Elevated glucocorticoid receptor binding in cultured human lymphoblasts following hydroxyurea treatment: lack of effect on steroid responsiveness.

While studying the effects of chemotherapy on glucocorticoid receptor (GR) binding levels in hematological malignancies, we observed a sizable increase in nuclear GR binding of [3H]dexamethasone in peripheral leukocytes from a chronic basophilic leukemia patient following treatment with hydroxyurea plus prednisone, but not after prednisone alone. This apparent clinical effect of hydroxyurea led to an examination of hydroxyurea effects on GR binding and sensitivity in the glucocorticoid-sensitive human lymphoblast cell line GM4672A. GR binding levels in GM4672A cells were measured following a 3-day exposure to 50 microM hydroxyurea, a concentration chosen to have a minimal but measurable effect on cellular growth rates with little or no effect on cellular viability. Under these conditions, nuclear [3H]dexamethasone receptor binding measured by Scatchard analysis using a whole-cell assay was elevated 2.4-fold over control values (P less than 0.05), while cytosolic residual receptor binding (measured at 37 degrees C) remained unchanged. Thus, the total cellular content of measurable GR was increased, and this increase was totally accounted for by GR capable of nuclear binding. Hydroxyurea treatment of GM4672A cells had no effect on the affinity of nuclear or cytosolic GR for [3H]dexamethasone. The increase in measurable nuclear-bound receptors occurred in a time-dependent manner over a period of 3 days and was fully reversible within 3 days following removal of hydroxyurea. The increase in receptor binding could not be explained by the slight alterations in cell cycle kinetics which occur at this low level of hydroxyurea. Despite increased receptor binding, cellular glucocorticoid responsiveness was unaltered as assessed by dexamethasone inhibition of cell growth and dexamethasone inhibition of a urokinase-like plasminogen activator. Thus, increased nuclear and total cellular GR binding levels in hydroxyurea-treated GM4672A cells are not associated with increased glucocorticoid responsiveness.

Effect of splenectomy on teardrop-shaped erythrocytes in agnogenic myeloid metaplasia.

Teardrop-shaped erythrocytes (TD) are frequently observed in the peripheral blood of patients with agnogenic myeloid metaplasia (AMM). These deformed cells may result from the myelofibrosis or the extramedullary hematopoiesis in the spleen. To determine the influence of the spleen on TD formation, we reviewed the presplenectomy (pre-S) and postsplenectomy (post-S) peripheral blood smears from 13 patients with AMM. The splenectomy was performed for a variety of reasons, including symptomatic hypersplenism or splenomegaly. The average number of TDs per 1,000 RBCs in the pre-S smears was 42 (range, 15 to 112 TDs), compared with 11 TDs in the post-S smears (range, 6 to 20 TDs)(P = less than .001). Only one of the 13 patients failed to exhibit this decrease in TDs post-S. There was no definite correlation between the number of TDs and the weight of the spleen removed at surgery, the interval since surgery, or age and sex of the patient. Based on this fourfold decrease in the number of TDs post-S, we conclude that the spleen in AMM play an important role in TD formation.

Outcome analysis of 34 pregnancies in women with essential thrombocythemia.

OBJECTIVE: To evaluate the clinical impact of essential thrombocythemia on the outcome of pregnancy or vice versa. DESIGN: A retrospective study. SETTING: All patients were seen at our tertiary referral center, and most were followed up by their local physicians. PATIENTS: From 1975 through 1991, 73 women younger than 50 years with essential thrombocythemia were seen at our institution. All patients were followed up through patient or physician contact. A detailed obstetric history, including peripartum complications and management, was obtained. RESULTS: Among the 73 women, 34 pregnancies occurred in 18 patients. There were two uncomplicated elective abortions and one ectopic pregnancy. Of the 31 other pregnancies, 17 (55%) resulted in live birth and 14 (45%) ended in spontaneous abortion (all but two in the first trimester). Abortion could not be predicted from history of disease complications before or during pregnancy or by the presence or absence of specific therapy during pregnancy. Preconception platelet counts in women whose pregnancies resulted in live birth were similar to those of women whose pregnancies ended in abortion. Other complications during pregnancy were rare. CONCLUSIONS: Patients with essential thrombocythemia have an increased risk of first-trimester abortion, which does not appear to be predictable or influenced by therapy. However, most patients are able to carry pregnancies to term with little or no risk of obstetric or thrombohemorrhagic complications during or after delivery. Overall, specific therapy during pregnancy did not appear to modify the clinical outcome, and the benefit of platelet apheresis during delivery could not be substantiated.

