[Essential thrombocythemia: conventional therapy].
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Adult↗
Biomedical subjects
P Rossi Ferrini
Publications and source records attributed to P Rossi Ferrini.
Early haemostatic modifications following cryopreserved graft infusion.
The nature of the graft used for the rescue of patients undergoing autologous bone marrow transplantation is that of a complex mixture of pharmacological agents and cellular debris known to have a number of effects on the haemostatic system. The present study was undertaken to evaluate the occurrence and the degree of haemostatic alterations during and immediately following graft infusion in 24 patients suffering from haematological malignancies. On day 0, before graft infusion, the majority of patients appeared with laboratory signs of enhanced thrombin generation, platelet activation, and endothelial damage, most likely due to the conditioning regimen. However, the graft infusion per se was accompanied in the short term by a further increment of some parameters indicating a thrombotic risk (as thrombin-antithrombin complex, beta-thrombo globulin, platelet factor four, and von Willebrand factor antigen, together with a concomitant prolongation of partial thromboplastin time and a reduction of prothrombin time. In contrast there was no further modification of antithrombin III or protein C levels nor an increase in fibrinopeptide A levels. We hypothesize that complex interactions between agents contained in the graft mixture and host haemostatic system are involved in the pathogenesis of the haemostatic alterations which followed cryopreserved graft infusion; however, in our series, these were not accompanied by clinical signs of thrombotic or haemorrhagic events.
Antithrombin III↗
Tumor necrosis factor alpha modulates the messenger RNA expression of hematopoietic growth factor genes in fresh blast cells from patients with acute myeloblastic leukemia.
Tumor necrosis factor alpha (TNF-alpha) has been previously shown to modulate the expression of hematopoietic growth factor genes in monocytes and other mesenchymal cells. As acute myeloblastic leukemia (AML) blasts can express and produce hematopoietic growth factors, the influence of TNF-alpha on the accumulation of mRNAs for c-myc, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, IL-6 and IL-1 beta was evaluated in fresh blasts from 13 patients with AML. Total cellular RNA was extracted from blast cells cultured for 24 hours with or without TNF-alpha (500 U/ml). The c-myc transcript level was decreased by TNF-alpha treatment in 9/13 cases, and increased in only one case. Among the growth factor genes, the GM-CSF gene was more often and consistently influenced by TNF-alpha, increased levels of its transcript being observed in 6/13 cases following treatment with the cytokine; in no case was there a reduction of GM-CSF mRNA. G-CSF and IL-6 transcripts were more heterogeneously influenced, whereas the IL-3 transcript was never detected in our AML samples. The IL-1 beta message was present in 8/13 untreated and in 13/13 TNF-alpha treated samples. Moreover, in untreated cells, GM-CSF, G-CSF and IL-6 expression was always associated with IL-beta expression. These findings indicate that TNF-alpha can modulate the levels of growth factor transcripts in AML blasts, and raise questions about the effects of TNF-alpha on leukemic hematopoiesis, considering that TNF-alpha, IL-1 and GM-CSF can synergistically stimulate the growth of AML clonogenic cells.
Gene Expression Regulation, Leukemic↗
Humoral regulation of megakaryocytopoiesis.
If compared to erythroid and granulomacrophage lineages, the knowledge of the regulation of megakaryocytopoiesis has progressed slowly, and only the recent advent of specific clonogenic methods has permitted studies aimed at investigating this aspect of hematopoiesis. The analysis of Mk differentiation and platelet production is still difficult, because methods such as the 75SeM or 35S incorporation are time consuming and their sensitivity is relatively low. A number of laboratories have been able to purify, partially or to homogeneity, fractions stimulating the proliferation and differentiation of megakaryocytes. The biochemical identity between IL-3 and the active fractions found in the C.M. of some cell lines stands for a role of this hemopoietin in the regulation of megakaryocytopoiesis. However, the function of Epo and, above all, of GM-CSF cannot be ruled out, on the basis of experimental works, although only in some clinical trials GM-CSF seems to have been able to modify the platelet number. Hopefully, data on the therapeutic use of rhIL-3, and the sequentiation and identification of a molecule capable of action on the maturative compartment will shed new light on the regulation of megakaryocytopoiesis and the possibility to correct its disorders.
Animals↗
Etoposide in remission induction of adult acute myeloid leukemia.
96 consecutive acute myelogenous leukemia (AML) patients were analyzed retrospectively with regard to the regimen used for remission induction. 35 patients received daunorubicin for 3 days, cytosine arabinoside and 6-thioguanine for 7 days. 61 were treated with the same regimen but 6-thioguanine was replaced by etoposide. Complete remission was achieved in 57 and 72% of patients, respectively (p = 0.06). In leukemias with monocytic phenotype (M4-M5), the remission rate was significantly higher with the etoposide-containing regimen (p = 0.02). Our findings suggest that the replacement of thioguanine by etoposide could be useful in induction therapy of AML.
Adult↗
Protein content and factor VIII complex in untreated, treated and monoclonal factor VIII concentrates.
