Platelet counts were investigated in 26 patients with P. falciparum malaria and 39 patients with P. vivax malaria before and after treatment. Before schizontocidal treatment 22 of 26 (85%) patients with P. falciparum malaria and 30 of 39 (72%) patients with P. vivax malaria had depressed platelet counts below 150,000/microliters blood. There was a correlation between low platelet counts and high counts of malarial plasmodia (parasitized red blood cells) in P. falciparum and P. vivax infections (p less than 0.001). Platelet survival, studied by malonaldehyde formation in three patients during the period of decreasing parasitaemia, revealed a shortened life span to 2--3 days in comparison to 7--10 days in normal controls. In all patients platelet counts rose to threefold the initial values within 5 days after clearance of parasites. The results demonstrate that, first, thrombocytopenia is a common feature in human malaria, second, thrombocytopenia induced by malaria is due to shortened life span in the peripheral blood and, third, some interaction is present between platelets and malaria plasmodia or parasitized red cells.
We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.
Undertreatment of older patients with acute myeloid leukemia (AML) can explain, in part, their inferior outcome when compared to that of younger patients. In agreement with the benefit seen by patients under age 60 from high-dose cytosine arabinoside (Ara-C), there are dose effects in the over 60s, in particular for daunorubicin, in induction treatment and for the duration of postremission treatment. The use of these effects can partly overcome the mostly unfavorable disease biology in older age AML, as expressed by the absence of favorable and the over-representation of adverse chromosomal abnormalities as well as the expression of drug resistance. We recommend an adequate dosage of 60 mg/m2 daunorubicin on 3 days in combination with standard dose Ara-C and 6-thioguanine given for induction and consolidation, and followed by a prolonged monthly maintenance chemotherapy for at least 1 year's duration. Further improvements in supportive care may help to deliver additional antileukemic cytotoxicity. As a novel approach, nonmyeloablative preparative regimens may open up the possibility of allogeneic transplantation for older patients with AML. Other new options like multidrug resistance modulators, antibody targeted therapies and molecular targeting are under clinical investigation. A questionnaire study in patients with AML showed that, according to patients' self-assessment, intensive and prolonged treatment did not result in a diminished quality of life. This finding did not vary by age, under or over 60 years. As the median age in this disease is more than 60 years, the adequate management of AML in older patients remains the major challenge.
SummaryOne hundred and ten patients with acute proximal deep-vein thrombosis were randomized in a sequential dose-finding design, to receive continuous intravenous infusion of napsagatran, a novel synthetic thrombin-inhibitor, at a fixed dose of 5 mg/h (n = 37) or 9 mg/h (n = 26), or APTT-adjusted unfractionated heparin (n = 47). Oral anticoagulants were started on the 2nd day and the study drug was discontinued from the 5th treatment day, as soon as the International Normalized Ratio was above 2.Control venogram (97 venogram pairs evaluable) after 5-8 days of treatment showed improvement in 3 napsagatran-treated patients (versus none in heparin-treated patients) and worsening in 4 napsagatran- treated patients (versus 2 in heparin-treated patients). The venographic Marder’s score did not change among the treatment groups. New lung scan perfusion defects (99 scintigram pairs evaluable) occurred in 4 (11%), 4 (21%), and 4 (10%) patients in the napsagatran (5 mg/h) group, in the napsagatran (9 mg/h) group, and in the heparin control group, respectively. There was no statistically significant difference in any of these endpoints between the 3 groups. No major bleeding was observed and the rare minor bleedings occurred at a similar rate in the three treatment groups.In conclusion, the ADVENT trial has shown data that suggest comparable efficacy and safety of a synthetic, direct thrombin inhibitor (napsagatran) and conventional heparin therapy for treatment of proximal DVT. These results suggest that synthetic direct thrombin inhibitors are a promising class of antithrombotic agents which deserves further development in this field.
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