Biomedical subjects
Publications and source records attributed to R J Jacobson.
We report a patient with Ph+ chronic myelogenous leukemia (CML) whose recurrent blast crises were associated with marrow eosinophilia and inv(16). After intensive chemotherapy, for each blast crisis, the patient reentered chronic phase with disappearance of both the inv(16) and the eosinophilia.
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A mouse IgG1 monoclonal antibody ED12F8C10 (C10) binds a constant percentage of peripheral blood neutrophils in the same individual when studied over time, defining a distinct subset of neutrophils in all normal individuals studied to date. Bone marrow studies confirm that the heterogeneity is present to the same degree at all stages of neutrophil development from the myelocyte to the mature neutrophil. Neither in vivo nor in vitro activation of neutrophils explains or significantly alters the relative percentages of C10-positive and -negative neutrophils in the same individual. With both activation and exudation, however, expression of the C10-defined epitope increases in intensity in the C10 binding subpopulation. Studies of NBT reduction, phagocytosis, adherence, light scattering characteristics, and monoclonal antibody surface binding have failed to demonstrate physical or functional differences between the C10-defined populations. We examined C10 binding in patients with different defects of phagocyte function. In two patients with neutrophil-specific granule deficiency, less than 1% of the neutrophils were found to be C10 positive, while neutrophils from a patient with idiopathic leukemoid reaction and recurrent infections demonstrated greater than 99% C10 binding. Although the present study does not delineate the physiologic significance of C10 binding heterogeneity, it firmly supports the concept of neutrophil heterogeneity at the level of surface antigen expression.
To assess the clonality of Wilms' tumor, glucose-6-phosphate dehydrogenase (G6PD) enzymes were studied in normal and tumor tissue from 11 black girls who were heterozygous for G6PD. Normal tissues expressed both A and B type G6PD, whereas only a single G6PD enzyme was found in all tumor specimens. These data support the clonal nature of Wilms' tumor. In the one patient with bilateral disease, type B G6PD was found in both a recurrence and a subsequent tumor in the contralateral kidney. This finding is consistent with either the chance occurrence of the same G6PD in independent tumors or persistence of the original malignant clone. Another patient, who presented with the nephroblastomatosis complex (a precursor of Wilms' tumor), also had only type B enzyme detected. Further studies in patients with bilateral disease or the nephroblastomatosis complex, including the use of molecular biologic probes, are needed to test the hypothesis that Wilms' tumor in these cases arises from a somatic mutation as a second event in persons with an underlying genetic alteration.
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.
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Three different neoplasms of B cell lineage, chronic lymphocytic leukemia, immunoglobulin A (IgA) myeloma and immunoglobulin G (IgG) myeloma were detected in three patients who had heavy occupational exposure to asbestos dust. Two of the patients had coexistent pulmonary asbestosis, whereas the third patient had a pleural mesothelioma subsequent to his initial presentation with myeloma. Defective cell-mediated immunity and hyperactivity of B cell function have previously been noted in patients with asbestosis. We suggest the possibility that these asbestos-related immunologic derangements may predispose to the development of immunoproliferative and lymphoproliferative neoplasms, since such tumors have been observed in a variety of other settings, characterized by protracted hyperactivity of the immune system.
Thirty-four Black patients (14 children and 20 adults) suffering from acute leukaemia were assessed at the haematology clinics of Baragwanath Hospital and Johannesburg General Hospital during a recent 2-year period. It is evident that acute leukaemia in Blacks has become more prevalent in the Johannesburg area than it was 20 years ago, the increase being most striking in the younger age group. The incidence of acute myelocytic and lymphocytic leukaemia in Black children was the same. In adults acute myelocytic leukaemia predominated. The remission rate of 90% achieved in patients with acute lymphoblastic leukaemia was similar to the rates described in Europe and the USA. Results in patients with acute myelocytic leukaemia were less favourable (35% with initial complete remission). The problems of management (limited isolation facilities), complications related to prolonged hospitalization (loss of earnings, problems of visiting), and difficulties with follow-up examination are outlined. In underdeveloped and developing countries, training paramedical personnel to assist with the outpatient care of patients with neoplastic disease might alleviate some of these problems.