Replacement therapy with clotting factor concentrates may expose the recipients not only to virus contamination but also to continuous stimulation of the immune system by repeated infusions of allogenic proteins. Concentrate purity is now a very important prerequisite to be taken into account in choosing what product can better meet the patient's needs. We compared protein content (albumin, fibrinogen, fibronectin, immunoglobulins) and factor VIII:C/vWF:Ag complex in untreated, treated and monoclonal factor VIII concentrates. Protein content is dramatically decreased in new treated ultrapure concentrates. Improved traditional fractionation methods allowed to obtain very high Factor VIII specific activity. New fractionation methods with immunoaffinity chromatography by means of monoclonal antibodies can give highly pure concentrates even if deliberately added albumin decreases factor VIII specific activity in final formulation. Otherwise monoclonal concentrates show a very high specific activity in terms of fibrinogen and immunoglobulin content, which, unlike albumin, are affecting the immune system in hemophiliacs.
Antibodies, Monoclonal↗
The influence of ofloxacin versus trimethoprim-sulfamethoxazole on the aerobic flora in granulocytopenic subjects.
Ofloxacin (300 mg twice a day) and trimethoprim-sulfamethoxazole (TMP-SMZ) (160 mg trimethoprim and 800 mg sulfamethoxazole twice a day) were given prophylactically to 19 adult patients with acute leukemia undergoing induction chemotherapy. The influence of the two regimens on the bacterial aerobic flora was evaluated. Both of the prophylactic regimens conditioned the aerobic microflora of the patients. Both groups acquired new microorganisms, prevalently gram-positive cocci, but also gram-negative bacteria with the TMP-SMZ regimen. Both treatment groups acquired yeasts.
Adult↗
A comparison of two assays for the in vitro chemosensitivity testing of human acute non-lymphoblastic leukemia cells.
In vitro chemosensitivity of blast cells from 19 patients, affected by acute non-lymphocytic leukemia, to cytosine arabinoside and daunorubicin was investigated. A semiautomated P-iodonitrotetrazolium violet (INT) colorimetric assay, based on the ability of viable cells to cleave piodonitrotetrazolium violet into a red formazan derivative and a short-term antimetabolic assay based on the uptake inhibition of [3H]-thymidine were compared in terms of their ability to predict clinical outcome. Both methods were able to discriminate between sensitive and resistant patients by in vitro cytosine arabinoside testing. On the contrary the assays carried out with daunorubicin failed to predict the clinical outcome. A good correlation was demonstrated between the results of the two different methodological approaches, validating the recently described INT sensitivity test.
Adult↗
Induction of differentiation of HL-60 cells along the monocytic pathway by 5-methyltetrahydrofolate.
Many compounds of different chemical structure can induce the HL-60 cell line to differentiate along the monocytic or granulocytic pathway, but the mechanism(s) of differentiation by these agents is not known. Experimental evidence suggests that DNA and/or membrane phospholipid transmethylation reactions may be of importance. Based on this background, we have studied the effects of various concentrations of (dl)-5-methyltetrahydrofolate (mTHF), a folate coenzyme involved in transmethylation reactions, on differentiation of HL-60 cells. Differentiation along the monocytic pathway was evidenced in kinetic, functional, cytochemical and immunophenotypical studies when cells were treated with high-dose (dl)-mTHF (1 x 10(-3)M). Some hypotheses on the mechanism(s) of (dl)-mTHF induced HL-60 cell differentiation are discussed with particular regard to a possible enhancement of lipid or DNA methylation via methionine formation by the (l) form or to inhibition of folate-dependent metabolism by the unnatural (d) form, hence of purine and thymine nucleotide synthesis.
Cell Cycle↗
Recombinant human erythropoietin has little influence on megakaryocytopoiesis in mice.
The availability of a preparation of recombinant human erythropoietin (rEp) prompted us to investigate the role of Ep in the regulation of megakaryocytopoiesis in mice, using experimental procedures by which the effects on the mitotic and post-mitotic compartment of megakaryocytes could be evaluated separately. In agar cultures of murine bone marrow cells, either serum-depleted or serum-supplemented, rEp (0.1-2 U/ml) did not stimulate megakaryocyte colony formation and when it was added to suboptimal amount of spleen cell-conditioned medium (SCM), it failed to show a significant synergistic activity. On the contrary, rEp increased the number of megakaryocytic colonies developed from splenic precursors in the presence of suboptimal amounts of SCM, although it was unable per se to stimulate colony formation. The effects of rEps on megakaryocyte maturation and platelet production were studied in vivo evaluating the incorporation of 75Se-selenomethionine into platelets, the platelet count and platelet size, and the number of megakaryocyte precursors (small acetylcholinesterase positive cells, sAchE) in the bone marrow of mice injected with 1-8 U of rEp. No modification of these parameters was found in comparison with control mice. On the other hand, rEp increased the number of recognizable splenic megakaryocytes in a dose-dependent fashion. These data suggest that rEp has little influence on megakaryocytopoiesis, at least at the doses we used and which are known to elicit a maximal response of erythropoiesis. However, a subset of megakaryocytes with particular kinetic properties, such as those in the spleen of mice, may be responsive to relatively high doses of rEp. The significance of this observation in the overall regulation of megakaryocytopoiesis remains to be determined.
