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.

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.

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.

Progress and survival factors in acute non lymphocytic leukemia. A 15 year analysis.

We analyzed a population of adults with acute non lymphocytic leukemia (ANLL) treated from 1972-1989 to identify prognostic factors and the influence of therapy over time. To 179 patients treated at Sunnybrook Medical Centre (SMC) were added 114 patients from published patient series from Princess Margaret Hospital (PMH) all treated during that period. All PMH and 98 SMC patients received one of three remission induction protocols: CAV (cyclophosphamide, cytosine arabinoside [ara-C], vincristine) 1973-1976 (n = 46); ACT (Adriamycin, ara-C +/- 6-thioguanine) 1976-1983 (n = 83); high dose ara-C and corticosteroids 1983-1987 (n = 83). The remainder either received supportive therapy only or minimally toxic therapy (e.g., low dose ara-C, 6-mercaptopurine) due to presenting complications such as advanced age, severe concurrent medical condition, or most recently at SMC only, mitoxanthrone and ara-C, and were excluded from analysis. Responses obtained at the two institutions were identical, no survival advantage of any particular protocol was seen. Overall median survival was 8.5 months for patients treated on protocol and 20 months for those entering complete remission. Patients treated with supportive or minimally toxic therapy (n = 76) had a median survival of less than two months. In multivariate analysis, the only important factors for survival were complete response to initial therapy; complete response to second induction therapy following either first relapse (n = 89) or lack of complete response to first therapy (n = 15); and normal cytogenetic analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

"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.

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.

The sensitivity to cytosine arabinoside of the blast progenitors of acute myeloblastic leukemia.

Two culture methods are available for the study of the blast cells of acute myeloblastic leukemia (AML). One is an assay for clonogenic precursors; it depends on their ability to form blast colonies in culture in the presence of methylcellulose and suitable growth factors. The other assesses the growth of blast cells in suspension culture, where growth is measured by increasing numbers of clonogenic cells. We have compared the two methods as assays for the cytotoxic effects of the chemotherapeutic drug cytosine arabinoside (Ara-C). Marked patient-to-patient variation was found using either method; however, the slopes of the dose-response curves were usually greater when cells were exposed to drug in suspension rather than in methylcellulose. Control experiments showed that the difference could not be explained by drug carry-over from the suspension cultures to the methylcellulose plates when clonogenic cells in the suspensions were assessed. Further, the survival curves for Adriamycin were very similar, regardless of which assay was used. No correlation was found between D10 Ara-C values measured in suspension or in methylcellulose. However, a significant association with outcome was found between D10 Ara-C in suspension and response to treatment with a regimen in which Ara-C was the only chemotherapeutic agent used. No such association was detected when the D10 values obtained with the clonogenic assay were compared with outcome for the same group of 15 patients. Finally, a feasibility experiment was performed in which blast cells were exposed to Ara-C repeatedly during exponential growth over 238 days. A dose-related inhibition of growth was observed; no evidence was seen of emerging drug-resistant cells. Nor did the morphology of the cells change as a result of drug exposure. We conclude that drug sensitivities of AML blast cells in culture are dependent on measurement methods, even when techniques affecting cell proliferation are compared. Measurements of drug sensitivity in culture may best be interpreted when the bases of the assay systems are understood.

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.

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.

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.

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.

Lineage infidelity in acute leukemia.

Blast cells from 20 patients with acute leukemia (13 diagnosed myeloblastic and 7 as lymphoblastic, using the FAB classification) were studied using antibodies to lineage-specific differentiation markers. The phenotypic findings were usually consistent with the clinical diagnosis. However, examples were encountered where individual blast cells had a cytoplasmic marker of one lineage and a surface marker of a different lineage (lineage infidelity). Six examples of intramyeloid (two different myeloid lineages in the same cell) and three examples of interlineage infidelity (myeloid and lymphoid markers in the same blast cell) were encountered. No doubly marked cells were found in control material consisting of normal marrow cells, marrow regenerating after transplantation, or multilineage colonies derived from marrow in culture. A significant trend was observed relating the presence of lineage infidelity and failure of remission-induction. The data are interpreted as support for abnormal gene expression in leukemia.

The contribution of blast cell properties to outcome variation in acute myeloblastic leukemia (AML).

The blast cell population in AML includes progenitors capable of colony formation in culture. Certain properties of these progenitors have been determined, including their capacity for self-renewal and their sensitivities to the chemotherapeutic drugs cytosine arabinoside (Ara-C) and adriamycin (Adria). Wide patient to patient variation was found in these properties, although they were stable during the course of the disease in each patient. We tested the properties, together with clinical risk factors, as attributes contributing to the variation in remission induction and survival. As univariate parameters, self-renewal and Ara-C sensitivity contributed to remission induction, but only self-renewal was related to survival. In multivariate analysis, self-renewal, age and percentage blasts in the marrow contributed to outcome variation; drug sensitivities were not significant. We conclude that self-renewal, a biological property of malignant AML clones, although measured in culture, plays a significant role in determining response to treatment and survival in AML.

Peripheral blood blast cell progenitors in human preleukemia.

Progenitors of blast cell colonies have been identified in acute leukemia. The peripheral blood of 18 of 25 patients with preleukemic states yielded low numbers of blast cell colonies, and the colony-forming cells were in an active proliferative state when assessed using short-term exposure to tritiated thymidine. The clinical significance of blast cell colonies is uncertain, but we suggest that further analysis of this cultural abnormality may lead to a better understanding of mechanisms and management in preleukemia.

The heritable nature of clonal characteristics in acute myeloblastic leukemia.

Marked patient-to-patient variation is observed when blood or marrow from AML patients is examined using colony methods in culture. Concentrations of the progenitors of colonies change with time during the course of the disease. We asked whether blast progenitor properties were more stable. We measured blast cell self-renewal and drug sensitivity (adriamycin and cytosine arabinoside) repeatedly in the courses of seven AML patients. These properties were found to be stable or slowly evolving. We conclude that capacity for renewal and sensitivities to certain chemotherapeutic drugs are heritable characteristics in leukemic clones.