BackgroundOptimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation.ObjectivesThe Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations.MethodsThis phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling.ConclusionShould RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials.
Summary Clofarabine is a second‐generation purine nucleoside analogue, which has shown promising activity in relapsed and refractory paediatric acute lymphoblastic leukaemia (ALL). This report summarizes the early United Kingdom experience of clofarabine for the treatment of paediatric ALL in 23 patients, outside of the context of a clinical trial. Our results demonstrated that clofarabine‐based chemotherapy regimes were effective and well‐tolerated in this heavily pre‐treated group, with an overall response rate of 67% when used in combination regimes. Responses were seen in both B and T cell disease and in patients with adverse cytogenetics.
We report the incidence and outcome of venous thrombosis (VT) in the UK acute lymphoblastic leukaemia (ALL) 2003 trial. VT occurred in 59/1824 (3.2%) patients recruited over 5 years with 90% occurring during a period of Asparagine depletion. Pegylated Escherichia Coli Asparaginase (Peg-ASP) 1000 units/m(2) was used throughout. Thirty-four children received further Peg-ASP, most with concurrent heparin prophylaxis. There were no episodes of bleeding or recurrent thrombosis. Optimal Asparagine depletion is central to success of modern regimes for treatment of ALL. This report confirms a significant risk of thrombosis with such therapy, but demonstrates that re-exposure to Asparaginase is feasible and safe.
Summary Trisomy 21 [Down's syndrome (DS)] and mutations in transcription factor GATA1 predispose neonates to a transient myeloproliferative disorder (TMD) and/or acute megakaryocytic leukaemia (AMKL). The role of trisomy 21 in their pathogenesis is unclear. We previously reported two rare neonates without DS who had TMD, one of whom progressed to AMKL. Trisomy 21 was detected only in blood cells at presentation with TMD/AMKL and disappeared with disease resolution. We now show that the blood cells at presentation of TMD harboured GATA1 genomic DNA mutations, suggesting a requirement for trisomy 21 in haematopoietic cells, rather than other cell types, for development of TMD/AMKL.
The current agricultural systems of broad areas of Australia are unsustainable, with large projected increases in salinisation, decreases in water quality and losses of biodiversity. Increased concentrations of greenhouse gases have been linked to global warming. The international response to this warming, the United Nations Framework Convention on Climate Change and its Kyoto Protocol, include provisions that enable greenhouse sinks, or the sequestration of carbon in soils and vegetation to be used by Parties as one strategy to fulfil their obligations. The Kyoto Protocol, which is yet to be ratified by Australia, also allows for trading in emission reductions, and this opens the possibility that investment in carbon sinks may help underwrite broader natural resource management objectives. This paper describes a study that examined the possibilities for improved land management in Western Australia arising from the development of carbon sinks. This considered (a) the likelihood of a carbon market developing and the likely depth of that market as a result of current national and international policies, (b) the data available to provide estimates on different types of sinks and (c) the likely benefits of wide-scale sink investment. The study was designed to quantify an upper limit to sink potential.
It was estimated that the total amount of carbon that could be sequestered by revegetating 16.8 Mha of cleared farmland was 2.2 Gt CO2-e, and 3.3 Gt CO2-e by destocking 94.8 Mha of Western Australian rangelands. It was considered that there were insufficient data to produce estimates of sequestration following changes in tillage practice in cropping systems or the revegetation of already salinized land. We conclude that carbon sinks are only likely to become profitable as a broad-scale stand-alone enterprise when carbon prices reach A$15/t CO2-e. However, below this price their value can be significant as an adjunct to reforestation schemes that are aimed at providing other products (wood, pulp, bioenergy) and land and water conservation benefits. Irrespective of this, carbon sinks provide an opportunity to both sequester carbon in a least-cost fashion and improve soil and watershed management.
#### Summary points
Presentation of acute leukaemia can be non-specific, and not always have the classic signs and symptoms of anaemia, bruising, bleeding, hepatosplenomegaly, and lymphadenopathy.
Diagnosis can be difficult, and delays can contribute to additional, sometimes life threatening problems during the period of initial treatment.
Relatively simple, inexpensive tests—a full blood count and examination of the blood film—will diagnose acute leukaemia in most cases.
Overall survival has risen from less than 5% in the 1960s to over 85% today.
Acute leukaemia is the commonest malignancy of childhood. In the United Kingdom, one in 2000 children develop the disorder, with around 450 new cases being diagnosed annually.1 However, most general practitioners will see a case of childhood leukaemia only once or twice in their careers2 and, since management generally takes place in tertiary referral centres, non-specialist paediatricians will encounter relatively few patients.
Compared with the 1970s, the outcome today for children with acute leukaemia has improved dramatically. Numerous high quality randomised controlled trials have shown that over 85% of children can now be cured.3 4 Goals for the future should focus on keeping treatment and side effects to a minimum for patients at low risk of recurrent disease, and improving the outcome for the small proportion of children at high risk of relapse.5
In this review, we summarise current knowledge about the presentation, diagnosis, and optimum management of children with acute leukaemia. We also suggest strategies for early diagnosis of the disease in primary care, which should minimise avoidable complications and allow for early supportive care.
Acute leukaemia arises from genetic mutations in blood progenitor cells. These mutations generate both an uncontrollable capacity for self-renewal and the developmental arrest of the progenitor cells at a particular point in their differentiation.6 The body is therefore overwhelmed by immature cells …
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