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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The availability of an in vitro assay able to detect hematopoietic progenitor cells closely related to those responsible for marrow engraftment following autologous bone marrow transplantation (ABMT) prompted us to establish a procedure aimed at maximally increasing the concentration of the cyclophosphamide derivative mafosfamide used for marrow purging. It, therefore, was the aim of the present study to investigate in a group of patients with acute nonlymphoblastic leukemia (ANLL; n = 19) and acute lymphoblastic leukemia (ALL; n = 19) in complete remission the effect of mafosfamide at the level of adherent blast colony-forming units (blast colony-forming units, CFU-Blast), as well as multipotential (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM), erythroid (erythroid burst-forming units, BFU-E), and granulocyte-macrophage (granulocyte-macrophage colony-forming units, CFU-GM) progenitor cells. When nonadherent marrow mononuclear cells (MNCs) were incubated (30 min, 37 degrees C) with increasing doses of mafosfamide (30-120 micrograms/ml), a statistically significant (p less than or equal to 0.0005) dose-dependent suppression of CFU-Blast growth was observed. The mean (+/- 1 standard error of the mean [SEM]) values of 50% inhibition (ID50) of the CFU-Blast growth were not significantly different for ANLL (106 +/- 5) and ALL (107 +/- 5) patients. Analysis of CFU-Blast ID50 distribution demonstrated that ID50 ranged from 100 to 120 micrograms/ml in 17 cases (45%), whereas it ranged from 60 to 100 micrograms/ml in 12 cases and from 120 to 160 micrograms/ml in 9 cases. A statistically significant (p less than or equal to 0.05), dose-dependent suppression of colony growth from multi-potential and lineage-restricted progenitor cells was also observed. However, the value of CFU-Blast ID50 was significantly higher (p less than or equal to 0.05) than CFU-GEMM, BFU-E, and CFU-GM ID50 and ID95 values. In conclusion, our data demonstrate that: 1) the CFU-Blast assay allows to detect on an individual basis the doses of mafosfamide used for marrow purging, and 2) the concentrations of mafosfamide extrapolated by using the CFU-Blast assay are significantly higher than those obtained with the CFU-GM assay. The absence of any detrimental effect on marrow engraftment in vivo supports the safety of the CFU-Blast assay to evaluate the dose of mafosfamide used for marrow purging before ABMT.
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PMID:Differential sensitivity of adherent CFU-blast, CFU-mix, BFU-E, and CFU-GM to mafosfamide: implications for adjusted dose purging in autologous bone marrow transplantation. 156 48

Disseminated intravascular coagulation (DIC) commonly occurs in patients with acute promyelocytic leukemia (APL, FAB-M3) but may also be seen in other subtypes of AML. DIC in patients with AML has been attributed to procoagulants released from granular fractions of leukemic blast cells. The present study was designed (i) to evaluate thrombin activity in patients with AML by measuring plasma levels of fibrinopeptide A (FPA) prior to chemotherapy, and (ii) to examine whether a relationship between FPA levels and the number of peripheral blast cells exists. Plasma levels of FPA were determined using a commercially available RIA kit. To remove fibrinogen and the majority of elastase-induced fibrinopeptides (A alpha 1-21) known to crossreact with the FPA (A alpha 1-16) antiserum used in this assay, plasma samples were treated with bentonite prior to further processing. The study was conducted on 5 patients with APL and on 22 patients with other subtypes of AML. Peripheral blast cell counts at initial diagnosis ranged from 2100 to 56,000/microliters in patients with APL and from 1900 to 151,000/microliters in patients with other AML subtypes. The mean (+/- 1 SEM) pretreatment plasma level of FPA was significantly higher (p = 0.021) in the 5 patients with APL (38.2 +/- 8.3 ng/ml) than in patients with other AML subtypes (8.1 +/- 0.7 ng/ml). No relationship was found between peripheral blast cell counts and the corresponding FPA levels in the total group of 27 patients. However, when considering the 5 patients with APL separately, a significant correlation was observed between peripheral blast cell number and FPA plasma levels (r = 0.88, p = 0.050). This study confirms that thrombin generation is considerably greater in patients with acute promyelocytic leukemia than in other subtypes of AML. We conclude that type and number of circulating blast cells and their related capacity to express procoagulant activities appear to be major determinants of excessive fibrinogen degradation in AML.
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PMID:Relationship of thrombin generation to peripheral blast cell count in patients with acute myeloblastic leukemia (AML). 236 38

