Prognostic Value of Histone Modifying Enzyme EZH2 in RCHOP-Treated Diffuse Large B-Cell Lymphoma and High Grade B-Cell Lymphoma.

BACKGROUND: DLBCL represent a heterogeneous group of aggressive diseases. High grade B-cell lymphomas (HGBCL) were recently individualized from DLBCL as a discrete diagnostic entity due to their worse prognosis. Currently, although most patients are successfully treated with RCHOP regimens, 1/3 will either not respond or ultimately relapse. Alterations in histone modifying enzymes have emerged as the most common alterations in DLBCL, but their role as prognostic biomarkers is controversial. We aimed to ascertain the prognostic value of EZH2 immunoexpression in RCHOP-treated DLBCL and HGBCL. RESULTS: We performed a retrospective cohort study including 125 patients with RCHOP-treated DLBCL or HGBCL. EZH2 expression levels did not differ between diagnostic groups or between DLBCL-NOS molecular groups. We found no associations between EZH2 expression levels and outcome, including in the subgroup analysis (GC versus non-GC). Nonetheless, EZH2/BCL2 co-expression was significantly associated with worse outcome (event free survival and overall survival). CONCLUSION: Although EZH2 mutations are almost exclusively found in GC-DLBCL, we found similar EZH2 expression levels in both DLBCL-NOS molecular groups, suggesting non-mutational mechanisms of EZH2 deregulation. These findings suggest that the use of EZH2 antagonists might be extended to non-GC DLBCL patients with clinical benefit. EZH2/BCL2 co-expression was associated with a worse outcome.

Self-harm as a predisposition for suicide attempts: A study of adolescents' deliberate self-harm, suicidal ideation, and suicide attempts.

The aim of this study was to analyze the predictive risk factors for self-harm in adolescents with and without suicidal ideation. 600 adolescents answered a questionnaire about self-harm and suicidal behaviors. A logistic regression analysis was conducted. Over half of the individuals with deliberate self-harm (DSH) presented significant suicide risk. There was a direct association between DSH and suicide attempts, with almost the totality of the adolescents with suicide attempts also reporting DSH. According to the prediction model, suicidal ideation and diversity of DSH behaviors are significant predictors of suicide attempts, with an augmentation in the diversity of DSH behaviors and suicidal ideation predicting suicide attempts. Depression and anxiety appeared also as significant predictors of suicide attempts in adolescent self-harmers. Considering that the majority of the sample was not from a clinical setting, an alarming finding was that one third of the total sample was at suicide risk. These results place DSH as a key variable for early intervention.

Subtyping Lung Cancer Using DNA Methylation in Liquid Biopsies.

BACKGROUND: Lung cancer (LCa) is the most frequently diagnosed and lethal cancer worldwide. Histopathological subtyping, which has important therapeutic and prognostic implications, requires material collection through invasive procedures, which might be insufficient to enable definitive diagnosis. Aberrant DNA methylation is an early event in carcinogenesis, detectable in circulating cell-free DNA (ccfDNA). Herein, we aimed to assess methylation of selected genes in ccfDNA from LCa patients and determine its accuracy for tumor subtyping. METHODS: Methylation levels of APC, HOXA9, RARß2, and RASSF1A were assessed in three independent study groups (study group #1: 152 tissue samples; study group #2: 129 plasma samples; study group #3: 28 benign lesions of lung) using quantitative methylation-specific PCR. Associations between gene promoter methylation levels and LCa subtypes were evaluated using non-parametric tests. Receiver operating characteristic (ROC) curve analysis was performed. RESULTS: In study group #2, HOXA9 and RASSF1A displayed higher methylation levels in small-cell lung cancer (SCLC) than in non-small-cell lung cancer (NSCLC). HOXA9 displayed high sensitivity (63.8%), whereas RASSF1A disclosed high specificity (96.2%) for SCLC detection in ccfDNA. Furthermore, HOXA9 methylation levels showed to be higher in squamous cell carcinoma in comparison with adenocarcinoma in study group #1. CONCLUSIONS: Methylation level assessments in ccfDNA may provide a minimally invasive procedure for LCa subtyping, complementing standard diagnostic procedures.

