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Disparities in minorities' representation in cancer clinical trials have been shown only in adult populations, which suggest that the main causes of these disparities relate to health system-based barriers, including issues of poverty (lack of insurance), poor access to trials, and an inadequate number of clinical trials. Initiatives that increase the participation of community physicians in cancer clinical research trials and increase low socioeconomic status patients' access to cancer trials will likely ameliorate this problem.

Myelofibrosis with myeloid metaplasia (MMM) is a clinicopathologic entity characterized by stem cell-derived clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis, and bone marrow fibrosis and osteosclerosis. Patients with MMM have shortened survival and their quality of life is compromised by progressive anemia, marked hepatosplenomegaly, and severe constitutional symptoms including cachexia. After decades of frustration with ineffective therapy, patients are now being served by promising treatment approaches that include allogeneic hematopoietic stem cell transplantation and immunomodulatory drugs. Recent information regarding disease pathogenesis, including a contribution to the myeloproliferative disorder phenotype by a gain-of-function JAK2 mutation (JAK2(V617F)), has revived the prospect of targeted therapeutics as well as molecular monitoring of treatment response. Such progress calls for standardization of response criteria to accurately assess the value of new treatment modalities, to allow accurate comparison between studies, and to ensure that the definition of response reflects meaningful health outcome. Accordingly, an international panel of experts recently convened and delineated 3 response categories: complete remission (CR), partial remission (PR), and clinical improvement (CI). Bone marrow histologic and hematologic remissions characterize CR and CR/PR, respectively. The panel agreed that the CI response category is applicable only to patients with moderate to severe cytopenia or splenomegaly.

Thrombopoiesis is a multistage process beginning with pluripotent hematopoietic stem cells, progressing through proliferating cells committed to megakaryocytopoiesis, to megakaryocytes, and eventually ending with the shedding of platelets from megakaryocytes. Many growth factors stimulate thrombopoiesis; this review addresses those that act through binding to the thrombopoietin receptor. The cloning of thrombopoietin in 1994 greatly accelerated progress in understanding the biology of thrombopoiesis and of hematopoiesis in general. Detailed structural and functional studies of the thrombopoietin receptor, coupled with novel molecular pharmacology approaches, have led to new classes of thrombopoietic mimetics. Initial clinical trials with recombinant thrombopoietins faltered as they encountered significant neutralizing antibodies or difficulty finding a significant clinical niche in support of chemotherapy. Ongoing studies with the new thrombopoietic agents have invigorated the field, with positive results now reported in idiopathic thrombocytopenic purpura.

We reviewed our blood and marrow transplantation (BMT) database from April 1982 to July 1996 and identified 111 of 474 patients with serum bilirubin concentration (SBR) > or = 34 micromol/l for two consecutive days within the first 20 days after related allogeneic or autologous BMT. Of the 111, 73 fulfilled the Seattle criteria for veno-occlusive disease of the liver (VOD) and had no other obvious cause for liver dysfunction. The patients were 16-60 years old (median, 39 years), and 41 were male (56%). Fourteen patients (19%) had autologous BMT, and 59 (81%) had allogeneic BMT. Twenty-eight (38%), 12 (16%), and 33 (45%) patients had severe, moderate, and mild VOD, respectively, by Seattle criteria. None of 23 patients with maximum (max) SBR > or = 257 micromol/l survived, all patients with max SBR < or = 128 micromol/l survived, and 7 of 15 patients (47%) with max SBR 128-257 micromol/l survived. The only pre-transplantation risk factor predictive of severe VOD was advanced disease state (P = 0.035), and the only transplant factors that predicted severe VOD were max SBR (P = 0.01) and maximum blood urea level (P = 0.03). Ten patients (all with creatinine levels > or = 150 micromol/l) were treated with tissue plasminogen activator; only two had a significant response and only one survived beyond day 120.