Hypothesizing that any effect of an increased serum iron and transferrin saturation on the risk of bacterial infection would be particularly important in immunosuppressed patients, we reexamined the effect of hyperferremia on bacterial growth in vitro and studied the pattern and prevalence of hyperferremia in patients receiving treatment for acute nonlymphocytic leukemia (ANLL). Growth of inocula of Escherichia coli and Staphylococcus aureus was significantly greater (1.3- to 5.8-fold) in fresh or heat-inactivated sera obtained from 10 healthy volunteers 3 hours after oral ingestion of ferrous sulfate (mean +/- SEM transferrin saturation 95% +/- 3%) than before (transferrin saturation 34% +/- 10%). Similarly, in heat-inactivated serum samples obtained from six patients with various malignancies, growth of E. coli was significantly greater (2.3- to 5.5-fold) with the elevated transferrin saturation (97% +/- 3%) present 1 to 7 days after receiving chemotherapy than with the normal transferrin saturation (33% +/- 9%) present before. In a prospective evaluation of serial serum iron studies in 12 patients receiving treatment for ANLL, five patients had normal serum iron concentrations initially, but in each patient the transferrin saturation was elevated after receiving chemotherapy, usually to greater than 90% for greater than 15 days in conjunction with prolonged, profound granulocytopenia and fever.
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PMID:Hyperferremia in immunosuppressed patients with acute nonlymphocytic leukemia and the risk of infection. 353 24

Eighteen patients with small cell carcinoma of the lung received high dose cyclophosphamide (180-200 mg/kg) intensification following five pulses of 'CHOP' chemotherapy (cyclophosphamide 750 mg/m2 i.v., adriamycin 50 mg/m2 i.v., vincristine 1.4 mg/m2 i.v., prednisolone 40 mg orally for 5 d). They received infusions of autologous bone marrow which had been stored at 4 degrees C for 34 h. Pancytopenia was predictable in onset and its duration acceptable. Recovery of neutrophils to greater than 1.0 x 10(9)/l was achieved in 17.5 +/-0.9 d (mean +/- SEM) and platelets to greater than 100 x 10(9)/l in 17.5 +/- 0.8 d. Four patients with acute myeloid leukaemia in complete remission received intensification with the supralethal combination of cyclophosphamide and total body irradiation followed by infusion of autologous marrow which had been stored at 4 degrees C for 54 h. Haematological reconstitution in these patients was acceptable but slower (greater than 1.0 x 10(9)/l neutrophils between days 26 and 40; greater than 20 x 10(9)/l platelets between days 23 and 77). Except in one case, normal peripheral counts were attained in all patients. It is concluded that bone marrow stored at 4 degrees C for up to 54 h is a simple and practical source of viable stem cells which have the capacity for acceptable haematological reconstitution.
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PMID:Haematological reconstitution following high dose and supralethal chemo-radiotherapy using stored, non-cryopreserved autologous bone marrow. 630 83

SEM observation of acute myeloblastic leukemia cells, incubated for 20 h with the mitogens pokeweed and phytohaemagglutinin, showed these to have elongated structures that were either smooth or partially covered by thumblike figures. By contrast, the chronic lymphocytic leukemia cells possessed more compact shapes and some were covered with blebs of varying sizes.
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PMID:SEM observation of cultured, mitogen-stimulated leukocytes. Cells obtained from patients with acute myeloblastic and chronic lymphocytic leukemias. 694 87

