Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD

<p>Objective: Posttraumatic stress disorder (PTSD) has been shown to be associated with altered glucocorticoid receptor (GR) activity. We studied the expression and functional properties of the receptor in peripheral blood mononuclear cells (PBMCs) from non-traumatized healthy individuals (healthy controls; n = 85), and war trauma-exposed individuals with current PTSD (n = 113), with life-time PTSD (n = 61) and without PTSD (trauma controls; n = 88). The aim of the study was to distinguish the receptor alterations related to PTSD from those related to trauma itself or to resilience to PTSD.</p><p>Methods: Functional status of the receptor was assessed by radioligand binding and lysozyme synthesis inhibition assays. The level of GR gene expression was measured by quantitative PCR and immunoblotting.</p><p>Results: Current PTSD patients had the lowest, while trauma controls had the highest number of glucocorticoid binding sites (B-max) in PBMCs. Hormone-binding potential (B-max/K-D ratio) of the receptor was diminished in the current PTSD group in comparison to all other study groups. Correlation between B-max and K-D that normally exists in healthy individuals was decreased in the current PTSD group. Contrasting B-max data, GR protein level was lower in trauma controls than in participants with current or life-time PTSD.</p><p>Conclusions: Current PTSD is characterized by reduced lymphocyte GR hormone-binding potential and by disturbed compensation between B-max and hormone-binding affinity. Resilience to PTSD is associated with enlarged fraction of the receptor molecules capable of hormone binding, within the total receptor molecule population in PBMCs. (C) 2013 Elsevier Inc. All rights reserved.</p>

Adjuvant vemurafenib in resected, BRAF V600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma. METHODS: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·026). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population