Prognostic value of histone marks H3K27me3 and H3K9me3 and modifying enzymes EZH2, SETDB1 and LSD-1 in colorectal cancer.

PURPOSE: Studies on the performance of epigenetic-based biomarkers in colorectal cancer (CRC) are scarce and have shown contradictory results. Thus, we sought to examine the prognostic value of histone-modifying enzymes (EZH2, SETDB1 and LSD-1) and histone post-translational marks (H3K27me3 and H3K9me3) in CRC. METHODS: A retrospective series of 207 CRC patients primarily submitted to surgery in a cancer center was included in this study. Clinicopathological data were retrieved. One representative paraffin block per case was selected for immunohistochemistry, including normal and CRC tissues whenever possible. The percentage of positive nuclear staining (digital image analysis) was used to classify patients into "low" and "high" expression groups for each biomarker. Correlations between immunoexpression levels, clinicopathological features and clinical outcomes [disease-specific (DSS) and disease-free (DFS) survival] were examined. Statistical significance was set at p < 0.05. RESULTS: CRC tissues showed significantly lower expression of SETDB1 and higher expression of the remainder four biomarkers compared to normal mucosa. High EZH2 expression correlated with disease recurrence/progression, whereas low LSD1 expression and high H3K9me3 and H3K27me3 expression were associated with more advanced stage. In multivariable analysis, cases with high LSD1 expression displayed significantly better DSS and DFS (HR 0.477, 95% confidence interval: 0.247-0.923) adjusted for pathological TNM stage. CONCLUSION: EZH2, SETDB1, LSD1, H3K9me3 and H3K27me3 expression are altered in CRC and may play a role in colorectal carcinogenesis. LSD1 immunoexpression levels independently predicted patient outcome in this cohort. Further investigations, using larger series, are warranted to confirm its potential clinical value and unravel underlying molecular mechanisms.

Depressive symptoms are associated with poor glycemic control among women with type 2 diabetes mellitus.

OBJECTIVE: In patients with type 2 diabetes mellitus, depressive symptoms may be associated with metabolic deterioration. The impact of sex on this association is unclear. The aim of this study is to analyze the relationship between depression and metabolic control by sex. The data presented is the side product of the clinical investigation by Rui Duarte, MD, Treatment Response in Type 2 Diabetes Patients with Major Depression from 2007. RESULTS: A sample of 628 outpatients with type 2 diabetes mellitus was taken from a specialized diabetes outpatient clinic. In a univariate analysis: women's glycohemoglobin mean levels were 8.99% whereas men's were 8.41% and the difference was statistically significant. The proportion of women (34.3%) with pathological levels of depression (Hospital Anxiety Depression Scale score ≥ 8) was significantly higher than men's (15.2%). A linear regression analysis performed by sex and controlling for demographic, clinical and psychological variables, showed poorer metabolic control in women with depressive symptoms. No association was observed in men. These results support depression as a predictor for poor metabolic control in women and the need for detecting depressive symptoms when glycemic levels deteriorate.

The role of affective temperament as a predictor of relapse in alcohol dependence.

BACKGROUND: Personality traits have been proposed as relapse risk factors in alcohol use disorders. So far, no study has assessed the association between affective temperamental traits and the prospective relapse risk. METHODS: This was a 3-month prospective naturalistic study, designed to assess the impact of affective temperaments in relapse. A sample of 61 alcohol-dependent patients was collected from an ambulatory clinical setting. Socio-demographic information, drinking and substance use habits, drinking status, craving and affective temperament traits were assessed. RESULTS: Age, age of onset of alcohol abuse and dependence and drug consumption correlate with drinking status. Male alcohol-dependent patients who relapsed presented higher scores on cyclothymic temperament than patients with an alcohol dependence diagnosis who remain sober. Hierarchical logistic regression indicates that cyclothymic temperament predicted relapse in a 3-month follow-up. However, the coefficient was marginally significant after controlling for all potential confounding predictors. CONCLUSIONS: Our results provide new insights about the role of affective temperaments in alcohol use disorders, specifically in predicting short-term relapse in detoxified male alcohol-dependent patients. Copyright © 2017 John Wiley & Sons, Ltd.