Enriched progenitor cell fractions from human bone marrow were induced to undergo myeloid maturation in culture using recombinant human interleukin-3 (rhIL-3) and granulocyte-macrophage colony stimulating factor (rhGM-CSF). A negative selection method using the murine monoclonal antibodies (MABs) PM81 (anti-CD15), AML-2-23 (anti-CD14), PC251 (anti-CD33), OKT11 (anti-CD2), and SCCL-1 (anti-CD71) and immunomagnetic beads coated with sheep anti-mouse IgG (Dynal A.S., Oslo, Norway) was used to remove the more mature cellular components of mononuclear cells from normal donor bone marrow samples. The resulting fraction of cells contained 35 to 40% CD34-positive cells, and less than 1% of cells expressed the receptors for the constant portion of immunoglobulin G Fc gamma RI or Fc gamma RII. A small population (3-5%) expressed Fc gamma RIII on day 0, and these cells were found by two-color flow cytometry to be primarily natural killer (NK) cells. The level of Fc gamma R expression was determined every 2 to 3 days on aliquots of the differentiating cells. Thirteen percent of the cultured bone marrow cells expressed Fc gamma RII after 48 hours in liquid culture with rhIL-3 and rhGM-CSF. The percent of cells expressing Fc gamma RII increased to a peak of 78% of the gated population on day 10. The mean fluorescence intensity (MFI) remained low for the first 8 to 10 days of culture, but at that time the MFI more than doubled. Fc gamma RI and Fc gamma RIII expression remained low throughout the culture period. The ability of the differentiating cells to perform antibody-dependent cellular cytotoxicity (ADCC) was determined at a single-cell level in a modified plaque assay using monolayers of ox erythrocyte (oxE) target cells. The purified progenitor cells, when placed in oxE monolayers sensitized with polyclonal rabbit anti-oxE antibody (AB), showed no plaque formation over control oxE layers. No increase in ability to generate cytolytic plaques in antibody-sensitized oxE layers was seen compared with unsensitized oxE layers until after 10 days of incubation in liquid culture. At that time, the percent of cells forming plaques in the AB-sensitized oxE layers was 34.4 +/- 10.7% (average +/- standard error of the mean [SEM]; n = 4) compared with 10.0 +/- 0.7% on the control oxE layers. The peak plaque formation appeared to coincide with the increase in MFI of a large population of the cultured cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effect of recombinant human interleukin-3 and recombinant human granulocyte-macrophage colony-stimulating factor on Fc gamma receptor expression and antibody-dependent cellular cytotoxicity of hematopoietic progenitor cells during in vitro myeloid maturation. 750 91

Acute leukaemia of infancy is associated with abnormalities at chromosome band 11q23, and has a poor prognosis. The gene involved. Mixed Lineage Leukaemia (MLL), has been identified and has the characteristics of a transcription factor. The BCL-2 gene responsible for blocking of programmed cell death is highly expressed in a number of haematological malignancies, both with and without the t(14;18) translocation. Those without the translocation include acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and chronic lymphocytic leukaemia (CLL). In these diseases the BCL-2 protein is implicated in drug resistance to apoptosis-inducing chemotherapeutic agents. High BCL-2 expression is also associated with autonomous growth of leukaemic blasts in culture and predicts a poor prognosis. The SEM cell line, established using blood lymphoblasts from a 5-year-old girl in first relapse with t(4;11) ALL, expresses lymphoid (CD19) and myeloid (CD13) cell surface markers. In cell culture, a subpopulation of cells (< 30%) express the BCL-2 protein. A reproducible model of true biphenotypic leukaemia in the SCID mouse has been established using the SEM-K2 cell line (a subclone of the SEM cell line). Between 5 and 50 million cells injected intravenously (i.v.) produce complete replacement of the murine bone marrow by day 30, associated with blood lymphoblastosis and infiltration of the spleen. No tumour masses were seen. Fluorescence in situ hybridization (FISH) analysis of the cell line and blood from the SCID-human (SCID-hu) chimaera has confirmed the presence of the t(4;11). Reverse transcriptional-polymerase chain reaction (RT-PCR) reveals that the breakpoint lies between exons 7 and 8 of the MLL-1 gene on chromosome 11 (the main breakpoint region). A further translocation, t(7;13), has been identified. Fluorescent antibody cell sorter (FACS) analysis of tumour material recovered from the SCID-hu model confirms expression of CD19 and CD13 identical to that of the cell line. In addition, BCL-2 expression in SCID-hu marrow is now seen in the majority of tumour cells. BCL-2 expression appears to confer a survival advantage to the blast cells in vivo. This reproducible model of biphenotypic leukaemia suggests that BCL-2 expression may play a role in leukaemogenesis. The model is suitable for the investigation of gene-targeted therapy, including antisense oligonucleotides, directed towards the MLL and BCL-2 genes.
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PMID:BCL-2 expression by leukaemic blasts in a SCID mouse model of biphenotypic leukaemia associated with the t(4;11)(q21;q23) translocation. 766 64