Myelodysplastic (preleukemia) syndromes: the bone marrow factory failure problem.

The myelodysplastic syndromes are a group of hematologic disorders that adversely affect the levels of hemoglobin, platelets, erythrocytes, and leukocytes. Although the cause of this syndrome is unknown, new diagnostic techniques have facilitated identification and classification of these diseases into five categories: refractory anemia (refractory cytopenia), refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Cytogenetic abnormalities may be present in more than 55% of the patients. Symptomatic patients should be assessed relative to life-threatening versus non-life-threatening cytopenias and age. Management consists of primarily supportive measures, although certain approaches that are currently being used or under investigation, such as concomitant administration of erythropoietin and other growth factors, show promise for the future.

Issues in the diagnosis and management of essential thrombocythemia.

OBJECTIVE: To summarize the current trends in the diagnosis and management of essential thrombocythemia (ET) and to discuss the treatment of young and pregnant patients with ET. DESIGN: We review our experiences in the diagnosis and management of ET. MATERIAL AND METHODS: A definitive diagnosis of ET at initial examination is seldom possible because of the low incidences of associated clonal cytogenetic abnormalities and palpable splenomegaly. The criteria of the Polycythemia Vera Study Group for the diagnosis of ET are provided, as are the clinical and laboratory features that help to distinguish ET from reactive thrombocytosis. RESULTS: Patients with ET have an almost normal life expectancy if thrombohemorrhagic complications are controlled. Although a previous history of thrombosis is an established risk factor for further episodes, the adverse effects of extreme thrombocytosis and age are less well defined. Determining which patients require therapy is controversial. The management of young or pregnant patients necessitates special considerations. CONCLUSION: Until additional data become available, no strong recommendations can be given in support of or against specific therapy for asymptomatic young patients. We favor treatment in asymptomatic patients with cardiovascular risk factors but not in asymptomatic women who are pregnant or are of childbearing age.

Primary thrombocythemia in the young patient.

Primary thrombocythemia is typically a disease of older patients and frequently is associated with thrombosis and hemorrhage. Seven female and two male patients younger than 30 years were evaluated because of platelet counts exceeding 1 million/mm3. No hemorrhagic or thrombotic problems existed before diagnosis or developed during the follow-up period of 14 months to 10 years. Platelet function studies done in six of the nine patients showed absent aggregation with epinephrine and variable aggregation with adenosine diphosphate, as are seen in other chronic myeloproliferative states. One patient had spontaneous aggregation. Secondary causes of thrombocytosis were excluded. Only one patient received specific chemotherapy, which was given before 1973. Thus, thrombocythemia without a secondary cause appears to be much more benign in the young patient than in the older, and aggressive chemotherapy to lower the platelet count is not necessarily justified unless serious complications develop.

Hemorrhagic cystitis complicating bone marrow transplantation.

Hemorrhagic cystitis is a potentially serious complication of high-dose cyclophosphamide therapy administered before bone marrow transplantation. As standard practice at our institution, patients who are scheduled to receive a bone marrow transplant are treated prophylactically with forced hydration and bladder irrigation. In an attempt to obviate the inconvenience of bladder irrigation, we conducted a feasibility trial of uroprophylaxis with mesna, which neutralizes the hepatic metabolite of cyclophosphamide that causes hemorrhagic cystitis. Of 97 patients who received standard prophylaxis, 4 had symptomatic hemorrhagic cystitis. In contrast, two of four consecutive patients who received mesna uroprophylaxis before allogeneic bone marrow transplantation had severe hemorrhagic cystitis for at least 2 weeks. Because of this suboptimal result, we resumed the use of bladder irrigation and forced hydration to minimize the risk of hemorrhagic cystitis.

