Fluorescence in situ hybridization (FISH) has become a powerful technique for prognostic assessment in multiple myeloma (MM). However, the existence of associations between cytogenetic abnormalities compels us to re-assess the value of each abnormality. A total of 260 patients with MM at the time of diagnosis, enrolled in the GEM-2000 Spanish transplant protocol, have been analyzed by FISH in order to ascertain the independent influence on myeloma prognosis of IGH translocations, as well as RB and P53 deletions. Survival analyses showed that patients with t(4;14), RB or P53 deletions had a significantly shorter survival than patients without these abnormalities. However, patients with RB deletions without other abnormalities in FISH analysis, displayed a similar outcome to those patients without genetic changes by FISH (46 vs 54 months, P ¼ 0.3). In the multivariate analysis the presence of t(4;14), RB deletion associated with other abnormalities, age 460 years, high proportion of S-phase cells and advanced stage of the disease according to the International Staging System retained their independent prognostic influence. In summary, RB deletion as a sole abnormality does not lead to a shortening in the survival of MM patients, whereas t(4;14) confers the worst prognosis in MM patients treated with high-dose chemotherapy.
This cooperative study assessed prognostic factors for overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in 541 patients with de novo myelodysplastic syndrome (MDS) and deletion 5q. Additional chromosomal abnormalities were strongly related to different patients' characteristics. In multivariate analysis, the most important predictors of both OS and AML transformation risk were number of chromosomal abnormalities (Po0.001 for both outcomes), platelet count (Po0.001 and P ¼ 0.001, respectively) and proportion of bone marrow blasts (Po0.001 and P ¼ 0.016, respectively). The number of chromosomal abnormalities defined three risk categories for AML transformation (del(5q), del(5q) þ 1 and del(5q) þ X2 abnormalities) and two for OS (one group: del(5q) and del(5q) þ 1; and del(5q) þ X2 abnormalities, as the other one); with a median survival time of 58.0 and 6.8 months, respectively. Platelet count (P ¼ 0.001) and age (P ¼ 0.034) predicted OS in patients with '5qÀsyndrome'. This study demonstrates the importance of additional chromosomal abnormalities in MDS patients with deletion 5q, challenges the current '5qÀsyndrome' definition and constitutes a useful reference series to properly analyze the results of clinical trials in these patients.
A study was made of the effects of 5-hydroxytryptamine (5-HT) on bradycardia induced in vivo by electrical stimulation of the vagus nerves in pithed rats pretreated with atenolol. 5-HT significantly decreased vagally induced, but not acetylcholine-induced, bradycardia. The first effect was blocked by methiothepin, ketanserin or methiothepin with ketanserin. When 5-HT1 and 5-HT2 receptors were blocked, 5-HT produced an increase in vagally induced bradycardia. Both the inhibition and the potentiation were blocked by simultaneous pretreatment with methiothepin, ketanserin and MDL-72222. The 5-HT2 receptor agonist m-CPP (1-(3-chlorophenyl) piperazine dihydrochloride) caused an inhibition of vagally induced bradycardia whereas the 5-HT3 receptor agonist m-CPBG (1-(m-chlorophenyl)biguanide hydrochloride) produced a significant increase. The data suggest the presence of presynaptic and/or ganglionic 5-HT2 receptors in parasympathetic innervation of the rat heart, stimulation of which inhibits the release of acetylcholine. The presence of 5-HT3 receptors is also suggested, stimulation of which induces the release of acetylcholine.
1 A study was made of the effects of 5-hydroxytryptamine (5-HT) on pressor response induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Intravenous infusion of 5-hydroxytryptamine at doses of 10 and 20 jig kg-' min-' reduced the pressor effects obtained by electrical stimulation at intervals of 10 min over the 1 h of infusion. 2 This inhibitory action of 5-HT was depressed by cyproheptadine and methiothepin but was not modified by ketanserin or MDL-72222. By contrast, the inhibitory action of 5-HT was lost in pithed rats that had been pretreated with exogenous noradrenaline.3 The 5-HT, receptor agonist 5-carboxamidotryptamine (5-CT) caused an inhibition of the pressor response, whereas the 5-HT3 receptor agonist, 1-phenylbiguanide, produced a variable but significant increase in the pressor response. The 5-HT2 receptor agonist, m-CPP, did not modify the pressor sympathetic response. 4 Our results suggest that 5-hydroxytryptamine interferes with sympathetic neurotransmission by inhibiting pressor effects as a result of stimulation of the complete sympathetic outflow, and that this inhibition is mainly through a presynaptic 5-HT1 mechanism.
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