In order to study the adhesive interactions of the human bone marrow microenvironment and acute myeloid leukaemic cells, we investigated the binding capacity of KG-1 cells upon human long-term bone marrow cultures derived from 17 healthy volunteers and 12 patients with acute myeloid leukemia. Adhesion was measured using a 51-chromium labelling assay. Adhesion of KG-1 cells upon 'normal' stromal layers: 33% +/- 4.0, n = 17 (mean +/- SEM) was higher as compared to the binding to 'leukaemic' stromas: 24% +/- 3.7, n = 12 (p < 0.05). Blocking monoclonal antibodies against adhesion molecules reduced the binding of KG-1 cells upon 'normal' stroma, when anti-VLA4 (p < 0.03), anti-Mac1 (p < 0.03) and anti-p150/95 (p < 0.04) were used. Binding of KG-1 cells on 'leukaemic' stromas was partly inhibited by anti-VCAM1 (p < 0.03). Blocking achieved by single or combined antibodies was never complete, suggesting that the adhesion is a multifactorial process, including a variety of adhesion molecules and/or adhesion mechanisms.
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PMID:Adhesive capacity of human long-term bone marrow cultures from normals and patients with acute myeloid leukaemia: the influence of adhesion molecules. 845 Jun 74

Human interleukin-9 (IL-9) stimulates the proliferation of primitive hematopoietic erythroid and pluripotent progenitor cells, as well as the growth of selected colony-stimulating factor (CSF)-dependent myeloid cell lines. To further address the role of IL-9 in the development of acute leukemia, we evaluated the proliferative response of three leukemic cell lines and 32 primary samples from acute myeloblastic leukemia (AML) patients to recombinant human (rh)-IL-9 alone and combined with rh-IL-3, granulocyte-macrophage CSF (GM-CSF), and stem cell factor ([SCF] c-kit ligand). The colony-forming ability of HL60, K562, and KG1 cells and fresh AML cell populations upon IL-9 stimulation was assessed by a clonogenic assay in methylcellulose, whereas the cell-cycle characteristics of leukemic samples were determined by the acridine-orange flow cytometric technique and the bromodeoxyuridine (BRDU) incorporation assay. In addition, the terminal deoxynucleotidyl transferase assay (TDTA) and standard analysis of DNA cleavage by gel electrophoresis were used to evaluate induction of prevention of apoptosis by IL-9. Il-9, as a single cytokine, at various concentrations stimulated the colony formation of the three myeloid cell lines under serum-containing and serum-free conditions, and this effect was completely abrogated by anti-IL-9 monoclonal antibodies (MoAbs). When tested on fresh AML samples, optimal concentrations of IL-9 resulted in an increase of blast colony formation in all the cases studied (mean +/- SEM: 19 +/- 10 colony-forming unit-leukemic [CFU-L]/10(5) cells plated in control cultures v 107 +/- 32 in IL-9-supplemented dishes, P < .02). IL-9 stimulated 36.8% of CFU-L induced by phytohemagglutinin-lymphocyte-conditioned medium (PHA-LCM), and it was the most effective CSF for promoting leukemic cell growth among those tested in this study (i.e., SCF, IL-3, and GM-CSF). The proliferative activity of IL-9 was also observed when T-cell-depleted AML specimens were incubated with increasing concentrations of the cytokine. Addition of SCF to IL-9 had an additive or synergistic effect of the two cytokines in five of eight AML cases tested for CFU-L growth (187 +/- 79 colonies v 107 +/- 32 CFU-L, P = .05). Positive interaction was also observed when IL-9 was combined with IL-3 and GM-CSF. Studies of cell-cycle distribution of AML samples demonstrated that IL-9 alone significantly augmented the number of leukemic cells in S-phase in the majority of cases evaluated. IL-9 and SCF in combination resulted in a remarkable decrease of the G0 cell fraction (38.2% +/- 24% v 58.6% +/- 22% of control cultures, P < .05) and induced an increase of G1- and S-phase cells. Conversely, neither IL-9 alone nor the combination of IL-9 and SCF had any effect on induction or prevention of apoptosis of leukemic cells. In summary, our results indicate that IL-9 may play a role in the development of AML by stimulating leukemic cells to enter the S-phase rather than preventing cell death. Moreover, IL-9 acts synergistically with SCF for recruiting quiescent leukemic cells in cell cycle.
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PMID:Interleukin-9 stimulates the proliferation of human myeloid leukemic cells. 861 12