Reinduction chemotherapy for acute nonlymphocytic leukemia.

Twenty-four patients who had a relapse after successful treatment of acute nonlymphocytic leukemia were re-treated with a chemotherapeutic program similar to that which produced the initial remission. Eight of the nine patients who achieved a second remission had received a three-drug reinduction regimen consisting of cytosine arabinoside, an anthracycline, and 6-thioguanine. An increased duration of initial remission before relapse (more than 26 weeks) predicted a greater likelihood of achieving a second remission.

Chronic myelomonocytic leukemia: natural history and prognostic determinants.

A retrospective clinical review of 41 patients with chronic myelomonocytic leukemia revealed a median age of 66 years and a male:female ratio of 2.4:1. The disease was preceded by a myelodysplastic syndrome of a different subtype in 24% of the patients and transformed into acute leukemia in 24%. Splenomegaly was present in 54% of the patients and reached massive proportions in 24%. Chromosomal abnormalities occurred in 34% of those studied, most commonly in the younger age group; the most frequent were trisomy 8, monosomy 7, and deletions involving the long arms of chromosomes 20 and X. Polyclonal hypergammaglobulinemia was detected in 47% of the patients in whom serum protein electrophoresis was done. The median survival was 3 years. With use of univariate analysis, the statistically significant prognostic determinants were hemoglobin level, the "modified Bournemouth score," and bone marrow blast cell percentage. When these factors were subjected to a multivariate analysis, only bone marrow blast cell percentage was an independent prognostic determinant. Orally administered hydroxyurea controlled leukocytosis and splenomegaly in some patients without affecting the overall prognosis.

A prospective study of airway reactivity before bone marrow transplantation.

The purposes of this study were to assess baseline airway function and to determine the frequency of airway reactivity in patients before bone marrow transplantation (BMT). The ratio of the forced expiratory volume at 1 second to the forced vital capacity (FEV1/FVC) was the measure of baseline airflow. Using methacholine challenge, we tested 53 patients before conditioning chemotherapy, total-body irradiation, and BMT. All patients had a baseline FEV1/FVC of 70% or more. The mean baseline FEV1/FVC was 84(+)/- 6%. The response to methacholine challenge was defined by the change in FEV1 from baseline (delta FEV1). A positive response (delta FEV1 of 20% or more) occurred in 11 of 53 patients (21%), a borderline response of (delta FV1 of less than 20% but greater than or equal to 10%) was was found in 10 (19%), and no response (Delta FEV1 of less than 10%) was elicited in 32 (60%). In our group of patients with a positive or borderline response to methacholine, we found no significant relationship to baseline FEV1/FVC, smoking history, hematologic diagnosis or study, or major post-BMT pulmonary complications including bronchiolitis obliterans. We concluded that pretransplantation airway reactivity, as measured by methacholine challenge and in the setting of normal baseline FEV1/FVC, was common before BMT. The presence of a borderline or positive response to methacholine challenge before transplantation was not associated with the development of either clinical or pathologically proven posttransplantation bronchiolitis obliterans.

A long-term retrospective study of young women with essential thrombocythemia.

