Response to 5-azacytidine of leukemic blast cells in suspension: a biological parameter associated with response to chemotherapy.

Sensitivities to drugs acting on cells in culture can be measured as dose-response curves, provided a quantitative assay is available for a relevant cell function. We have used two such assays in the study of the blast cells of acute myeloblastic leukemia. Colony formation in culture with methylcellulose detects principally terminal divisions, while growth of clonogenic cells in suspension reflects self-renewal. In a previous study different cytosine arabinoside and 5-azacytidine dose-response curves were obtained with the two assays. For the former the slope of the dose-response curve measured in suspension was steeper than that obtained using the clonogenic assay. For the latter, 5-azacytidine, the relationship between sensitivity in suspension and in methylcellulose was reversed. Further, for cytosine arabinoside, sensitivity in suspension but not in methylcellulose was associated with successful remission-induction. In this article we report an association between 5-azacytidine sensitivity in suspension and successful remission induction, for patients treated only with high-dose cytosine arabinoside. There was no correlation between the 5-azacytidine dose-response curve in methyl-cellulose and clinical outcome. A model is presented that may explain these findings, based on the hypothesis that there are genetic mechanisms responsible for blast cell renewal.

Myelodysplastic syndrome with prolonged reticulocyte survival mimicking hemolytic disease.

A patient with myelodysplastic syndrome (refractory anemia) with marked and persistent reticulocytosis is presented. A referring diagnosis of hemolytic disease had been made. However, the 51Cr red cell survival was normal (T1/2 24 days). Reticulocyte morphology, red cell creatine content, and in vitro reticulocyte survival studies have suggested that the reticulocytosis arose as a consequence of delayed maturation of the reticulocytes. Two patients with myelodysplastic syndrome and delayed reticulocyte maturation have previously been described; in both patients, however, red cell survival was also shortened. Anemia with reticulocytosis, mimicking hemolytic disease, may be an unusual presentation of myelodysplastic syndrome.

Lazy leucocyte syndrome--disorder of the granulocyte membrane?

An adult with long-standing neutropenia had the functional granulocyte abnormalities typical of the lazy leucocyte syndrome. Scanning electron microscopy of the patient's neutrophils showed alteration in the surface configuration of the cell with coarsening of the normal fine ruffles and the appearance of knob-like projections. Similar functional and anatomical changes were induced in normal neutrophils by treatment with vinblastine. The lazy leucocyte syndrome may be a consequence of altered membrane microfilamentous protein structure or function, and undue rigidity of the affected neutrophils may explain the clinicopathological features of the disease.

Idiopathic acquired sideroblastic anaemia transforming to acute myelosclerosis.

A case of idiopathic acquired sideroblastic anaemia transforming to acute myelofibrosis is reported. The appearance of atypical megakaryocytic proliferation in idiopathic acquired sideroblastic anaemia may presage the development of an acute myelofibrotic phase of this usually chronic disease.

A new translocation in chronic myeloid leukemia--t(4;9;22)--resulting in a masked Philadelphia chromosome.

A patient with chronic myeloid leukemia is described in whom a novel complex translocation was found among chromosomes #4, #9, and #22, resulting in a "masked" Philadelphia chromosome. The breakpoint in chromosome #4 (band q21) is in the same region as the breakpoint seen in the t(4;11), which is associated with some forms of acute leukemia.

Chronic myeloid leukemia with a Philadelphia chromosome involving a t(21;22).

A second example of chronic myeloid leukemia showing translocation of material from the long arm of chromosome #22 to the long arm of chromosome #21, ( 21q +:22q-), is reported. The patient presented with the typical clinico-pathologic features of the disease.

Deletion of the long arm of chromosome 5 in essential thrombocythemia.

A 51-year-old woman with no history of prior chemotherapy or radiation therapy was diagnosed with essential thrombocythemia (ET) according to the diagnostic criteria established by the Polycythemia Vera Study Group (PVSG). Cytogenetic analysis of bone marrow metaphases revealed both normal female karyotype and a single clonal abnormality, 46,XX,del(5)(q22q35). While chromosomal abnormalities have been reported in ET, their incidence is very low, and no specific abnormality has been found. Many of the reported cases of ET with chromosomal aberrations, including 5q-, do not meet the diagnostic criteria proposed by the PVSG, and may represent one of the other myeloproliferative disorders or a myelodysplastic syndrome. Furthermore, it is important to distinguish the 5q- syndrome, which may present with thrombocytosis and megakaryocytic hyperplasia, from ET. Our patient appears to be the first example of untreated ET clearly meeting the PVSG criteria in which 5q- was the only clonal abnormality seen at diagnosis.

