MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review

BackgroundThe DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use.MethodsWe performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients.ResultsMethylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP.ConclusionsWe cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.     

Hematopoietic stem cell-derived pericytic cells in brain tumor angio-architecture

Bone marrow-derived cells are recruited into tumor vasculature in response to angiogenic signals, and some of the cells within the newly forming tumor vessels are hematopoietic stem cells (HSCs) in origin. Previous studies suggest that bone marrow-derived pericytes are associated with newly formed vessels in tumors. In this study, we used an orthotopic rat glioma model (RT-2/RAG) to examine the contribution of long-term hematopoietic stem cell (LT-HSC)-derived pericytic cells to brain tumor angiogenesis. Mice (RAG-2/KO5.2) were lethally irradiated, and their hematopoietic cells were repopulated by transplantation of double fluorescence-activated cell-sorted LT-HSCs that express green fluorescent protein (GFP+). RT-2/RAG cells were then injected into the striatum of the chimeric mice 6 weeks post-transplantation. The animals were sacrificed 9 days after tumor implantation, and the incorporation and lineage-specific marker expression profile of the GFP+ cells within the growing tumor and tumor periphery were analyzed. LT-HSC-derived GFP+ cells were noted to incorporate onto the surface of tumor vessels within the perivascular space. LT-HSC-derived GFP+ cells express the pericyte progenitor marker, platelet-derived growth factor receptor-beta (PDGFR beta), as well as mature perictyte markers such as nerve/glial antigen 2 proteoglycan (NG2), alpha-smooth muscle actin (alpha SMA), and desmin. These LT-HSC-derived cells may represent a population of progenitor or committed pericytes within the neovascular tree and may play a role in shaping the angio-architecture in the vascular niche of brain tumors.     

Asylum seekers' expectations of and trust in general practice: a qualitative study

Background

The UK has substantial minority populations of short-term and long-term migrants from countries with various types of healthcare systems.

Aim

This study explored how migrants'' previous knowledge and experience of health care influences their current expectations of health care in a system relying on clinical generalists performing a gatekeeping role.

Design of study

Two qualitative methods.

Setting

Glasgow, UK.

Method

Focus groups or semi-structured interviews were conducted with 52 asylum seekers. Analyses identified several areas where previous experience affected current expectations. An overview of health systems in each country of origin was established by combining responders'' accounts with World Health Organization statistics.

Results

Asylum seekers had previous experience of a diverse range of healthcare systems, most of which were characterised by a lack of GPs and direct access to hospital-based specialists. For some responders, war or internal conflict resulted in a complete breakdown of healthcare systems. Responders'' accounts also highlighted the difficulties that marginalised groups had in accessing health care. Although asylum seekers were generally pleased with the care they received from the NHS, there were areas where they experienced difficulties: confidence in their GP and access to hospital-based specialists and medication. These difficulties encountered might be explained by previous experience.

Conclusion

GPs and other healthcare professionals need to be aware that experience of different systems of care can have an impact on individuals'' expectations in a GPled system. If these are not acknowledged and addressed, a lack of confidence and trust in the GP may undermine the effectiveness of the clinical consultation.     

Homozygous bisalbuminemia or homozygous mutant albumin?

IntroductionBisalbuminemia is a genetic condition in which an albumin variant is found in serum in addition to normal albumin.Methods and materialsSerum protein electrophoresis using the Sebia HYDRASYS electrophoresis system was performed on an 84 year old male.ResultsSerum protein electrophoresis showed a single albumin band migrating faster than normal albumin.ConclusionThe presence of a homozygous albumin variant band, albumin Naskapi, is noted.     

