001) in AF patients compared to controls. In linear mixed models adjusting for demographics, clinical variables, and other CT measurements, the average LA, interatrial septum, LA appendage, and anterior walls remained significantly thinner in AF patients. After adjusting for the same potential confounders, history of AF was associated with reduced density in the LA anterior wall and increased density below the right inferior pulmonary vein and in the LA appendage.

Conclusion

Application of an automated measurement algorithm to CT imaging of the atrium identified significant thinning of the LA wall and regional alterations in tissue density in patients with a history of AF. These findings suggest differences in LA tissue composition can be noninvasively identified and quantified using CT.

We evaluate the topographic distribution of diffuse midline gliomas and hemispheric high-grade gliomas in children with respect to their normal gene expression patterns and pathologic driver mutation patterns. We identified 19 pediatric patients with diffuse midline or high-grade glioma with preoperative MRI from tumor board review. 7 of these had 500 gene panel mutation testing, 11 patients had 50 gene panel mutation testing and one 343 gene panel testing from a separate institution were included as validation set. Tumor imaging features and gene expression patterns were analyzed using Allen Brain Atlas. Twelve patients had diffuse midline gliomas and seven had hemispheric high-grade gliomas. Three diffuse midline gliomas had the K27M mutation in the tail of histone H3 protein. All patients undergoing 500 gene panel testing had additional mutations, the most common being in ACVR1, PPM1D, and p53. Hemispheric high-grade gliomas had either TP53 or IDH1 mutation and diffuse midline gliomas had H3 K27M-mutation. Gene expression analysis in normal brains demonstrated that genes mutated in diffuse midline gliomas had higher expression along midline structures as compared to the cerebral hemispheres. Our study suggests that topographic location of pediatric diffuse midline gliomas and hemispheric high-grade gliomas correlates with driver mutations of tumor to the endogenous gene expression in that location. This correlation suggests that cellular state that is required for increased gene expression predisposes that location to mutations and defines the driver mutations within tumors that arise from that region.

Background

Amino acid PET imaging of brain tumors has been shown to play an important role in predicting tumor grade, delineation of tumor margins, and differentiating tumor recurrence from the background of postradiation changes, but is not commonly used in clinical practice because of high cost. We propose that PET/MRI imaging of patients grouped to the day of tracer radiosynthesis will significantly decrease the cost of PET imaging, which will improve patient access to PET.

Methods

Seventeen patients with either primary brain tumors or metastatic brain tumors were recruited for imaging on 3T PET/MRI and were scanned on 4 separate days in groups of 3 to 5 patients. The first group of consecutively imaged patients contained 3 patients, followed by 2 groups of 5 patients, and a last group of 4 patients.

Results

For each of the patients, standard of care gadolinium-enhanced MRI and dynamic PET imaging with ¹⁸F-FDOPA amino acid tracer was obtained. The total cost savings of scanning 17 patients in batches of 4 as opposed to individual radiosynthesis was 48.5% ($28 321). Semiquantitative analysis of tracer uptake in normal brain were performed with appropriate accumulation and expected subsequent washout.

Conclusion

Amino acid PET tracers have been shown to play a critical role in the characterization of brain tumors but their adaptation to clinical practice has been limited because of the high cost of PET. Scheduling patient imaging to maximally use the radiosynthesis of imaging tracer significantly reduces the cost of PET and results in increased availability of PET tracer use in neuro-oncology.

Abstract Long-term neurocognitive deficits in pediatric brain tumor survivors are challenging to both predict and treat. In a previous cohort analysis, we identified the genetic variant for ApoE4 reliably correlates with decreased neurocognitive function over time. Herein, we present case-control analyses comparing neurocognitive outcomes of ApoE4 carriers versus non-carriers in a group of pediatric brain tumor survivors. Utilizing an existing cohort of pediatric brain tumor patients from a diverse population, we isolated cases heterozygous for ApoE4 and matched these to controls carrying ApoE3. Priority was placed on matching cases and controls along variables previously identified to impact neurocognition – time from radiation and hydrocephalus or seizures at diagnosis. Student t-tests and lowess smoothing regression were used to compare outcomes in 6 neurocognitive domains over multiple time points. Twenty matched cases and controls were included in the analyses. At baseline, there were no statistically significant differences between cases and controls in any domain. Over time, ApoE3 controls performed statistically significantly higher across an increasing number of neurocognitive domains than ApoE4 carriers. Using smoothing regression, cases visibly performed worse over time as compared to controls and as seen by decreasing neurocognitive scores across all domains. ApoE4 carrier status strongly correlates with neurocognition function over time in pediatric brain tumor survivors. This effect appears across multiple domains and may show evidence of progressive deterioration with each year from treatment. Our results identify ApoE4 as a possible genetic predictor for neurocognitive outcomes in pediatric brain tumor survivors and support further investigation of this genetic variant.

