Marrow transplantation for acute nonlymphoblastic leukemia in first remission.
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Acute Disease↗
Biomedical subjects
J W Singer
Publications and source records attributed to J W Singer.
Acute nonlymphocytic leukemia: expression in cells restricted to granulocytic and monocytic differentiation.
Two patients with acute nonlymphocytic leukemia who were heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate dehydrogenase were studied to determine the number and type of cells in which the disease arises. Both type A and B isoenzymes were found in normal tissues, but the myeloblasts showed only one enzyme type, indicating that at the time of study, the disease had a clonal origin. The observation in one patient that erythroid cells did not arise from this clone contrasts with conclusions reached in patients previously studied with chromosomal markers. The results suggest that in this patient, the leukemic clone suppressed expression of normal granulopoiesis but did not inhibit erythroid differentiation from normal progenitors. They suggest also that the disease is heterogeneous. In some patients, the disease is expressed in cells with differentiation restricted to the granulocyte-macrophage pathway; in others, it involves stem cells that also differentiate into erythrocytes. This heterogeneity may reflect differences in causation and could have prognostic importance.
Acute Disease↗
Angioimmunoblastic lymphadenopathy with retinitis and drug related exacerbations: a clinicopathological case study.
A patient with angioimmunoblastic lymphadenopathy with dysproteinemia was followed over a three year period from diagnosis to death. He presented with arthralgias, uveitis and respiratory insufficiency and developed hyperuricemic renal failure upon institution of treatment. Aggressive combination chemotherapy was required to reverse progressive thrombocytopenia and pulmonary involvement. A complete remission was achieved twice. There was a striking temporal relationship between the administration of antibiotics or allopurinol and exacerbations of the disease. Hypocomplementemia and transient evidence of vasculitis suggested the presence of immunecomplexes. Serial lymph node biopsies showed the progression of this disorder from a pleomorphic immunoblastic proliferation to a lymphocyte-depleted, fibrotic process, in parallel with a decline from hyper- to hypogammaglobulinemia. This case illustrates the broad clinical spectrum of angioimmunoblastic lymphadenopathy with dysproteinemia and suggests that aggressive treatment is necessary in selected patients.
Agammaglobulinemia↗
Co-culture studies in transfused and untransfused patients with aplastic anemia.
Co-culture studies have two potential values: (1) In untransfused patients with AA they may be able to detect the small population of patients who have immunologically mediated disease and who therefore may respond to immunosuppressive therapy; (2) In transfused AA patients under consideration for allogenic marrow transplantation, inhibition in the coculture assay may indicate sensitization to minor histocompatibility antigens. Preliminary data indicates that this test may be more sensitive than the chromium release assay and should be added to a battery of prospective in vitro tests designed to detect those patients at risk for marrow graft rejection.
Anemia, Aplastic↗
Marrow transplantation from donors other than HLA-identical siblings.
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Adolescent↗
Polycythemia vera. Increased expression of normal committed granulocytic stem cells in vitro after exposure of marrow to tritiated thymidine.
In previous studies of two patients with polycythemia vera (PV) and heterozygous at the X-linked locus for glucose-6-phosphate dehydrogenase (G-6-PD), only type A isoenzyme was found in non-lymphoid hematopoietic cells. However, some granulocytic and erythrocytic colonies grown in vitro had type B G-6-PD and therefore arose from presumably normal progenitors. In this study we exposed marrow cells from these same two patients to high-specific activity tritiated thymidine (3HTdR) before culture to kill cells actively synthesizing DNA. Individual granulocytic colonies were plucked and tested for G-6-PD after 14 d of culture. The frequency of type B colonies rose after exposure to 3HTdR from 8/101 to 11/36 in patient 1 and from 0/32 to 6/31 in patient 2 (P less than 0.003). No increase in the frequency of normal erythroid bursts after 3HTdR exposure was seen, implying that in PV, early granulopoiesis, and erythropoiesis are regulated differently. The results demonstrated that only type A granulocytic colonies, arising from the abnormal clone, were removed by the 3HTdR. In addition, for patient 2, statistical analysis indicated there was an absolute increase in normal granulocytic colonies detected in culture. Thus, PV clonal colony-forming units in culture (CFU-C) cycle more rapidly than do normal CFU-C and may suppress proliferation of normal CFU-C in vitro.
Cell Division↗
Chronic myelocytic leukemia (CML): failure to detect residual normal committed stem cells in vitro.
Granulocytic colonies grown in culture from marrow and peripheral blood from five patients with Ph1-positive CML and heterozygous at the G-6-PD locus were analyzed for G-6-PD in order to identify CFU-C that do not arise from the CML clone. The patients had both B and A enzymes in normal tissues, but their CML clones typed as B. Whereas about 50% of colonies from normal subjects heterozygous as the G-6-PD locus show type-A G-6-PD and 50% type B, only two of the 1308 colonies from the CML patients had type-A G-6-PD. These data provide little evidence for persistence of normal committed stem cells in CML, a finding in contrast to that made previously in polycythemia vera, another clonal stem cell myeloproliferative disorder.
Adult↗
Coculture studies of 16 untransfused patients with aplastic anemia.
