Stroke complicating acute myocardial infarction. A meta-analysis of risk modification by anticoagulation and thrombolytic therapy.

BACKGROUND. The objective of this meta-analysis was to examine the impact of systemic anticoagulation and thrombolysis on the total incidence of stroke following myocardial infarction. Additionally, we sought to compare the relative risk of stroke with different thrombolytic agents. METHODS. A computerized and manual literature search for controlled clinical trials of anticoagulants and thrombolytic agents in myocardial infarction reporting on total strokes in treated and control patients was used. Pooling was performed by calculating the Mantel-Haenszel odds ratio and 95% confidence interval (CI). RESULTS. The Mantel-Haenszel pooled odds ratio for anticoagulation trials was 0.46 (95% CI, 0.30 to 0.64), suggesting a benefit of anticoagulant therapy. However, a statistically significant degree of variability (heterogeneity) was present among study results. The odds ratios for all thrombolytic trials, tissue plasminogen activator, and streptokinase trials, respectively, were 1.08 (95% CI, 0.87 to 1.35), 1.28 (95% CI, 0.76 to 2.17), and 1.02 (95% CI, 0.80 to 1.30), suggesting no overall excess of stroke with thrombolysis. The pooled odds ratio for three studies directly comparing streptokinase and tissue plasminogen activator was 0.73 (95% CI, 0.61 to 0.86), suggesting an excess of stroke for patients treated with tissue plasminogen activator in comparison with streptokinase-treated patients. CONCLUSIONS. The available data may support a role for anticoagulants in reducing the incidence of stroke after myocardial infarction, but the heterogeneity among the trials makes interpretation of this effect difficult. Although the available data do not indicate an increase in stroke with thrombolysis, a direct comparison of tissue plasminogen activator and streptokinase reveals an excess of strokes with tissue plasminogen activator.     

Immunohistochemical analysis of 1844 human epithelial and haematopoietic tumours and sarcomas for IDH1R132H mutation

Sahm F, Capper D, Meyer J, Hartmann C, Herpel E, Andrulis M, Mechtersheimer G, Petersen I, Paulus W & von Deimling A
(2011) Histopathology  58, 1167–1172
Immunohistochemical analysis of 1844 human epithelial and haematopoietic tumours and sarcomas for IDH1R132H mutation Aims: Mutations in the isocitrate dehydrogenase 1 gene have been identified recently to play a key role in diffuse astrocytoma and oligodendroglioma as well as in acute myeloid leukaemia. In glioma, IDH1R132H is the most common mutation type, which is associated with younger patient age and longer patient survival compared to wild‐type status. Sequencing analyses of carcinomas and lymphomas have detected IDH1 mutations in only a small fraction of cases. In those studies, IDH1R132H was also the most frequent mutation. The aim of the present study was to analyse a comprehensive series of human tumours for IDH1R132H mutation. Methods and results: A total of 1844 formalin‐fixed paraffin‐embedded tumours, including carcinomas, sarcomas and haematopoietic tumours were investigated immunohistochemically using a mutation‐specific antibody for IDH1^R132H. Our positive control series consisted of a collection of diffuse astrocytomas and oligodendrogliomas. No IDH1R132H mutation was found in this series. Conclusions: IDH1R132H mutations occur almost exclusively in glioma and acute myeloid leukaemia.     

Markers of cardiac collagen turnover are similar in patients with mild and more severe symptoms of heart failure

Cardiac fibrosis plays an important role in the pathophysiology of heart failure. The authors sought to determine whether biomarkers of cardiac fibrosis for milder clinical degrees of heart failure are comparable to those of more advanced disease. Procollagen types I and III amino-terminal peptides (PINP and PIIINP) and type I collagen telopeptide (ICTP) were compared between aldosterone-antagonistnaive patients with heart failure and New York Heart Association class I or II (n=22/23) and class III or IV (n=42/3) symptoms. Median (interquartile) range concentrations of PINP (63.3 [44.2-88.8] vs 48.6 [37.8-74.9] microg/L), ICTP (7.0 [5.4-16.8] vs 6.5 [4.7-12.7] microg/L), and PIIINP (4.7 [3.2-7.0] vs 4.7 [2.9-7.3] microg/L) were comparable between patients with mild and moderate to severe disease, respectively. These data suggest that patients with mild heart failure may have similar degrees of cardiac fibrosis to patients with more severe disease and support the examination of antifibrotic therapy, including aldosterone antagonists, in milder degrees of heart failure.     