Objective: To analyze experience with total parenteral nutrition (TPN) for hematopoietic stem cell transplantation (HSCT) at our institution compared with reports in the literature., Patients and Methods: We reviewed medical records of 100 patients (53 men and 47 women) who underwent HSCT from 1992 to 2001. Data were abstracted on demographics, primary diagnosis, type of transplantation, myeloablative regimen, length of hospital stay, time to engraftment, 1- and 5-year survival, initiation and duration of TPN, and TPN-related complications., Results: Seventy-one transplantations were autologous, 27 allogeneic, and 2 syngeneic. The median age of the patients was 51 years (range, 19-71 years). We initiated TPN when patients' oral caloric intake was less than 50% of their estimated needs (4 to 7 days after the start of myeloablative therapy; median, 1.2 days after HSCT; range, 8 days before HSCT to 13 days after HSCT). We discontinued TPN when oral intake was more than 50% of estimated needs (median duration, 16 days for autologous and 24 days for allogeneic transplantations, with the shortest duration in breast cancer patients and the longest duration in those treated with cyclophosphamide). Mean weight loss was less than 2%. No differences in patient characteristics, myeloablative regimen, or diagnosis were observed between patients who required and those who did not require TPN. Infection, hospital stay, time to engraftment, and mortality were comparable to published reports., Conclusion: In patients undergoing HSCT, TPN should not be initiated until oral caloric intake is less than 50% of estimated needs. During the period of inadequate oral intake, TPN maintains stable body weight with longer duration of support needed for patients undergoing allogeneic than for those undergoing autologous transplantations.

Several options exist for treating essential thrombocythemia and polycythemia vera. One approach is to assign the patient to a risk category from which treatment recommendations follow. The principal risks of essential thrombocythemia include thrombosis, major hemorrhage, and conversion to leukemia or myelofibrosis. Risk factors for thrombosis include age and prior thrombosis. Smoking and obesity have been implicated in isolated series. High-risk patients with essential thrombocythemia can be defined as those 60 years of age or older or those who have had a thrombosis at any age. These patients should be treated with hydroxyurea. If hydroxyurea cannot be tolerated, anagrelide and interferon-alpha (IFN-alpha) are alternatives. Low-dose aspirin (40 to 325 mg) can be used for patients whose platelet counts are < 1,500 x10(9)/L. Low-risk patients are those less than 60 years old who have not had thrombosis, who have no cardiovascular risk factors, and whose platelet counts are < 1,500 x 10(9)/L. These patients can be observed or placed on low-dose aspirin. Intermediate-risk patients are those less than 60 years who have not had thromboses, but who have platelet counts > 1,500 x 10(9)/L or who have significant cardiovascular risk factors. These patients should have their risk factors treated and may be given low-dose aspirin if the platelet count is < 1,500 x 10(9)/L. They can be observed or treated with anagrelide, hydroxyurea, or IFN-alpha. The Mayo Clinic experience suggests that no specific treatment affects outcomes of pregnancies. In high-risk pregnant women who need treatment, IFN-alpha is used. The principal risks of polycythemia vera are thrombosis, postpolycythemia myeloid metaplasia, and acute leukemia. Risk factors for thrombosis include age, the use of phlebotomies, the rate of phlebotomies, and a prior history of thrombosis. Platelet counts have not been definitively linked to an increased risk of thrombosis. High-risk polycythemia vera patients are those 60 years of age or older (some groups use 70 years) or those of any age who have had thrombosis. They should be treated with phlebotomy and hydroxyurea or IFN-alpha. Selected patients may be treated with anagrelide. A typical target range for phlebotomy is a hematocrit of < 42% for women and < 45% for men. Low-dose aspirin can be used if the platelet count is < 1,500 x 10(9)/L. Low-risk patients are those less than 60 years old who have had no thrombosis, no cardiovascular risk factors, and whose platelets are < 1,500 x 10(9)/L. These patients can be managed with phlebotomy alone or phlebotomy and low-dose aspirin. Intermediate-risk patients are those who are less than 60 years old, who have not had thrombosis, but who have platelet counts > 1,500 x 10(9)/L or who have cardiovascular risk factors. The cardiovascular risk factors should be treated, along with phlebotomy alone or with IFN-alpha. Low-dose aspirin is reasonable for those with platelet counts < 1,500 x 10(9)/mL. Anagrelide can be used with phlebotomy in selected patients. Women of childbearing age who are in the low-risk or intermediate-risk group can be treated with phlebotomy alone and low-dose aspirin if the platelet count is < 1,500 x 10(9)/L. For high-risk patients or pregnant patients, IFN-alpha can be added., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

