The reliability of the Epworth Sleepiness Score in a sleep clinic population.

Despite the Epworth Sleepiness Score being widely used, there are limited studies of its reliability in clinical practice. The aim of this study was to assess the reliability of the Epworth Sleepiness Score in a clinical population. The study included patients referred to Middlemore Hospital sleep service between October and November 2014, aged over 17 years, with at least two Epworth Sleepiness Score measurements at up to three different points on the diagnostic pathway: on General Practitioner referral (GP Epworth Sleepiness Score); at overnight oximetry assessment (Oximetry Epworth Sleepiness Score); and at a specialist clinic (Specialist Epworth Sleepiness Score). No treatment was administered between scores. One-hundred and thirty-three patients were included in the study. There was a median of 91 days from GP Epworth Sleepiness Score to Oximetry Epworth Sleepiness Score, and 11 days from Oximetry Epworth Sleepiness Score to Specialist Epworth Sleepiness Score. There was poor test-retest reliability between GP Epworth Sleepiness Score and Specialist Epworth Sleepiness Score; 72.4% and 17.8% of patients had an absolute difference of more than 2 and 8 Epworth Sleepiness Score points, respectively. A Bland-Altman plot of mean Epworth Sleepiness Score versus the difference between GP Epworth Sleepiness Score and Specialist Epworth Sleepiness Score demonstrated a wide scatter of data and 95% confidence interval for the difference in Epworth Sleepiness Score for an individual patient of -14 to +10. There was similar variability between GP Epworth Sleepiness Score and Oximetry Epworth Sleepiness Score. The reliability of the Epworth Sleepiness Score is unproven in clinical settings. This study shows poor test-retest reliability of Epworth Sleepiness Score, particularly between primary and secondary care, arguing against the use of Epworth Sleepiness Score for clinical decision-making or prioritisation of services without first assessing the reliability of the Epworth Sleepiness Score in the relevant clinical population.

Loss of heterozygosity of TRIM3 in malignant gliomas.

BACKGROUND: Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Besides sharing common growth features with other types of solid tumors, gliomas are highly invasive into adjacent brain tissue, which renders them particularly aggressive and their surgical resection inefficient. Therefore, insights into glioma formation are of fundamental interest in order to provide novel molecular targets for diagnostic purposes and potential anti-cancer drugs. Human Tripartite motif protein 3 (TRIM3) encodes a structural homolog of Drosophila brain tumor (brat) implicated in progenitor cell proliferation control and cancer stem cell suppression. TRIM3 is located within the loss of allelic heterozygosity (LOH) hotspot of chromosome segment 11p15.5, indicating a potential role in tumor suppression. METHODS: Here we analyze 70 primary human gliomas of all types and grades and report somatic deletion mapping as well as single nucleotide polymorphism analysis together with quantitative real-time PCR of chromosome segment 11p15.5. RESULTS: Our analysis identifies LOH in 17 cases (24%) of primary human glioma which defines a common 130 kb-wide interval within the TRIM3 locus as a minimal area of loss. We further detect altered genomic dosage of TRIM3 in two glioma cases with LOH at 11p15.5, indicating homozygous deletions of TRIM3. CONCLUSION: Loss of heterozygosity of chromosome segment 11p15.5 in malignant gliomas suggests TRIM3 as a candidate brain tumor suppressor gene.

IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival.

BACKGROUND: Low-grade gliomas (LGGs) are rare brain neoplasms, with survival spanning up to a few decades. Thus, accurate evaluations on how biomarkers impact survival among patients with LGG require long-term studies on samples prospectively collected over a long period. METHODS: The 210 adult LGGs collected in our databank were screened for IDH1 and IDH2 mutations (IDHmut), MGMT gene promoter methylation (MGMTmet), 1p/19q loss of heterozygosity (1p19qloh), and nuclear TP53 immunopositivity (TP53pos). Multivariate survival analyses with multiple imputation of missing data were performed using either histopathology or molecular markers. Both models were compared using Akaike's information criterion (AIC). The molecular model was reduced by stepwise model selection to filter out the most critical predictors. A third model was generated to assess for various marker combinations. RESULTS: Molecular parameters were better survival predictors than histology (ΔAIC = 12.5, P< .001). Forty-five percent of studied patients died. MGMTmet was positively associated with IDHmut (P< .001). In the molecular model with marker combinations, IDHmut/MGMTmet combined status had a favorable impact on overall survival, compared with IDHwt (hazard ratio [HR] = 0.33, P< .01), and even more so the triple combination, IDHmut/MGMTmet/1p19qloh (HR = 0.18, P< .001). Furthermore, IDHmut/MGMTmet/TP53pos triple combination was a significant risk factor for malignant transformation (HR = 2.75, P< .05). CONCLUSION: By integrating networks of activated molecular glioma pathways, the model based on genotype better predicts prognosis than histology and, therefore, provides a more reliable tool for standardizing future treatment strategies.

The 10q25.3-26.1 G protein-coupled receptor gene GPR26 is epigenetically silenced in human gliomas.

Loss of heterozygosity (LOH) of the entire chromosome 10 is the most frequent genetic alteration in human glioblastoma (GBM). In addition to PTEN/MMAC1 on 10q23.3, clustering of partial deletion break-points on 10q25.3-26.1 points to a second suppressor locus. The proposed target gene DMBT1 was not confirmed. By somatic deletion mapping of this region, we identified the complementary DNA encoding the human homologue of rat orphan G protein-coupled receptor GPR26. GPR26 is highly expressed in fetal and adult brain, but frequently reduced or absent in glioma cells and biopsies, due to de novo methylation of its 5' CpG island. Silencing of GPR26 was reversed with 5-aza-deoxycytidine and the histone deacetylase inhibitor trichostatin A. Furthermore, overexpression of GPR26 in HEK and in U87 glioma cells increased intracellular cAMP concentration which is considered to induce astrocytic differentiation. Interestingly, we observed concomitant silencing of GPR26 with O6-methylguanine-DNA methyl transferase (MGMT), a DNA repair gene co-localized on 10q25.3-26.1 (p=0.0001). We conclude that epigenetic silencing is a common mechanism in malignant gliomas that simultaneously inactivates MGMT and GPR26. The 10q25.3-26.1 region may contain an important epigenetic pathway in brain tumorigenesis.

Evaluation of the effects of human leukocyte IFN-alpha on the immune response to the HBV vaccine in healthy unvaccinated individuals.

HBV vaccine needs 3 injections over 6 months to induce immunity. Thus, the use of adjuvants capable of inducing earlier immune protection would be highly desirable. Most adjuvants may act by inducing cytokines, and among them, type I interferons (IFNs), deserve a special attention in view of the potent immunomostimulatory activity observed in mouse models and on dendritic cell functions. The aim of the present trial was to evaluate the effects of IFN-alpha administered as an adjuvant of HBV vaccine in healthy unvaccinated individuals. No significant enhancing effect on the antibody response was observed, in spite of an early and transient upregulation of costimulatory molecule expression on peripheral blood mononuclear cells, which may be suggestive of an IFN-mediated activation of antigen presenting cells. We conclude that, under the conditions used in this trial, natural IFN-alpha does not act as an adjuvant of the HBV vaccine in healthy unvaccinated individuals.