A novel double heterozygous, HbD Punjab/HbQ India, hemoglobinopathy

IntroductionHemoglobinopathies and thalassemias together form the most common genetic disease in the world. Double heterozygosity, in which there is a hemoglobin variant, in both the α- and non-α globin chains, is very unusual. A novel double heterozygosity of the α chain variant HbQ India with the non-α chain HbD Punjab is described.Methods and materialsThe index case is a 39 year old female of Indian origin. HPLC analysis using the Bio Rad β thalassemia method and electrophoresis at both alkaline and acid pH were performed.ResultsHPLC shows four major bands and electrophoresis at alkaline pH shows 3 bands and 2 bands at acid pH.DiscussionBoth the HPLC and electrophoresis at alkaline and acid pH are consistent for the double heterozygous hemoglobin variants HbQ India and HbD Punjab.ConclusionThis is the first literature report of the double heterozygosity of HbQ India/HbD Punjab     

Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis

Monocytes (Mo) and macrophages (MΦ) are emerging therapeutic targets in malignant, cardiovascular, and autoimmune disorders. Targeting of Mo/MΦ and their effector functions without compromising innate immunity's critical defense mechanisms first requires addressing gaps in knowledge about the life cycle of these cells. Here we studied the source, tissue kinetics, and clearance of Mo/MΦ in murine myocardial infarction, a model of acute inflammation after ischemic injury. We found that a) Mo tissue residence time was surprisingly short (20 h); b) Mo recruitment rates were consistently high even days after initiation of inflammation; c) the sustained need of newly made Mo was fostered by extramedullary monocytopoiesis in the spleen; d) splenic monocytopoiesis was regulated by IL-1β; and e) the balance of cell recruitment and local death shifted during resolution of inflammation. Depending on the experimental approach, we measured a 24 h Mo/MΦ exit rate from infarct tissue between 5 and 13% of the tissue cell population. Exited cells were most numerous in the blood, liver, and spleen. Abrogation of extramedullary monocytopoiesis proved deleterious for infarct healing and accelerated the evolution of heart failure. We also detected rapid Mo kinetics in mice with stroke. These findings expand our knowledge of Mo/MΦ flux in acute inflammation and provide the groundwork for novel anti-inflammatory strategies for treating heart failure.     

Sleep quality and sleepiness in persons with implantable cardioverter defibrillators: outcome from a clinical randomized longitudinal trial

Background: Patients receiving an implantable cardioverter defibrillator (ICD) report various types and degree of sleep disruptions, but little is known regarding their characteristics, duration, and associated factors. The purposes of this study were: (1) to describe the effect of a psychoeducational intervention on sleep quality and daytime sleepiness, (2) to describe patterns of sleep over time, and (3) to identify predictors of poor sleep in an ICD population. Methods: A randomized longitudinal intervention trial was designed to test the effects of a psychoeducational intervention, which included a sleep education and counseling session in patients receiving their initial ICD. Patients (n = 236; 75% men; mean age 58.4 [±11.2] from the PsychoEducationAl Intervention for ICD PatiEnts (PEACE) trial comprised the study population. Variables related to sleep were measured by the Pittsburgh Sleep Quality Inventory (PSQI) and Epworth Sleepiness Scale (ESS). Results: No psychoeducational intervention effects on sleep outcomes were observed. However, 67.2% of the patients reported poor sleep quality at baseline, and 56.8% had low sleep quality at 6 months based on PSQI scores >5; one‐third (32.6%) were excessively sleepy based on ESS scores ≥10 at 6 months. Anxiety, depression, physical function, pain intensity, and pain severity were all highly correlated to each other across time. Female gender was a significant covariate for the PSQI. New York Heart Association (NYHA) class was a significant covariate for sleepiness (Epworth). Conclusions: Low sleep quality and daytime sleepiness are found at time of insertion and over time in patients with ICD. Female gender, higher NYHA class, as well as two latent factors encompassing increased anxiety, depressive symptoms, and decreased physical function and increased pain, were significant predictors of poor sleep quality and sleepiness over time. These data help identify those at higher risk for sleep problems after ICD. PACE 2012; 35:431–443)