Background Approximately one-fi h of women who develop early breast cancer have HER2-positive tumours, which if untreated, have a worse prognosis than HER2-negative tumours. Trastuzumab is a selective treatment targeting the HER2 pathway. Although the results on e icacy seem to support its use, there are potential cardiac toxicities which need to be considered, especially for women at lower risk of recurrence, or those at increased cardiovascular risk. Objectives To assess the evidence on the e icacy and safety of therapy with trastuzumab, overall and in relation to its duration, concurrent or sequential administration with the standard chemotherapy regimen in patients with HER2-positive early breast cancer. Search methods We searched the Cochrane Breast Cancer Group's (CBCGs) Specialised Trials Register, and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, EMBASE, BIOSIS, TOXNET, and the WHO ICTRP search portal (up to February 2010). Selection criteria RCTs comparing the e icacy and safety of trastuzumab alone, or in combination with chemotherapy, or no treatment, or standard chemotherapy alone, in women with HER2-positive early breast cancer including women with locally advanced breast cancer. Data collection and analysis We collected data from published and unpublished trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included duration (less or greater than six months) and concurrent or sequential trastuzumab administration. Main results We included eight studies involving 11,991 patients. The combined HRs for overall survival (OS) and disease-free survival (DFS) significantly favoured the trastuzumab-containing regimens

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Inherited deficiencies of plasma proteins involved in blood coagulation generally lead to lifelong bleeding disorders, whose severity is inversely proportional to the degree of factor deficiency. Haemophilia A and B, inherited as X-linked recessive traits, are the most common hereditary hemorrhagic disorders caused by a deficiency or dysfunction of blood coagulation factor VIII (FVIII) and factor IX (FIX). Together with von Willebrand's disease, a defect of primary haemostasis, these X-linked disorders include 95% to 97% of all the inherited deficiencies of coagulation factors. The remaining defects, generally transmitted as autosomal recessive traits, are rare with prevalence of the presumably homozygous forms in the general population of 1:500,000 for FVII deficiency and 1 in 2 million for prothrombin (FII) and factor XIII (FXIII) deficiency. Molecular characterization, carrier detection and prenatal diagnosis remain the key steps for the prevention of the birth of children affected by coagulation disorders in developing countries, where patients with these deficiencies rarely live beyond childhood and where management is still largely inadequate. These characterizations are possible by direct or indirect genetic analysis of genes involved in these diseases, and the choice of the strategy depends on the effective available budget and facilities to achieve a large benefit. In countries with more advanced molecular facilities and higher budget resources, the most appropriate choice in general is a direct strategy for mutation detection. However, in countries with limited facilities and low budget resources, carrier detection and prenatal diagnosis are usually performed by linkage analysis with genetic markers. This article reviews the genetic diagnosis of haemophilia, genetics and inhibitor development, genetics of von Willebrand's disease and of rare bleeding disorders.

BackgroundBusy clinicians need easy access to evidence-based information to inform their clinical practice. Publishers and organizations have designed specific tools to meet doctors’ needs at the point of care. ObjectiveThe aim of this study was to describe online point-of-care summaries and evaluate their breadth, content development, and editorial policy against their claims of being “evidence-based.”MethodsWe searched Medline, Google, librarian association websites, and information conference proceedings from January to December 2008. We included English Web-based point-of-care summaries designed to deliver predigested, rapidly accessible, comprehensive, periodically updated, evidence-based information to clinicians. Two investigators independently extracted data on the general characteristics and content presentation of summaries. We assessed and ranked point-of-care products according to: (1) coverage (volume) of medical conditions, (2) editorial quality, and (3) evidence-based methodology. We explored how these factors were associated.ResultsWe retrieved 30 eligible summaries. Of these products, 18 met our inclusion criteria and were qualitatively described, and 16 provided sufficient data for quantitative evaluation. The median volume of medical conditions covered was 80.6% (interquartile range, 68.9% - 84.2%) and varied for the different products. Similarly, differences emerged for editorial policy (median 8.0, interquartile range 5.8 - 10.3) and evidence-based methodology scores (median 10.0, interquartile range 1.0 - 12.8) on a 15-point scale. None of these dimensions turned out to be significantly associated with the other dimensions (editorial quality and volume, Spearman rank correlation r = -0.001, P = .99; evidence-based methodology and volume, r = -0.19, P = .48; editorial and evidence-based methodology, r = 0.43, P =.09).ConclusionsPublishers are moving to develop point-of-care summary products. Some of these have better profiles than others, and there is room for improved reporting of the strengths and weaknesses of these products.

It has long been thought that an individual thrombotic tendency increases the risk of myocardial infarction, especially in young adults. Several “prothrombotic” genetic factors that may influence the individual thrombotic risk have been identified. To investigate the association between the risk of myocardial infarction at a young age and genetic factors thought to be associated with an increased tendency to thrombosis (the polymorphisms 4G/5G of the PAI-1 gene, PIA1/PIA2 of the platelet glycoprotein IIIa, C3550T of the platelet glycoprotein Ib gene, G10976A of the factor VII gene, C677T of the methylenetetrahydrofolate reductase gene, G1691A of the factor V gene, and G20210A of the prothrombin gene), we performed a case-control study evaluating 200 survivors (185 men, 15 women) of myocardial infarction who had experienced the event before the age of 45 years and 200 healthy subjects with a negative exercise test, individually matched for sex, age, and geographic origin with the cases. The presence of the PIA2 polymorphic allele was the only prothrombotic genetic factor associated with the risk of myocardial infarction at a young age. The odds ratio for carriers of the PIA2 allele compared with those of the PIA1 allele was 1.84 (95% confidence intervals (CI) 1.12 to 3.03). There was a significant interaction between the presence of the PIA2 allele and smoking: with their simultaneous presence, 46% (95% confidence intervals 11% to 81%) of premature myocardial infarctions were attributable to the interaction between the two factors. In conclusion, carrying the PIA2 polymorphic allele of platelet glycoprotein IIIa was the only genetic prothrombotic factor associated with the risk of developing myocardial infarction at a young age. The clinical expression of this genetic predisposition seems to be enhanced by smoking.

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Gene polymorphisms associated with the plasma levels of fibrinogen, factor VII, and plasminogen activator inhibitor 1 (PAI-1)-hemostasis proteins that help to predict the risk of atherothrombotic disease-were compared in 124 healthy individuals > or = 100 years old and 130 young, healthy individuals to identify genetic influences on extreme longevity. We investigated the restriction fragment length polymorphism G/A-455 located in the promoter of the beta-fibrinogen gene, the guanine insertion/deletion polymorphism 4G/5G in the promoter of the PAI-1 gene, and the R353Q substitution polymorphism in exon 8 of the factor VII gene. Alleles and genotypes associated with elevated plasma levels of fibrinogen and factor VII were found with similar frequencies in centenarians and in the comparison group. However, in centenarians there was a significantly higher frequency of the 4G allele and of the homozygous 4G4G genotype associated with high PAI-1 levels. Since high PAI-1 is considered a predictor of recurrent myocardial infarction in young men, it is intriguing that the corresponding genetic marker is more frequent in centenarians who have escaped major age-related atherothrombotic disease and reached the extreme limits of human life. Homozygosity for the 4G allele, despite its association with impaired fibrinolysis, is compatible with successful aging.

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