OBJECTIVE: To describe presenting clinical manifestations, long-term disease complications, prognostic indicators, and outcome of pregnancy for women younger than 50 years with essential thrombocythemia. PATIENTS AND METHODS: We retrospectively reviewed the records of all patients with essential thrombocythemia evaluated at Mayo Clinic, Rochester, Minn, between 1969 and 1991 and identified 74 young women (median age, 35 years; range, 18-48 years) with essential thrombocythemia. The diagnosis was based on previously established criteria. Median follow-up was 9.2 years (range, 0.2-26.2 years). RESULTS: Overall survival was similar to that of an age- and sex-matched control population. Thrombotic events (except superficial thrombophlebitis) occurred at and after diagnosis in 11 patients (15%) and 13 patients (18%), respectively. A history of thrombosis at diagnosis was significantly associated with recurrent thrombosis (P = .03). A platelet count higher than 1500 x 10(9)/L at diagnosis was significantly associated with gastrointestinal tract bleeding and subsequent development of venous (but not arterial) thrombosis (P = .04). Major hemorrhagic events occurred in only 3 patients (4%) after diagnosis. Only 1 patient developed acute leukemia. Thirty-four pregnancies occurred in 18 patients. Of these, 17 (50%) resulted in live births. Of the 17 patients with unsuccessful pregnancies, 14 had spontaneous abortions, 1 had an ectopic pregnancy, and 2 had elective abortions. Preconception platelet count, thrombotic history, or specific therapy was not useful in predicting pregnancy outcome. CONCLUSION: Young women with essential thrombocythemia can expect long survival with a low incidence of life-threatening thrombohemorrhagic complications or acute leukemia. There is an increased incidence of first-trimester miscarriages that may not be influenced by specific therapy.

Essential thrombocythemia in young adults.

Essential thrombocythemia is typically a disorder of adults in the sixth or seventh decade of life and is characterized by frequent thrombohemorrhagic complications. In young patients, the optimal management of complications is controversial. We studied 56 young adults (33 female and 23 male patients) with a diagnosis of essential thrombocythemia. The mean duration of follow-up was 4.68 years. The mean platelet count at diagnosis was 1,328,000/mm3. Platelet aggregation studies in 21 patients demonstrated hypoaggregation to epinephrine; spontaneous platelet aggregation was present in 4. At diagnosis, 39 patients were asymptomatic, and thrombocytosis was discovered incidentally. Throughout follow-up (up to 20 years), 24 patients remained asymptomatic. Thrombotic complications developed in 24 patients; they were life-threatening in only 3. The most common vaso-occlusive symptoms were migraine headache (in 12 patients) and erythromelalgia (in 3). Minor hemorrhagic complications occurred in six patients, and none was life-threatening. Serious complications (one cerebral and two myocardial infarctions) occurred in three patients, all of whom recovered. Two deaths occurred, neither of which was attributable to essential thrombocythemia. The treatment regimens used were chemotherapy in 9 patients, antiaggregating agents in 7, radioactive phosphorus in 1, the newer platelet-lowering agent anagrelide in 10, and only observation in 29. No treatment-related acute leukemias developed. This series of young patients with essential thrombocythemia, the largest to date, demonstrates a low incidence of life-threatening complications and a favorable long-term prognosis. Therapeutic recommendations should remain conservative, and potential leukemogens should be avoided unless serious complications develop. Anagrelide may be useful in young patients with thrombocythemia who are symptomatic.

Mast cell leukemia: report of a case and review of the literature.

We report the clinical and pathologic findings in one case of mast cell leukemia observed in a series of 60 patients with systemic mast cell disease. The leukemic variant of systemic mast cell disease is rapidly fatal (mean duration of survival, less than 6 months) in contrast to most nonleukemic cases, which follow an indolent clinical course. On the basis of our case and eight previously reported cases, mast cell leukemia is characterized by a substantial increase in atypical mast cells in the peripheral blood, diffuse infiltration with atypical mast cells in the bone marrow, a strong association with peptic ulcer disease, prominent constitutional symptoms, and hepatosplenomegaly. These cases should be distinguished from malignant mastocytosis without a substantial number of circulating atypical mast cells and also cases of acute nonlymphocytic leukemia that arise in the background of systemic mast cell disease.

Outcome of recipients of bone marrow transplants who require intensive-care unit support.

