Similarity of p53 expression by CD34+ cells in chronic myeloid leukemia and normal progenitors detected by flow cytometry.
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Biomedical subjects
Publications and source records attributed to J M Goldman.
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Umbilical cord blood has been used to effect hematological reconstitution and there are sufficient stem cells available in the cord blood obtainable from a single placenta to reconstitute an adult patient. Umbilical cord blood might therefore, have widespread potential use in the field of bone marrow transplantation. We compared alloreactivity of paired samples of adult and cord peripheral blood mononuclear cells, by measuring frequencies of both alloreactive T helper cells and cytotoxic T cell precursors (CTLp), using limiting dilution analysis. In addition we compared the phenotype of adult and neonatal PBMC, using monoclonal antibody staining. Cord PBMC in general showed higher frequencies of alloreactive Th than adult PBMC, with statistically significant differences in 6 out of 10 experiments. There was no statistically significant difference between adult and cord CTLp frequencies. Adult and cord PBMC surface phenotype was similar, except that cord blood contained fewer lymphocyte function-associated-3 (LFA-3) positive (memory) cells.
A proportion of patients receiving allogeneic bone marrow transplants (BMT) for chronic myeloid leukaemia (CML) in first chronic phase relapse; most of these relapses show features of chronic phase disease. We report here a series of five patients seen at a single institution over a 10 year period who developed blast crisis as the first sign of relapse after BMT for CML in chronic phase. The blast cells were myeloid in three cases and lymphoid in two. In one case the relapse may have occurred in cells of donor origin. The possible explanations for this unusual sequence of events include incipient transformation that was not detected before BMT, undetected relapse into chronic phase proceeding into transformation post-BMT, and transformation occurring de novo post-BMT in small numbers of residual leukaemic stem cells.
The involvement of the BCRlABL fusion gene in patients with Philadelphia (Ph) chromosome positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) is well characterised, but the molecular events underlying the cases of Ph-negative CML and ALL that lack BCR gene involvement and those that cause transformation of Ph-positive CML are unknown. The murine ABL gene can be activated by genetic events that do not involve the BCR gene, including the introduction of two specific point mutations in exons VII and XI respectively, as found in the homologous sequence of the v-abl oncogene. We therefore sought evidence for analogous point mutations in the ABL gene in patients with Ph-negative, BCR-negative CML (n = 25), Ph-negative ALL (n = 18) and in Ph-positive CML in transformation (n = 28). We used restriction fragment length polymorphism and single strand conformational polymorphism techniques to analyse DNA amplified fragments of selected ABL coding regions from leukaemia cells. We identified only normal wild-type DNA sequences. The absence of these transforming point mutations does not exclude the possibility that the ABL gene in such patients could be activated by other means.
Patients with newly diagnosed CML have Ph-negative stem cells in their marrow and peripheral blood. A minority can be restored to durable Ph-negative haemopoiesis by treatment with interferon-alpha but in general autografting with marrow collected after IFN treatment has not proved feasible. Some patients autografted with blood-derived stem cells collected in chronic phase have achieved durable Ph-negative haemopoiesis and selected patients autografted with 10-day incubated marrow cells have also achieved complete remission. An alternative approach involves collection and isolation of Ph-negative stem cells that may then be used for autografting. Different lines of evidence suggest that induction of remission for all patients with CML should be an attainable goal.
A radioimmunoassay was used to measure concentrations of immunoreactive human calcitonin (HCT) in plasma and leucocytes from patients with various leukaemic and myeloproliferative disorders. Plasma immunoreactive HCT concentrations were increased in 32 out of 33 patients with chronic granulocytic leukaemia (CGL) and in all eight patients with acute myeloid leukamia (AML) at presentation or in relapse. Out of 11 patients with other myeloproliferative disorders, eight had increased plasma immunoreactive HCT concentrations. Buffy-coat-cell extracts and culture media from peripheral leucocytes of patients with CGL also contained increased immunoreactive HCT concentrations. In contrast, plasma from patients with chronic lymphocytic leukaemia, acute lymphoblastic leukaemia, and AML in remission had low or undetectable immunoreactive HCT concentrations. Increased plasma and cellular concentrations of immunoreactive HCT may be a consequence of abnormal proliferation of myeloid cells and might prove to be valuable in predicting relapse in patients with myeloid leukaemias.
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Six patients with chronic granulocytic leukaemia (CGL) in transformation were treated with cytotoxic drugs or cytotoxic drugs plus total body irradiation, followed by infusion of reconstituted autologous peripheral blood cells that had been collected from them at diagnosis and stored in liquid nitrogen for up to 58 months. In four cases the blood and bone-marrow appearances were rapidly restored to those of typical chronic-phase disease. In three of these patients transformation recurred at 74, 32, and 26 weeks respectively. One patient was still in second chronic phase at eight weeks. One of the patients who entered a second transformation was restored to a third chronic phase by further treatment with cytotoxic drugs and a second autograft. Cryopreserved autologous blood cells may thus restore some patients with CGL in transformation to chronic-phase disease and so may help to prolong life.
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Seven patients with chronic granulocytic leukaemia in transformation were treated with combination cytotoxic drugs only or cytotoxic drugs plus total body irradiation followed by transfusion of reconstituted cryopreserved autologous buffy coat cells. Four of the patients were restored to second chronic phase disease which lasted 74, 32, 26 and 12 weeks respectively. Three other patients derived little benefit from the procedure. Buffy coat cells from patients with CGL apparently contain enough pluripotential stem cells to provide effective autografts in most cases. Lymphoid as well as myeloid reconstitution can usually be achieved. Buffy coat cells may thereby be superior to bone marrow cells for this purpose. Aggressive cytoreductive treatment followed by autografting appears to be a promising approach to the palliative management of patients with CGL in transformation.
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30 patients with acute leukaemia being treated with cytotoxic drugs were investigated in a randomised trial to determine whether oral administration of co-trimoxazole in addition to non-absorbable antibiotics would reduce the rate of infection. Three significant differences were observed between the co-trmoxazole and the control groups: (i) 15 of the 16 (94%) control patients but only 8 of the 14 (57%) patients on co-trimoxazole developed infections and required additional antibiotics intravenously; (ii) although the duration of severe neutropenia (neutrophils less than 0.1 times 10(9)/1) was similar in the two groups, control patients required intravenous antibiotics on average after 2 days of neutropenia, whereas patients receiving co-trimoxazole required these only after 12 days; and (iii) the only 2 patients who died of infection were in the control group. Prophylaxis with co-trimoxazole is important in preventing or delaying the development of infection in neutropenic patients receiving therapy for acute leukaemia.
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