We studied the effects of peripheral blood lymphocytes from 16 untransfused patients with severe aplastic anemia (AA) of diverse etiologies on the growth of granulocyte-macrophage colonies from normal marrows. Normal lymphocytes in our system increased the number of granulocytic colonies by 31 +/- 6% (mean +/- SEM). Lymphocytes from 3 of 16 untransfused AA patients significantly inhibited growth in HLA-matched sibling marrows (-30%, -40%, and -37%; p less than 0.01). Although these results suggest that the majority of cases of AA are not mediated by a coculture-detectable immunologic mechanism, studies using lymphocytes obtained from AA patients before transfusions may detect the subpopulation whose disease is immune-mediated and who may therefore respond to immunosuppressive therapy.
Adolescent↗
Unicellular or multicellular origin of human granulocyte-macrophage colonies in vitro.
The assumption that human granulocyte-macrophage colonies have a unicellular origin and thus are true clones has been directly tested. Cells from seven females heterozygous for the common glucose-6-phosphate dehydrogenase (G-6-PD) gene (GdB) and the variant GdA were cultured in semisolid medium for granulocyte-macrophage colony growth and the enzyme type of individual colonies was determined. When the colony density was less than 20/dish, more than 95% of colonies had either type A or type B G-6-PD, but not both. At colony densities greater than 30/dish, between 15% and 75% of colonies had both enzyme types and therefore arose from more than one cell. These results are consistent with a unicellular origin for the colonies only when they are cultured at low densities. With increasing colony density, there was a greater frequency of colonies with both type A and type B activity, suggesting that accurate enumeration of committed stem cells can only be performed at low colony concentrations.
Blood Protein Electrophoresis↗
Granulopoietic increase by BCG in mice.
Repeated doses of the non-specific immunostimulant BCG were injected intraperitoneally, followed by serial measurement of serum colony stimulating factor (CSF), and CFU-C number and percent synthesizing DNA. Following primary challenge with BCG, CSF remained at low levels until day 7, rose to a peak by day 10, and remained elevated through 14 days. Secondary challenge resulted in a bi-phasic CSF response with a small peak on day 1 and a larger one by day 7. Following secondary challenge, the percent of CFU-C in 'S' phase doubled in 24 hours; CFU-C significantly increased in number by 48 hours. The studies suggest that the marrow toxicity of cycle active cytotoxic drugs might be altered by non-specific immunostimulants such as BCG.
Animals↗
In vitro marrow culture techniques in aplastic anaemia and related disorders.
In vitro studies of marrow growth from patients with AA have generally confirmed the hypothesis that the disease is due to stem cell injury. By studies of marrow growth from AA patients (when possible) and their relatives to detect altered sensitivity of marrow stem cells to drugs or toxins, it may be possible better to identify suspected aetiological agents, and study genetic susceptibility to toxic AA. Lack of adequate stimulation has not been shown to be aetiological in AA as both ESF and CSF levels are generally higher than normal. Serum from AA patients has not been shown to be toxic to marrow and recent data suggesting that lymphocytes mediate some cases of AA have been questioned. Further studies of committed stem cell growth and the interaction between lymphocytes and stem cells are indicated in attempting to understand the complex of diseases that result in marrow aplasia.
Adult↗
Effect of peripheral blood lymphocytes from patients with aplastic anemia on granulocytic colony growth from HLA-matched and -mismatched marrows: effect of transfusion sensitization.
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Anemia, Aplastic↗
Time- and dose-dependent changes in ejection fraction determined by radionuclide angiography after anthracycline therapy.
Twenty patients receiving anthracycline chemotherapy were studied by the technique of radionuclide ejection fraction (EFrn). This technique is capable of detecting noninvasively small changes in left ventricular function. Two patterns of anthracycline toxicity emerged: (a) an acute toxicity observable between 24 and 72 hours after administration of greater than 60 mg/m2 of anthracycline with some recovery noted by 72-96 hours (no changes were observed within the first 4 hours after administration of the drug), and (b) a chronic dose-dependent decrease in left ventricular function when studies were performed 3 weeks after the last dose of anthracycline. After anthracyclines were stopped, four of four patients showed significant recovery in left ventricular function. We concluded that the radionuclide EFrn is a sensitive noninvasive index of left ventricular function which can be used to serially study patients receiving anthracycline therapy and can potentially be used to evaluate pharmacologic means for preventing anthracycline cardiotoxicity.
Adult↗
Time- and dose-dependent changes in ejection fraction after anthracycline therapy.
Cardiac toxicity due to anthracycline therapy is dose related, and congestive failure is a major limiting factor to therapy. Radionuclide cardiac evaluation provides a sensitive noninvasive method for detecting changes in cardiac function. Fifteen patients receiving either doxorubicin or daunomycin were evaluated with radionuclide ejection fractions (EFrn). The data indicate that the EFrn can detect an acute depressant cardiac action of these drugs as early as 24 hr after drug administration. In addition, a cumulative or chronic cardiac depression was noted; cumulative dosage of doxorubicin or daunomycin correlated with a reduced EFrn (p less than 0.001). We conclude that (1) the EFrn can noninvasively detect significant changes in cardiac function at low cumulative doses of doxorubicin or daunomycin and (2) the EFrn may be useful in evaluating cardiac function in patients during doxorubicin or daunomycin therapy.
Adult↗