To determine the outcome and prognostic factors associated with bone marrow transplantation (BMT), we reviewed the clinical course of 35 adult recipients of such a transplant who were admitted to our intensive-care unit (ICU). This constituted 24% of patients who underwent BMT for treatment of hematologic disorders during the study period. The reasons for admission to the ICU were postsurgical care in 5, respiratory failure in 25, shock in 4, and renal failure in 1. The in-hospital mortality was 20% for the postsurgical patients and 87% for the others. None of the postsurgical patients required mechanical ventilation, whereas 90% of the others did, and the associated mortality was 93%. Infection was the cause of the respiratory failure in all but 3 of the 25 patients and was associated with 95% mortality. Complications that involved multiple organs increased the mortality to 100%. No significant differences were found in age, sex, type of BMT, serologic tests for cytomegalovirus, history of graft-versus-host disease, conditioning regimen for BMT, and duration of stay in the ICU and the hospital between survivors and nonsurvivors. The APACHE II (acute physiology and chronic health evaluation) prognostic scoring system underestimated mortality and had no correlation with the duration of stay in the ICU or the hospital. Vasopressors, total parenteral nutrition, and transfusion of blood components in the ICU had no influence on the outcome. Open-lung biopsy was helpful in making specific diagnoses, and pulmonary artery catheters were used in most patients to guide therapy but did not improve survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytogenetic and molecular detection of residual leukemic cells after allogeneic bone marrow transplantation in chronic granulocytic leukemia.

Allogeneic bone marrow transplantation (BMT) is a therapeutic modality with a curative potential for chronic granulocytic leukemia. Approximately 20% of patients have a hematologic relapse after BMT. The frequency of cytogenetic or molecular relapse (or both), despite hematologic remission, is reportedly higher. We performed allogeneic BMT in 32 patients with chronic granulocytic leukemia by using unmanipulated donor marrow and a conditioning regimen that consisted of cyclophosphamide and total-body irradiation. Of these 32 patients, 23 had cytogenetic studies after BMT. Seven of these patients had cytogenetically detectable Philadelphia chromosomes some time after BMT, during hematologic remission. The Philadelphia chromosome was detected transiently in two patients, and the fraction of abnormal metaphases exceeded 25% in three patients. None of the patients with negative results of cytogenetic studies or with the presence of the Philadelphia chromosome in less than 25% of analyzed metaphases had a clinical relapse, whereas two of the three patients with more than 25% abnormal metaphases had clinical relapses. Our results suggest that the detection of more than 25% abnormal metaphases during cytogenetic studies for chronic granulocytic leukemia after BMT may imply an incipient clinical relapse. We review the current literature that discusses isolated cytogenetic or molecular relapses of chronic granulocytic leukemia after BMT.

Immunologic, clinical, and pathologic aspects of human graft-versus-host disease.

The three necessary factors in the development of graft-versus-host disease are the histoincompatibility of the host and the effector cells of this process, the immunoincompetence of the host, and the capability of effector cells to proliferate and attack host tissues protractedly in vivo. The disease may affect the alimentary tract, liver, bronchopulmonary tree, bone marrow, reticuloendothelial system, vascular endothelial cells, or epidermis. Graft-versus-host disease is potentially reversible or controllable if prompt, aggressive therapy is instituted. The recommended treatment is a combination of methotrexate, high-dose prednisone, and antithymocyte globulin.

Acute lymphocytic leukemia in adults: a retrospective study and analysis of current management options.