"Jumping" translocations involving band 3q13.3 in a case of acute monocytic leukemia.

We report a case of acute monocytic leukemia (FAB-5a) with a very aggressive clinical course and multiple chromosomal abnormalities. There were several sublines, each with trisomy 8 and a translocation involving 3q13.3 as a common breakpoint region. This region is an uncommon site of chromosomal breakage in malignancies and has not hitherto been reported as a breakpoint site in "jumping" translocations.

Chronic myeloid leukemia: physical and functional similarities to acute leukemia.

Blast crisis, closely resembling acute leukemia, is the usual terminal event in chronic myeloid leukemia. Using physical ("fingerprint") and cultural (colony-forming) methods, we have demonstrated distinctive patterns in the stable phase of chronic myeloid leukemia and in blast crisis. An unusual fingerprint alteration preceding the onset of the terminal phase is noted, and cell culture perturbation is evident at different stages of the disease. Our findings indicate that the application of these methods to the study of hemopoietic disorders is valid, and suggest that the use of such techniques may allow a better understanding of the complex cellular events occurring in the course of chronic myeloid leukemia.

Foregoing renal dialysis: a case study and review of ethical issues. The End-Stage Renal Disease Group.

End-stage renal disease is treated by long-term dialysis when renal transplantation is not feasible. At a late stage in the disease, for a variety of reasons, dialysis is frequently stopped. This is one of the most common causes of death in dialysis patients. Ethical issues related to withdrawal of dialysis are therefore commonly encountered in nephrology practices. A case study involving discussions to forego dialysis in an incompetent patient is presented, and the ethical issues raised by this case, particularly related to the concepts of medical futility, informed choice, and justice are discussed. Finally, procedural approaches are suggested that will help to address the ethical problems raised and to assist in decision making at the time that the discontinuation of dialysis is being considered.

Levamisole: evidence for activity on human haemopoietic progenitor cells.

Levamisole, which has immunostimulant activity, is now being used to treat some forms of cancer. We report that the drug enhances granulocyte colony formation. The mechanism of action appears to be partly through modulation of molecules on cell membranes. The molecular content of colony-stimulating activity (CSA) released into leucocyte-conditioned medium by cells of leukaemic and some preleukaemic patients can be quantitatively altered by levamisole, both in vitro and in vivo, but the CSA produced is qualitatively similar to that released by normal cells. The demonstrated levamisole enhancement of colony formation, and altered CSA types detected in leucocyte-conditioned medium, makes this drug a promising candidate for treatment of selected leukaemic states and in preleukaemia.

An approach to human preleukemia using cell culture studies.

Cell culture methods applied to the study of acute leukemia have indicated the presence of many abnormalities. Utilizing this knowledge, we have applied cell culture techniques to the evaluation of a patient population with a recognized risk of developing leukemia. We demonstrate that cultural abnormalities present in some patients with sideroblastic anemia are similar to those seen in acute leukemia, and that these perturbations may be shown before leukemia develops. This study suggests that cell culture abnormalities may reflect mechanisms operative in vivo, and preceding the development of overt leukemia.

Stem cell characterization of neutropenia: velocity sedimentation and mass culture analysis.

Human bone marrow obtained from patients with neutropenia contains a cell population which is absent or diminished in normal marrow. The abnormal population is composed of cells of volume 200-300 mum3 which sediment at 5-5 to 8-5 mm/h. Normal marrow contains one cell class giving rise to increased numbers of grnaulocyte colonies after mass culture, while marrow obtained from neutropenic patients, or from patients with marrow regeneration, shows two such populations; one of these cell classes corresponds to the abnormally large cells demonstrated on velocity sedimentation analysis. This population of large cells may represent a group of either self-renewing cells related to the committed granulocyte progenitors or the pluripotent stem cell.

Multiple myeloma with initial presentation in the jaw: a clinical-pathologic discussion.

A 39-year-old white female presented with jaw pain initially interpreted as a manifestation of an odontogenic infection. Mandibular radiographs revealed lytic lesions suggesting a diagnosis of myeloma, which was subsequently confirmed by abnormalities in serum and urinary proteins and in bone marrow. Chemotherapy produced a transient response, but eventual relapse with extramedullary plasmacytomas and plasma cell leukemia led to death. The clinicopathologic implications of this case are presented and discussed.