Prevalence of Neurobehavioral, Social, and Emotional Dysfunction in Patients Treated for Childhood Craniopharyngioma: A Systematic Literature Review

<div><p>Background</p><p>Craniopharyngiomas (CP) are locally invasive and frequently recurring neoplasms often resulting in neurological and endocrinological dysfunction in children. In addition, social-behavioral impairment is commonly reported following treatment for childhood CP, yet remains to be fully understood. The authors aimed to further characterize the prevalence of neurobehavioral, social, and emotional dysfunction in survivors of childhood craniopharyngiomas.</p> <p>Materials and Methods</p><p>A systematic literature review was conducted in PubMed to identify studies formally assessing neurobehavioral, social, and emotional outcomes in patients treated for CP prior to 18 years of age. Studies published between the years 1990-2012 that reported the primary outcome (prevalence of neurobehavioral, social, emotional/affective dysfunction, and/or impaired quality of life (QoL)) in ≥10 patients were included.</p> <p>Results</p><p>Of the 471 studies screened, 11 met inclusion criteria. Overall neurobehavioral dysfunction was reported in 51 of 90 patients (57%) with available data. Social impairment (i.e. withdrawal, internalizing behavior) was reported in 91 of 222 cases (41%). School dysfunction was reported in 48 of 136 patients (35%). Emotional/affective dysfunction was reported in 58 of 146 patients (40%), primarily consisting of depressive symptoms. Health related quality of life was affected in 49 of 95 patients (52%). Common descriptors of behavior in affected children included irritability, impulsivity, aggressiveness, and emotional outbursts.</p> <p>Conclusions</p><p>Neurobehavioral, social, and emotional impairment is highly prevalent in survivors of childhood craniopharyngioma, and often affects quality of life. Thorough neurobehavioral/emotional screening and appropriate counseling is recommended in this population. Additional research is warranted to identify risk factors and treatment strategies for these disorders.</p> </div

Flow diagram detailing the flow of information and study selection through the systematic review process.

<p>Flow diagram detailing the flow of information and study selection through the systematic review process.</p

The Role of Epigenetic Modification in Tumorigenesis and Progression of Pituitary Adenomas: A Systematic Review of the Literature

<div><p>Background</p><p>Pituitary adenomas (PAs) are commonly occurring neoplasms with diverse endocrine and neurological effects. Although somatic gene mutations are uncommon in sporadic PAs, recent studies lend support to epigenetic modification as a potential cause of tumorigenesis and tumor progression.</p> <p>Methods</p><p>A systematic literature review of the PubMed and Google Scholar databases was conducted to identify abstracts (n=1,082) pertaining to key targets and mechanisms implicated in epigenetic dysregulation of PAs published between 1993-2013. Data regarding histopathological subtype, target genes, mode of epigenetic modification, and clinical correlation were recorded and analyzed.</p> <p>Results</p><p>Of the 47 that studies met inclusion criteria and focused on epigenomic assessment of PAs, only 2 were genome-scale analyses. Current evidence supports epigenetic alteration in at least 24 PA genes, which were categorized into four groups based on function and epigenetic alteration: 1) Sixteen tumor suppressor genes silenced via DNA methylation; 2) Two oncogenes overexpressed via histone acetylation and hypomethylation; 3) Three imprinted genes with selective allelic silencing; and 4) One epigenome writer inducing abnormal genome-scale activity and 5) Two transcription regulators indirectly modifying the genome. Of these, 5 genes (<i>CDKN2A, GADD45y, FGFR2</i>, caspase-8, and <i>PTAG</i>) showed particular susceptibility to epigenetic modification, with abnormal DNA methylation in >50% of PA samples. Several genes displayed correlations between epigenetic modification and clinically relevant parameters, including invasiveness (<i>CDKN2A; DAPK; Rb1</i>), sex (<i>MAGE-A3</i>), tumor size (<i>GNAS1</i>), and histopathological subtype (<i>CDKN2A; MEG3; p27; RASSF1A; Rb1</i>).</p> <p>Conclusions</p><p>Epigenetic modification of selected PA genes may play a key role in tumorigenesis and progression, which may translate into important diagnostic and therapeutic applications.</p> </div

Flow diagram depicting systematic review search results according to phases.