Epigenetic changes, such as alteration of DNA methylation patterns, have been proposed as a molecular mechanism underlying the effect of alcohol on the maintenance of adult stem cells. We have performed genome-wide gene expression microarray and DNA methylome analysis to identify molecular alterations via DNA methylation changes associated with exposure of human dental pulp stem cells (DPSCs) to ethanol (EtOH). By combined analysis of the gene expression and DNA methylation, we have found a significant number of genes that are potentially regulated by EtOH-induced DNA methylation. As a focused approach, we have also performed a pathway-focused RT-PCR array analysis to examine potential molecular effects of EtOH on genes involved in epigenetic chromatin modification enzymes, fibroblastic markers, and stress and toxicity pathways in DPSCs. We have identified and verified that lysine specific demethylase 6B (KDM6B) was significantly dysregulated in DPSCs upon EtOH exposure. EtOH treatment during odontogenic/osteogenic differentiation of DPSCs suppressed the induction of KDM6B with alterations in the expression of differentiation markers. Knockdown of KDM6B resulted in a marked decrease in mineralization from implanted DPSCs in vivo. Furthermore, an ectopic expression of KDM6B in EtOH-treated DPSCs restored the expression of differentiation-related genes. Our study has demonstrated that EtOH-induced inhibition of KDM6B plays a role in the dysregulation of odontogenic/osteogenic differentiation in the DPSC model. This suggests a potential molecular mechanism for cellular insults of heavy alcohol consumption that can lead to decreased mineral deposition potentially associated with abnormalities in dental development and also osteopenia/osteoporosis, hallmark features of fetal alcohol spectrum disorders.

Abstract

OBJECTIVE

To identify genetic predictors of neurocognition, CMBs, brain volume, and WM changes in pediatric brain tumor survivors.

METHODS

Patients were selected from an existing cohort (RadART) if they had: 1) at least one neurocognitive evaluation using computer-based CogState; 2) available DNA; 3) standard imaging. Candidate gene or genome-wide genotyping was performed on all patients. CMBs were identified using a semi-automated algorithm developed in MATLAB. Volume of T2/FLAIR WM signal abnormality was measured using a semi-automated method based on a convolutional neural network. Brain volume and cortical thickness were measured using FreeSurfer volumetric analysis. Logistic and linear regression were done to compare phenotypes with candidate genotypes. Genome-wide efficient mixed-model analysis was done to compare neurocognition and CMBs. Gene set analysis was done using https://fuma.ctglab.nl/.

RESULTS

APOE4 was a candidate variant associated with non-lobar, larger volume CMBs (p< 0.05). At the GWAS-level (n=225), specific genes trended with visual memory, psychomotor function, and CMB count (p< 5x10-8). Using gene set analyses, there were gene set trends seen with CMB count and psychomotor function. Small sample size and low mutant allele frequency limited reliability of these findings. Preliminary volumetric analysis show reduced volume within the right parietal, medial occipital and inferior temporal lobes with increased cortical thickness in the left occipital and medial parietal lobe in patients carrying the ApoE4 allele. WM signal assessments are ongoing.

CONCLUSION

Genetic markers may be associated with neurocognition, CMBs, brain volume and WM changes in pediatric brain tumor survivors; however, larger cohorts are needed to confirm specific gene relevance.

Abstract

OBJECTIVE

To identify genetic predictors of neurocognition, CMBs, brain volume, and WM changes in pediatric brain tumor survivors.

METHODS

Patients were selected from an existing cohort (RadART) if they had: 1) at least one neurocognitive evaluation using computer-based CogState; 2) available DNA; 3) standard imaging. Candidate gene or genome-wide genotyping was performed on all patients. CMBs were identified using a semi-automated algorithm developed in MATLAB. Volume of T2/FLAIR WM signal abnormality was measured using a semi-automated method based on a convolutional neural network. Brain volume and cortical thickness were measured using FreeSurfer volumetric analysis. Logistic and linear regression were done to compare phenotypes with candidate genotypes. Genome-wide efficient mixed-model analysis was done to compare neurocognition and CMBs. Gene set analysis was done using https://fuma.ctglab.nl/.

RESULTS

APOE4 was a candidate variant associated with non-lobar, larger volume CMBs (p<0.05). At the GWAS-level (n=225), specific genes trended with visual memory, psychomotor function, and CMB count (p<5x10-8). Using gene set analyses, there were gene set trends seen with CMB count and psychomotor function. Small sample size and low mutant allele frequency limited reliability of these findings. Preliminary volumetric analysis show reduced volume within the right parietal, medial occipital and inferior temporal lobes with increased cortical thickness in the left occipital and medial parietal lobe in patients carrying the ApoE4 allele. WM signal assessments are ongoing.

CONCLUSION

Genetic markers may be associated with neurocognition, CMBs, brain volume and WM changes in pediatric brain tumor survivors; however, larger cohorts are needed to confirm specific gene relevance.