The current dogma about polycythemia vera (PV) is that one or more genetic mutations in a hematopoietic stem cell (HSC) cause abnormal proliferation and differentiation of the progeny of that stem cell. This model ignores two fundamental characteristics of biologic systems that must be considered if regulation is to be understood: first, at a molecular level, biochemical processes are intrinsically stochastic; and second, ontogeny and hematopoiesis are branching processes-with one cell dividing into two cells, and so on. Why is it important to add an understanding of the stochastic, branching nature of HSC function to a description of the genes and gene products only? Why not just say one understands the regulation of normal hematopoiesis, or PV, when all the genes and gene products actively transcribed have been identified? The answer is that within a branching, stochastic process, one mutation can cause more than one outcome (phenotype) in the future. There will be one or more related outcomes that will be highly likely and others that will be less likely. Although most patients will have similar phenotypes, some will differ, but not because they have different underlying mutations. Mathematics will probably play an increasingly important role in describing and analyzing the regulation that occurs as the genetic program of HSC is expressed within a clone over time. Semin Hematol 38(suppl 2):5-9., (Copyright 2001 by W.B. Saunders Company.)

Purpose: Discrepancies in the quoted prednisone dosages in the regimens reported as the only standard CHOP regimen stimulated our interest in reviewing the medical literature regarding this issue and to assess whether practicing hematologists and oncologists in the U.S. are aware of the different dose schedules of prednisone in the published CHOP programs., Methods: Sixteen textbooks and chemotherapy reference books were reviewed. A MEDLINE search of English-language articles published between January 1970 and December 1998 was performed. An eight-point questionnaire was sent via e-mail with responses obtained from 421 hematology/oncology physicians in the U.S., Results: Sixteen textbooks and chemotherapy reference books reviewed quoted only one prednisone dosage as part of the standard CHOP regimen; the prednisone dosages quoted as standard varied between publications. More than 4,000 eligible non-Hodgkin's lymphoma patients have been treated with the CHOP chemotherapy as part of 43 different clinical trials reviewed. The dosages of prednisone and prednisolone used varied among six different levels. Thirty percent (127/421) of practicing U.S. physicians were not aware of the existence of more than one prednisone dose schedule as part of the CHOP regimen. The three most frequently used dosages are 100 mg/days 1-5 (67%), 100 mg/m(2)/days 1-5 (17%), and 60 mg/m(2)/days 1-5 (13%)., Conclusions: Discrepancies in steroid dosages used as part of the reported standard CHOP regimens are common and not well recognized in the medical literature nor by practicing U.S. hematologists/oncologists. Based on this study, a prednisone dose of 100 mg/day for five days should be considered the standard dose.

Anagrelide, an inhibitor of platelet aggregation, decreases the number of platelets in normal subjects and in patients with myeloproliferative disorders. We describe studies aimed at discovering the general mechanism(s) by which anagrelide acts. We examined three hypotheses: (1) anagrelide shortens platelet survival, (2) anagrelide inhibits the proliferation of megakaryocytic-committed progenitor cells (CFU-M), and (3) anagrelide inhibits maturation of megakaryocytes. We observed that anagrelide did not shorten platelet survival. Proliferation of CFU-M in vivo was not affected by anagrelide, although high concentrations of anagrelide inhibited CFU-M in vitro. In-vivo and in-vitro anagrelide altered the maturation of megakaryocytes, causing a decrease in their size and changing other morphometric features. We conclude that anagrelide decreases the number of platelets primarily by interfering with the maturation of megakaryocytes.

Among the chronic myeloproliferative disorders, polycythemia vera and essential thrombocythemia are unique because of their association with thrombohemorrhagic manifestations and their relatively indolent clinical course. Patients with essential thrombocythemia may not have a significant shortening of life-expectancy and most may not require specific therapy. However, patients with polycythemia vera have a significant risk of transformation of polycythemia vera into acute leukemia or postpolycythemic myelofibrosis (or both). 'High-risk-for-thrombosis' patients with either polycythemia vera or essential thrombocythemia require specific therapy with a platelet-lowering agent to prevent thrombotic complications. Currently, the standard agent used for this is hydroxyurea. However, its tetratogenic and leukemogenic potential has been of concern. As a result, new platelet-lowering agents are being evaluated in the treatment of polycythemia vera and essential thrombocythemia. Anagrelide and interferon alfa are two such agents and have been shown to be effective in reducing platelet counts in patients with chronic myeloproliferative disorders. The putative mechanism of action of these drugs, their specific activity in polycythemia vera and essential thrombocythemia, side-effect profile, and current indications are discussed herein.

