Thalidomide was administered to 83 patients with myelodysplastic syndrome (MDS), starting at 100 mg by mouth daily and increasing to 400 mg as tolerated. Thirtytwo patients stopped therapy before 12 weeks (minimum period for response evaluation), and 51 completed 12 weeks of therapy. International Working Group response criteria for MDS were used to evaluate responses. Intent-to-treat (ITT) analysis classified all off-study patients as nonresponders. Off-study patients belonged to a higher risk category (P ‫؍‬ .002) and had a higher percentage of blasts in their pretherapy bone marrow than patients who completed 12 weeks of therapy (P ‫؍‬ .003). No cytogenetic or complete responses were seen, but 16 patients showed hematologic improvement, with 10 previously transfusion-dependent patients becoming transfusion independent. Responders had lower pretherapy blasts (P ‫؍‬ .016), a lower duration of pretherapy platelet transfusions (P ‫؍‬ .013), and higher pretherapy platelets (P ‫؍‬ .003). Among responders, 9 had refractory anemia (RA); 5 had RA with ringed

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The impact of Abeta deposition upon cholinergic intrinsic cortical and striatal, as well as basal forebrain long projection neuronal systems was qualitatively and quantitatively evaluated in young (2-6 months) and middle-aged (10-16 months) APPswe/PS1DeltaE9 transgenic (tg) mice. Cholinergic neuritic swellings occurred as early as 2-3 months of age in the cortex and hippocampus and 5-6 months in the striatum of tg mice. However, cholinergic neuron number or choline acetyltransferase (ChAT) optical density measurements remained unchanged in the forebrain structures with age in APPswe/PS1DeltaE9 tg mice. ChAT enzyme activity decreased significantly in the cortex and hippocampus of middle-aged tg mice. These results suggest that Abeta deposition has age-dependent effects on cortical and hippocampal ChAT fiber networks and enzyme activity, but does not impact the survival of cholinergic intrinsic or long projection forebrain neurons in APPswe/PS1DeltaE9 tg mice.

Summary. Thirty patients with myelodysplastic syndromes (MDS) were treated with thalidomide at 100 mg/d p.o., increased as tolerated to 400 mg/d for 12 weeks. Levels of apoptosis, macrophage number, microvessel density (MVD), tumour necrosis factor alpha (TNF-a), transforming growth factor beta (TGF-b), interleukin 6 (IL-6), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were determined in the serum, bone marrow (BM) plasma and BM biopsies before and after therapy. Pretherapy biological characteristics of MDS patients were compared with similar studies performed in 11 normal volunteers. Ten patients demonstrated haematological improvement in the erythroid series, six becoming transfusion independent. Responders had a higher pretherapy platelet count (P , 0´048) and lower BM blasts (P , 0´013). Median time to response was 10 weeks, and four remain in remission beyond a year. Pretherapy MDS BMs showed higher MVD (P , 0´001) and TGF-b (P , 0´03) and higher serum TNF-a (P , 0´008) compared with normal control subjects. After therapy, only BM TGF-b decreased significantly (P , 0´002). Pretherapy haemoglobin was directly related to serum VEGF (P , 0´001) in responders and inversely related in nonresponders (P , 0´05), suggesting the possibility that angiogenesis may be a primary pathology in the former and a consequence of anaemia-induced hypoxia in the latter. We conclude that thalidomide has important clinical and biological effects in at least a subset of MDS patients, but the precise mechanism of its action remains unknown and requires further study including a larger number of patients.