Animals↗
[GM-CSF: its clinical administration; the treatment of aplasia].
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Anemia, Aplastic↗
Low dose cytosine arabinoside in adult acute non-lymphoid leukemia.
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Adolescent↗
Prognostic factors in Hodgkin's disease.
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Analysis of Variance↗
Proliferation and cell loss of human leukemic cell subpopulations in liquid culture.
A kinetic study was performed on leukemic blasts from patients with acute myeloid leukemia, separated into 2 subpopulations by a specific density gradient. The growth curve and the [3H]-thymidine uptake were simultaneously analyzed. While cumulative nucleotide uptake fitted with the growth kinetics in the low-density fraction, such a concordance was not found in the high-density subpopulation. That indicated the occurrence of simultaneous growth and loss in the high density fraction, which could not be evaluated by a simple numerical determination.
Cell Division↗
Human parvovirus infection in haemophiliacs first infused with treated clotting factor concentrates.
A group of 27 first infused haemophiliacs was studied for association between heat-treated clotting factor concentrates and transmission of human parvovirus B19. The prevalence rate of B19 antibody, detected by the Immunoelectroosmophoresis (IEOP) reaction, was 55.5% in this group of first infused subjects, significantly higher than the 29.3% of the control group of 58 healthy blood donors but lower than the 93.3% of antibody positive subjects in a group of 30 haemophiliacs multitreated with unheated products. Five of 17 B19 antibody negative patients produced human parvovirus IgM, detectable by radioimmunoassay, after the first treatment with heated concentrates; two of them developed viraemia 6 and 10 days, respectively, after the first infusion dose. These results lead to the conclusion that human parvovirus is transmissible by blood derivatives even when they have been exposed to steam- or dry-heat treatment.
Adolescent↗
Multi-variate analysis of factors governing the pharmacokinetics of exogenous factor VIII in haemophiliacs.
The pharmacokinetics of Factor VIII was evaluated by mathematical modeling in a large-scale study in 62 haemophilia-A subjects, in whom 137 plasma Factor VIII-time curves were measured during single dose (n = 87) and repeated-dose (n = 47) treatments for prophylaxis or minor bleeding episodes. The pharmacokinetic parameters [mean (SD)] estimated from single-dose curves were: clearance 3.85 ml.h-1.kg-1, volume of distribution 58.2 ml.kg-1, mean residence time 15.9 h. Parameters calculated from repeated-dose curves were: clearance 3.93 ml.h-1.kg-1, volume of distribution 61.8 ml.kg-1, and half-life 12.2 h. In patients with mild haemophilia, pharmaco-statistical analysis revealed that the endogenous synthesis of Factor VIII was constant and was not influenced by the administration of exogenous Factor VIII. The coefficient of variation for intra-individual variability of Factor VIII kinetics (estimated according to the Standard Two-Stage method) was 20.7% in single-dose curves and 23.2% in repeated-dose curves.
Adolescent↗
In vitro short-term sensitivity test for the prediction of response to chemotherapy in acute non-lymphocytic leukemia.
In order to evaluate the predictive potential of a short-term antimetabolic assay for acute non-lymphocytic leukemia cells, the activity of daunomycin and cytosine arabinoside in suppressing [3H]-uridine uptake was tested in peripheral blood samples from 31 patients. Independently of the in vitro results, the patients were treated with standard combinations including the two drugs or with cytosine arabinoside alone. The clinical response to chemotherapy, and the in vitro [3H]-uridine uptake inhibition were compared retrospectively. A significant decrease of [3H]-uridine uptake after in vitro exposure to both drugs occurred in 12 patients who achieved complete remission after combination therapy, and was particularly evident for 5 patients who needed only one course of therapy. A similar result was obtained in patients treated with cytosine arabinoside alone. This method may represent a useful tool in clinical practice, by indicating a fraction of leukemic patients particularly sensitive to therapy.
Acute Disease↗
Partial purification and biochemical characterization of human plasma thrombopoietin.
A factor that stimulates the incorporation of 75Selenomethionine into the newly formed platelets of recipient mice (thrombopoietin, TPO) has been partially purified from the plasma of thrombocytopenic patients. The activity was precipitated at 60-80% ammonium sulfate saturation and further purified with hydrophobic interaction chromatography. Thrombopoietin was retained by concanavalin-A-Sepharose. Using HPLC size-exclusion chromatography, an approximate molecular weight of 40,000 dalton was calculated. The overall purification factor was about 2,100-fold. TPO was stable in a pH range from 5 to 9 and was heat-sensitive, and the biological activity was destroyed by trypsin treatment and by dithiothreitol. The partially purified molecule did not stimulate the proliferation of megakaryocyte progenitors in vitro and had no effect on the growth of erythroid or granulocyte-macrophage colonies; when administered in-vivo, TPO significantly affected the mean platelet volume and increased the number of small acetylcholinesterase cells in the bone marrow. TPO appears to be specific for the megakaryocytic lineage and active on the postmitotic compartment of megakaryocytes.
Glycoproteins↗