Anagrelide is an oral imidazoquinazoline agent with an anti-cyclic AMP phosphodiesterase activity and inhibits platelet aggregation in both humans and animals. In addition, it has in humans a species-specific platelet-lowering activity observed at dose levels lower than those required to inhibit platelet aggregation. Because of this, the drug has been tested in patients with clonal thrombocytosis and has been shown to have potent platelet-reducing activity in essential thrombocythemia (ET) and related disorders. The mechanism of action may involve the drug's interference with megakaryocyte maturation. More than 90% of patients with ET respond to anagrelide regardless of the presence or absence of previous therapy. The responses are durable with a median maintenance dose of approximately 2 to 2.5 mg/day. Side effects are related mostly to the drug's direct vasodilating and positive inotropic effects and include headache, fluid retention, tachycardia, and arryhthmias. The place of anagrelide therapy in the current management of patients with ET is discussed.

Etoposide (125 mg/m2/d) and carboplatin (200 mg/m2/d) were administered by continuous 5-day intravenous infusion to 10 patients with relapsed or refractory acute leukemia (7 ANLL, 1 ALL, 2 blast crisis of CGL). No complete or partial response was observed despite dose-limiting toxicity characterized by severe diarrhea in four patients and neutropenic colitis in two additional cases. We cannot recommend the present schedule of drug administration for the treatment of acute leukemia.

Between June 1989 and June 1992, 12 patients with advanced multiple myeloma underwent peripheral blood stem cell autotransplantation after high-dose chemotherapy and radiotherapy. The conditioning regimen included melphalan (140 mg/m2), high-dose cyclophosphamide (120 mg/kg), methylprednisolone (2 g daily x 7), and total body irradiation (9-12 Gy). Transplant morbidity included severe mucositis (n = 7) and acute renal failure (n = 2) related to infusion of the stem cells. Engraftment was delayed (n = 4) in this heavily pretreated population, and two patients had complete graft failure. Despite the advanced nature and chemotherapy-refractory state of their disease, 11 of 11 evaluable patients achieved an objective response. Six patients survived to leave the hospital, and four remain alive--one died of acute leukemia induced by prior melphalan exposure. Three of the four are relapse-free at a median of 24.9 months (range, 18-28 months). Some patients with advanced refractory multiple myeloma can achieve objective responses from highdose chemoradiotherapy with peripheral blood stem cell rescue. Harvesting peripheral blood stem cells from high-risk patients early in their disease for later use may decrease the risk of graft failure. Peripheral blood stem cell transplantation after high-dose chemotherapy and total body irradiation can produce durable responses in patients with advanced refractory myeloma.

To summarize recent information about acute porphyrias and to provide clinicians with a practical diagnostic and management approach, we reviewed the pertinent literature and our clinical experience. The acute porphyrias are characterized by recurrent attacks of abdominal pain with or without additional manifestations of autonomic dysfunction or neuropsychiatric symptoms. On the basis of the potential of these disorders to affect the skin, they are further subdivided into neuroporphyrias and neurocutaneous porphyrias. During acute attacks, acute porphyria is always associated with increased levels of urinary porphyrin precursors. Between attacks, patients with neurocutaneous porphyrias may have normal urinary porphyrins; therefore, stool porphyrins, which are invariably increased, are the most helpful. Latent disease can be detected by the measurement of either urinary and stool porphyrins or cellular enzyme activity. Specific intravenous therapy with hematin has resulted in biochemical remissions, but its clinical benefit remains controversial. Measurement of urinary and stool porphyrins or porphyrin precursors is critical for the diagnosis of clinically overt acute porphyria. Enzyme assays are helpful in supporting the diagnosis but are best used to identify family members with latent disease. Preventive measures and supportive therapy are the mainstays of current management of patients with porphyria.

Immunofluorescent staining (immunofluorescence bone marrow aspirate) and immunoperoxidase staining (immunoperoxidase bone marrow biopsy) were compared in 26 patients with plasma cell dyscrasia and less than 10% marrow plasma cells. Their clinical diagnoses included monoclonal gammopathy of undetermined significance (13 patients), treated multiple myeloma (four patients), multiple myeloma with less than 10% marrow plasma cells (two patients), primary systemic amyloidosis (two patients), monoclonal gammopathy of undetermined significance with neuropathy (two patients), angiofollicular lymph node hyperplasia (two patients, all with the POEMS [polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes] syndrome), and primary (amyloidosis) amyloid neuropathy (one patient). The percentage of plasma cells was greater than 5% in 23% of patients and less than or equal to 5% in 77% of patients. With immunofluorescence bone marrow aspirate and immunoperoxidase bone marrow biopsy, light-chain restriction was demonstrated in 84% of all cases and accurately determined in 96% of all cases as shown by serum and urine paraprotein analysis or tissue amyloid typing. Monoclonal populations of plasma cells can be readily identified with immunofluorescence bone marrow aspirate and immunoperoxidase bone marrow biopsy in most patients with paraproteins and marrow plasmacytoses not diagnostic of multiple myeloma.