Homogeneous protein synthesis elongation factor Tu from Escherichia coli forms aggregates at high concentrations of ammonium sulfate which have a filamentous appearance in the light microscope. Electron microscopy of negatively stained preparations shows that these aggregates are paracrystalline, including three different forms. On the basis of analyses by optical diffraction, this polymorphism can be explained in terms of three different tubular foldings of the same basic two-dimensional surface lattice. This can be compared with that underlying the structure of actin filaments, thus providing a crucial test of the putative relationship between the elongation factor and actin [Rosenbusch, J. P. et al. (1976) J. Supramol. Struct. 5, 391-396]. The differences between the surface lattices, in conjunction with the negative results of sensitive immunochemical tests for possible cross-reactivities between the two proteins, suggest that any such relationship is very remote.
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A Black patient with hepatocellular cancer and an increased red cell mass (erythrocytosis) is described. Assay of the patient's serum in ex-hypoxic polycythaemic mice showed the presence of erythropoietic activity. To determine the incidence of erythrocytosis in Southern African Blacks with hepatocellular cancer, haemoglobin and haematocrit values in 117 such patients were reviewed. Four patients (3,4%) had haemoglobin levels above the upper limit of normal and 2 (1,7%) of the patients had raised haematocrit values. Fifty-eight per cent of the patients were anaemic when they were first seen.
In three patients with chronic myelocytic leukemia who were heterozygous at the X-linked glucose-6-phospháte dehydrogenase locus, lymphocytes were studied to determine if they had the same stem cell origin as the leukemic myeloid cells. Normal tissues such as skin had both B and A glucose-6-phosphate dehydrogenase isoenzymes, but the leukemic myelogenous cells displayed only one isoenzyme type, consistent with their clonal origin. A population of cells with undoubted thymus-derived (T)-lymphocyte characteristics had both isoenzymes. Presumably, then, these T cells did not arise from the leukemic stem cell, either because they antedated the development of leukemia in that stem cell or, more likely, because they arose from progenitors not involved by the disease. In contrast, another population of lymphocytes showed only one isoenzyme type, suggesting that it arose from the chronic myelocytic leukemia stem cell. However, although this population contained many cells with the characteristics of bone marrow-derived (B) lymphocytes, it is not certain that the single enzyme produced by the cells over all can be attributed to B lymphocytes rather than to contaminating non-B-lymphoid cells.
Waldenström's or primary macroglobulinaemia has rarely been documented in Black Africans. Six South African Negro patients with Waldenströms macroglobulinaemia were assessed and followed during a 10-year period from 1966 to 1976. The hyperviscosity syndrome was the presenting feature in four patients and one patient each presented with the nephrotic syndrome and a lacrimal mass respectively. On initial evaluation of the six patients, the serum IgM varied from 1.3 to 4.8 g% and in two patients cryoglobulinaemia was found. The patients received supportive treatment, chemotherapy, and when necessary, plasmaphoresis. One patient was lost to follow-up, one patient died 7 years after the onset of his illness, but the remaining four patients are alive 18 months to 5 years after presenting with their disease. Although the disease occurred in a younger age group (mean age 43 years) than in Caucasians it did not differ in clinical features or response to treatment from other parts of the world.
A 64-yr-old female developed acute myeloblastic leukemia following radiation and drug therapy for colon carcinoma. The patient was heterozygous for glucose-6-phosphate dehydrogenase (G-6-PD) and displayed types A and B isoenzymes in nonhematopoietic tissue. In contrast, only type B G-6-PD was observed in peripheral blood white cells. In addition, a karyotypic abnormality was found in peripheral blood and marrow cells but not in skin fibroblasts. The data are consistent with a clonal origin of this leukemia.
The glucose-6-phosphate dehydrogenase (G-6-PD) types and chromosomes of hematopoietic and other tissues were determined in a woman with agnogenic myeloid metaplasia. The patient was heterozygous at the X-linked G-6-PD locus so that both B and A isoenzymes were found in nonhematopoietic cells. In contrast, only one G-6-PD type was found in granulocytes, red cells, and platelets. She also had a distinctive chromosome abnormality in blood cells but not in other tissues. These results indicate that agnogenic myeloid metaplasia is a disorder of a pluripotent stem cell and provide strong evidence that it is of clonal origin. In contrast to blood cells, the patient's cultured marrow "fibroblasts" had normal chromosomes and both B and A G-6-PD types, suggesting that the marrow fibrosis is a secondary abnormality. Thus, at least in this case of agnogenic myeloid metaplasia, the hematopoietic cell proliferation appears to be clonal, and, by inference, possibly neoplastic, whereas the marrow fibrosis is probably not clonal, and therefore appears to be secondary.