OBJECTIVE: To examine current therapeutic modalities for acute lymphocytic leukemia (ALL) in adults, analyze prognostic variables, and offer treatment recommendations. DESIGN: We reviewed our experience with 90 adult patients with ALL examined at the Mayo Clinic between 1982 and 1992 and used it as a background for discussion of prognostic factors and management options in adult patients with ALL. MATERIAL AND METHODS: The pretreatment characteristics of patients, types of induction chemotherapy, and postremission treatment, including bone marrow transplantation (BMT), were analyzed for prognostic significance for each of three outcomes: complete remission (CR) rate, duration of CR, and overall survival of patients. RESULTS: Of the 90 study patients, 80 had received induction chemotherapy. Overall long-term survival for treated patients was 25%. None of the 10 patients younger than 18 years of age underwent BMT, and their long-term survival was 80%. Of the other 70 patients, who were 18 years old or older, 42 (60%) had a CR with induction chemotherapy. Of these 42 patients, 31 did not undergo BMT, and their long-term survival was less than 13%. BMT was done in six patients during a first CR (with 100% survival), in four during a later CR (with 50% survival), and in six with disease (with 17% survival). The median age of patients who received chemotherapy was 50 years (range, 19 to 87) and that of patients who underwent BMT was 34 years (range, 18 to 46). Overall, age was the only significant prognostic factor. CONCLUSION: With our application of current chemotherapy, the outcome in adult patients (18 years old or older) with ALL was dismal. The results were considerably better in patients younger than 18 years of age or in those who underwent BMT as post-remission therapy. Comprehensive assessment of our experience and that in the literature, however, did not resolve issues about current management. Participation of patients in comparative trials is critical for determining the best therapy for ALL in adults.

Acute myelomonocytic leukemia after irradiation and chemotherapy for Ewing's sarcoma.

A case is presented in which the diagnosis of acute myelomonocytic leukemia was made 16 months after the start of irradiation and chemotherapy for Ewing's sarcoma. The association of these two diseases is rare. The etiologic role of therapy in the development of leukemia is speculative in this case. However, there is need for surveillance for secondary neoplasms of all types so that the benefits of therapy may be properly weighed against the risks.

Striational autoantibodies: quantitative detection by enzyme immunoassay in myasthenia gravis, thymoma, and recipients of D-penicillamine or allogeneic bone marrow.

Striational autoantibodies (StrAb) are a useful serologic marker of thymoma in patients with myasthenia gravis (MG). We compared a standard immunofluorescence method with a new enzyme immunoassay (EIA) for detection of StrAb. Retrospective testing of 264 stored sera by the two methods yielded well-correlated results (58 sera were positive by both assays; r = 0.8). For 104 patients with spontaneously acquired MG or thymoma, results were 100% concordant, of which 53% were positive. For 34 recipients of D-penicillamine, StrAb were found in 15% by EIA and in 6% by immunofluorescence. StrAb were detected in two of four bone marrow recipients by EIA and in one by immunofluorescence. Prospective testing of 434 fresh sera (of which 49 were positive by the two methods) yielded discordant results in only 4. Serial EIA quantitation of StrAb in two patients with MG and thymoma proved useful in monitoring immunosuppressant therapy and in a third patient predicted recurrence of the tumor. A high prevalence of StrAb was detected by both assays in elderly patients with spontaneous MG, but StrAb were more readily quantifiable by EIA. The EIA method proved to be highly sensitive and specific for detecting StrAb in patients with thymoma with and without MG, in patients treated with D-penicillamine, and in those with graft-versus-host disease after bone marrow transplantation.

Endomyocardiopathy with eosinophilia.

Five patients were seen at the Mayo Clinic over an 8-year period with the following complex of clinical and morphologic features; striking eosinophilia, cardiomyopathy, hepatosplenomegaly, and either a rapidly fatal or a prolonged, debilitating illness. In recent years, controversy has raged over the precise designation of this syndrome, with proposals ranging from eosinophilic leukemia to hypereosinophilic syndromes. To focus on the major target organ of the disease, we have favored the term endomyocardiopathy with eosinophilia. Experience with these five patients showed that (1) eosinophilia can persist for many years before symptoms appear; (2) progressive restrictive cardiac disease was the major cause of death and debility; (3) osmiophilic cytoplasmic inclusions are present in eosinophils of these patients and also in cells from other patients with marked eosinophilia; and (4) echocardiography may prove to be a useful noninvasive tool to diagnose and follow the progress of cardiac involvement. Although none of these patients was thought to have leukemia, intensive therapy with steroids or cytotoxic agents, or both, is considered necessary to control the progression of the disease.