The presence of the gadolinium-based contrast agent depositions in the brain and symptoms of gadolinium neurotoxicity - A systematic review

<div><p>Background and purpose</p><p>Gadolinium based contrast agents (GBCAs) are widely used in magnetic resonance imaging, but recently, high signal intensity in the cerebellum structures was reported after repeated administrations of contrast- enhanced magnetic resonance images. The aim of this systematic review was to investigate the association between increased signal intensity in the dentate nucleus and globus pallidus in the brain and repeated administrations of GBCAs. Additionally, we focused on possible short- and long-term consequences of gadolinium use in those patients.</p><p>Methods</p><p>Systematic review of retrospective investigations in PubMed and Medline was performed in July 2016. Primary outcomes included the presence of increased signal intensity within the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in patients following administrations of GBCAs. Two independent reviewers were responsible for search and data extraction.</p><p>Results</p><p>25 publications satisfied inclusion criteria (19 magnetic resonance images analyses, 3 case reports; 3 autopsy studies). Magnetic resonance images of 1247 patients with increased signal intensity on unenhanced T1-weighted MR images were analyzed as well as tissue specimens from 27 patients. Signal intensity correlated positively with the exposure to GBCAs and was greater after serial administrations of linear nonionic than cyclic contrast agents. Gadolinium was detected in all tissue examinations.</p><p>Conclusions</p><p>High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted magnetic resonance images were associated with previous administration of GBCAs. Signal intensity correlated negatively with stability of contrast agents. Clinical significance of gadolinium deposition in the brain remains unclear. There is a strong need for further research to identify type of gadolinium deposited in the brain as well as to gather knowledge about long-term consequences.</p></div

Publications included in the systematic review.

<p>Publications included in the systematic review.</p

Flow Diagram based on PRISMA Statement [4].

<p>Flow Diagram based on PRISMA Statement [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0171704#pone.0171704.ref004" target="_blank">4</a>].</p

Whole-genome DNA methylation characteristics in pediatric precursor B cell acute lymphoblastic leukemia (BCP ALL)

<div><p>In addition to genetic alterations, epigenetic abnormalities have been shown to underlie the pathogenesis of acute lymphoblastic leukemia (ALL)—the most common pediatric cancer. The purpose of this study was to characterize the whole genome DNA methylation profile in children with precursor B-cell ALL (BCP ALL) and to compare this profile with methylation observed in normal bone marrow samples. Additional efforts were made to correlate the observed methylation patterns with selected clinical features. We assessed DNA methylation from bone marrow samples obtained from 38 children with BCP ALL at the time of diagnosis along with 4 samples of normal bone marrow cells as controls using Infinium MethylationEPIC BeadChip Array. Patients were diagnosed and stratified into prognosis groups according to the BFM ALL IC 2009 protocol. The analysis of differentially methylated sites across the genome as well as promoter methylation profiles allowed clear separation of the leukemic and control samples into two clusters. 86.6% of the promoter-associated differentially methylated sites were hypermethylated in BCP ALL. Seven sites were found to correlate with the BFM ALL IC 2009 high risk group. Amongst these, one was located within the gene body of the <i>MBP</i> gene and another was within the promoter region- <i>PSMF1</i> gene. Differentially methylated sites that were significantly related with subsets of patients with <i>ETV6-RUNX1</i> fusion and hyperdiploidy. The analyzed translocations and change of genes’ sequence context does not affect methylation and methylation seems not to be a mechanism for the regulation of expression of the resulting fusion genes.</p></div

Principal component analysis 3D plot based on 500 probes with the highest differences in methylation level among genetic subtypes and remaining pre-B ALL patients.

<p>The plot is presented in three different layouts to enable visualization of separate clusters.</p

PCA based on 118,871 sites differentially methylated between BCP ALL and control samples.

<p>PCA based on 118,871 sites differentially methylated between BCP ALL and control samples.</p

Top ten KEGG pathways connected with genes containing sites differentially methylated between specific genetic subtype and remaining BCP ALL patients.

<p>Top ten KEGG pathways connected with genes containing sites differentially methylated between specific genetic subtype and remaining BCP ALL patients.</p

Unsupervised hierarchical clustering of promoter regions-associated methylation profiles in leukemic and control samples.

<p>Unsupervised hierarchical clustering of promoter regions-associated methylation profiles in leukemic and control samples.</p

The most important DM sites in patients from particular BCP ALL subgroups extracted using the lasso penalized logistic regression analysis.

<p>The most important DM sites in patients from particular BCP ALL subgroups extracted using the lasso penalized logistic regression analysis.</p

PCA based on filtered probes set minimizing the variation of methylation profiles in leukemic samples.

<p>PCA based on filtered probes set minimizing the variation of methylation profiles in leukemic samples.</p