The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma

Current knowledge about molecular mechanisms underlying disease progression and drug resistance in multiple myeloma (MM) is still limited. Here, we analyzed the potential pathogenetic role of the Y-box binding protein YB-1 in MM. YB-1 is a member of the cold-shock domain protein superfamily and involved in various cellular functions such as proliferation. Immunohistochemical analyses revealed that neither normal bone marrow (BM) plasma cells (PCs), premalignant PCs of patients with monoclonal gammopathy of unknown significance (MGUS), nor MM cells with a mature morphology showed expression of YB-1 in situ. In contrast, YB-1 was strongly expressed in situ in normal PC precursor blasts as well as in a MM subset and in vitro in all of the evaluated MM cell lines. The YB-1-expressing MM cells were characterized by an immature morphology and a highly proliferative phenotype as defined by Ki 67 expression. We observed that siRNA-mediated knockdown of YB-1 decreased proliferation and induced apoptosis in MM cells even in the presence of BM stromal cells. Furthermore, we found that overexpression of YB-1 mediated resistance toward doxorubicin-induced apoptosis in MM cells. Thus, YB-1 contributes to disease progression, survival, and drug resistance in MM and might therefore provide an attractive therapeutic target.     

Percutaneous transluminal coronary angioplasty versus thrombolysis in acute myocardial infarction: A meta-analysis

While percutaneous transluminal coronary angioplasty (PTCA) as a primary modality for treating acute myocardial infarction (MI) has been shown to have important advantages over thrombolysis, a survival benefit has not been demonstrated because of the small size of the individual trials. To increase the statistical power to detect a survival benefit, we performed a meta-analysis of trials of PTCA and thrombolysis. We pooled the data for all randomized, controlled trials; randomized, controlled trials stratified according to thrombolytic agent [streptokinase vs. tissue plasminogen activator (TPA)]; and all trials. Pooling was performed by calculating the Mantel-Haenszel odds ratio with the Robins, Greenland, and Breslow estimate of variance. Calculation of the Q statistic was performed to assess heterogeneity. For all four analyses, the odds ratio indicated a significant survival advantage of PTCA over thrombolysis: all randomized controlled trials [0.57,95% confidence index (CI): 0.48,0.68)]; streptokinase trials [0.61,95% CI: 0.43,0.87); TPA trials (0.52,95% CI: 0.36,0.76); all trials (0.51,95% CI: 0.43,0.61). The Q statistic was not significant for any of the analyses. The results of our meta-analysis support the hypothesis that PTCA is associated with a significant reduction in mortality compared with thrombolysis.     

Rationale and design of a clinical trial of a low-molecular-weight heparin in preventing clinically important venous thromboembolism in medical patients: the prospective evaluation of dalteparin efficacy for prevention of venous thromboembolism in immobilized patients trial (the PREVENT study)

The utility of low-molecular-weight heparin (LMWH) in the prophylaxis of venous thromboembolic disease has been examined using the surrogate endpoint of venographically identified thrombi. The largest portion of these thrombi were asymptomatic calf-vein thrombi. The clinical relevance of this observation is a matter of debate. The present study is designed to evaluate the impact of an LMWH on clinically important endpoints. The current study is a randomized, prospective, double-blinded, multicenter, multinational, controlled clinical trial comparing dalteparin with placebo in moderately high-risk hospitalized medical patients. A total of 3300 patients will be randomized to receive either 5,000 IU per day of dalteparin or placebo for 14 days. Patients will undergo appropriate evaluation for any symptomatic episodes and all patients will undergo a bilateral compression ultrasound (CUS) on day 21 to search for asymptomatic proximal thrombi. The primary endpoint is the combination of objectively confirmed symptomatic deep vein thrombi (DVT), fatal or non-fatal pulmonary emboli, all proximal DVT, and sudden death. This study will be the first study to examine clinically important endpoints in evaluating the effect of a LMWH in hospitalized medical patients. This study also is the first study to use CUS rather than venography in concordance with contemporary medical practice. This trial is thus designed to address this important question in a clinically relevant manner.