<p>Flow diagram depicting systematic review search results according to phases.</p

A Pilot Genome-Scale Profiling of DNA Methylation in Sporadic Pituitary Macroadenomas: Association with Tumor Invasion and Histopathological Subtype

<div><p>Pituitary adenomas (PAs) are neoplasms that may cause a variety of neurological and endocrine effects. Although known causal contributors include heredity, hormonal influence and somatic mutations, the pathophysiologic mechanisms driving tumorigenesis and invasion of sporadic PAs remain unknown. We hypothesized that alterations in DNA methylation are associated with PA invasion and histopathology subtype, and that genome-scale methylation analysis may complement current classification methods for sporadic PAs. Twenty-four surgically-resected sporadic PAs with varying histopathological subtypes were assigned dichotomized Knosp invasion scores and examined using genome-wide DNA methylation profiling and RNA sequencing. PA samples clustered into subgroups according to functional status. Compared with hormonally-active PAs, nonfunctional PAs exhibited global DNA hypermethylation (mean beta-value 0.47 versus 0.42, <i>P</i> = 0.005); the most significant site of differential DNA methylation was within the promoter region of the potassium voltage-gated channel <i>KCNAB2</i> (FDR = 5.11×10⁻¹⁰). Pathway analysis of promoter-associated CpGs showed that nonfunctional PAs are potentially associated with the ion-channel activity signal pathway. DNA hypermethylation tended to be negatively correlated with gene expression. DNA methylation analysis may be used to identify candidate genes involved in PA function and may potentially complement current standard immunostaining classification in sporadic PAs. DNA hypermethylation of <i>KCNAB2</i> and downstream ion-channel activity signal pathways may contribute to the endocrine-inactive status of nonfunctional PAs.</p></div

Gene expression.

<p>A, Linear regression analysis showed negative trend of DNA methylation and gene expression. B, Three overlapped significant genes of DNA methylation and gene expression when compared NFAs to FAs. C, gene <i>ODAM</i> expression in one FA subject of d0079 which secreted hormones of GH and TSH, <i>GAPDH</i> gene expression was used as control.</p

Top 30 significant genes with differential DNA methylation between NFAs and FAs.

a<p>Probe_CpG: the Illumina HM450 probe ID.</p>b<p>SD: standard deviation.</p>c<p>NFA-FA: the mean beta value subtractive difference between NFA tumors and FA tumors.</p>d<p>FDR: False Discovery Rate.</p>e<p>TSS200: 200 bp within transcription start site.</p>f<p>TSS1500: 1500 bp within the transcription start site.</p><p>* Promoter Associated.</p><p>Link to the whole information of the Probe_CpG: <a href="http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL13534" target="_blank">http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL13534</a>.</p

Patient and tumor characteristics.

<p>M: Male, F: Female; Age: Year unit; PRL: Prolactin; TR × CC: Transverse (mm) × Antero-posterior (mm). The average size of all PAs was 23.55 TR mm × 19.36 CC mm; NA: Not applicable. Invasion: “0” represents noninvasive PAs, “1” represents invasive PAs; Ave: Average; Knosp: Knosp grade of PAs.</p

Hierarchical Clustering of DNA methylation in 24 PA cases.

<p>The HM450 probes (7,674) with the highest 2% of standard deviation across the set of 383,718 global HM450 probes were used.</p

Global CpG DNA methylation profiles in PAs.

<p>A, Comparison of mean DNA methylation levels across 383,718 HM450 probes in noninvasive (Knosp grade 0, 1) and invasive (Knosp grade 2, 3, 4) PAs. B, Mean DNA methylation levels in PA cases across the five different Knosp grades (0–4) among the set of 383,718 HM450 probes. C, Comparison of mean DNA methylation levels across 383,718 HM450 probes in FAs and NFAs. P-value was calculated via simple t-test. D, Comparison of mean DNA methylation levels across 383,718 HM450 probes in only NFAs. P-value was calculated via simple t-test. All of the above DNA methylation beta values are shown as mean ± SEM in different groups. E and F, DNA methylation levels in gene regions (TSS1500, TSS200, 5′UTR, 1stExon, gene body and 3′UTR) for NFAs (panel E) and FAs (Panel F). TSS200: 200 bp within transcription start site; TSS1500: 1500 bp within transcription start site; UTR: untranslated region; 1stExon: the first exon of gene.</p