The toxicity and outcome after high-dose ara-C/daunorubicin (HDara-C/DNR) consolidation therapy in de novo AML was compared in 11 patients who received an idarubicin-containing induction therapy (IDA; from June 1995 to March 1997) and 16 patients pretreated with daunorubicin (DNR; from July 1990 to May 1995) for induction. The DNR group consisted of two cohorts, one (n = 6) of patients who had received, as had the IDA group, two induction and one intermediate-dose ara-C consolidation courses, and another (n = 10) of patients who had been pretreated with one induction and one consolidation course prior to HDara-C/DNR. There was no difference in the relative dose between the three cohorts. Following HDara-C/DNR, the IDA-pretreated patients experienced a more prolonged myelosuppression during consolidation therapy compared with the DNR group. Duration of neutropenia (< 500 neutrophils/microl) following HDara-C/DNR was 31.2 +/- 16 days (mean +/- SEM) in the IDA group compared with 18.7 +/- 5 days in the DNR group (p < .001 Mann-Whitney U-test). The duration 'of thrombocytopenia (platelets < 25000/microl) was 34.8 +/- 20 days in the IDA group vs. 18.5 +/- 6 days in the DNR group (p < .005). The more prolonged myelosupression was associated with a longer duration of fever (18.9 +/- 24 vs. 6.9 +/- 5.2 days). A greater incidence, length (11 +/- 8 vs. 1.2 +/- 2 days), and severity of diarrhea were observed in the IDA-pretreated group. Three of 11 IDA patients experienced WHO grade III-IV diarrhea. In the IDA group two patients developed severe enterocolitis with Candida septicemia, and one of these patients died. One patient in the IDA group died during prolonged aplasia. In the DNR group 6/16 patients experienced grade I-II diarrhea. Two patients in each group died during consolidation therapy. The CR rate was 87% in the IDA group and 79% in the DNR group. Relapse-free survival after HDara-C is 50% at a median follow-up of 60 months in the DNR group and 45% after a median follow-up of 17 months in the IDA group. Whether the advantage of the superior response rate in the IDA-treated patients may be lost during HDara-C consolidation treatment due to increased toxicity remains to be proven in larger trials.
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PMID:Comparison of toxicity and outcome in patients with acute myeloid leukemia treated with high-dose cytosine arabinoside consolidation after induction with a regimen containing idarubicin or daunorubicin. 961 32


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