Between April 1982 and July 1990, 101 patients underwent allogeneic or syngeneic bone marrow transplantation at the Mayo Clinic. This patient population consisted of 30 with acute nonlymphocytic leukemia, 25 with acute lymphoblastic leukemia, 29 with chronic granulocytic leukemia, and 17 with other diseases (aplastic anemia in 7, myelodysplastic syndrome in 5, and lymphoma in 5). The results achieved in our patients who underwent transplantation in first complete remission of both acute nonlymphocytic leukemia and acute lymphoblastic leukemia compare favorably with previously reported results. Only 1 of 15 patients (7%) with acute nonlymphocytic leukemia and 2 of 8 patients (25%) with acute lymphoblastic leukemia who underwent transplantation in first complete remission had a relapse. Thus, we recommend early bone marrow transplantation during initial complete remission for patients with either of these disorders who have adverse prognostic factors. In contrast, of 12 patients with either acute nonlymphocytic leukemia or acute lymphoblastic leukemia who underwent transplantation during relapse, 11 died within 6 months. Therefore, such patients should be offered new experimental treatments. Our patients with chronic granulocytic leukemia fared better when they underwent transplantation early during the course of their disease rather than during the accelerated or blast phase. Prospective studies are needed to determine the best approach in these patients.

Our understanding of the biology of leukemia and myelodysplasia is still only partial. The diagnosis of myelodysplasia is often based on quantitative and qualitative findings in the peripheral blood and bone marrow. These findings are often shared by other disorders. There is a need for sensitive and inexpensive laboratory tests to determine clonality and karyotypic abnormalities in this disorder. Future classifications of these syndromes will need to be based on morphologic and biologic markers that are closely linked to disease progression, response to treatment, and survival. Our limited understanding of the pathogenesis of MDS decreases the specificity and effectiveness of our therapeutic interventions. Agents that are minimally toxic such as CRA, danazol, 1,25-dihydroxyvitamin D3, androgens, and pyridoxine are seldom useful. Antileukemic therapy and allogeneic bone marrow transplantation have a major role to play in patients younger than 45 years of age; in older patients these treatment modalities remain controversial because of their toxicity. Hematopoietic growth factors, used alone or in combination, may improve the quality of life and improve survival of patients with MDS. Growth factors may also decrease treatment-related mortality associated with chemotherapy and bone marrow transplantation and render these treatment modalities available for a higher percentage of patients. The development of more specific differentiating agents may permit hematopoietic differentiation while minimizing side effects.

We studied the prognostic value of computed tomography (CT) of the brain for neurologic morbidity in patients with thrombotic thrombocytopenic purpura. On review of Mayo Clinic records for 1975 through 1985, we found 32 patients with thrombotic thrombocytopenic purpura, 20 of whom had undergone CT of the brain during their hospitalization. Despite major neurologic symptoms and signs, normal CT findings were associated with complete neurologic recovery. Seventy percent of patients with normal results of CT of the brain recovered and had no neurologic deficits, whereas 80% of patients with CT abnormalities died or had permanent neurologic sequelae. A review of the literature supports these conclusions. Thus, we suggest that CT of the brain be done in any patient with thrombotic thrombocytopenic purpura and neurologic deficits. Regardless of the severity of neurologic involvement, normal CT findings should encourage continued vigorous treatment of the patient because a normal scan supports the possibility of full clinical recovery.

The purpose of this paper is to describe a model of megakaryocytopoiesis as a branching process with stochastic processes regulating critical control points of differentiation along the stem cell megakaryocyte platelet axis. Progress of cells through these critical control points are regulated by transitional probabilities, which in turn are regulated by influences such as growth factors. The critical control points include transition of resting megakaryocytic stem cells (CFU-meg) into proliferating stem cells, the cessation of cytokinesis, and the cessation of DNA synthesis. A computerized computational method has been developed for directly fitting the stochastic branching model to colony growth data. The computational model has allowed transitional probabilities to be derived from colony size data. The model provides a unifying explanation for much of the heterogeneity of stages of maturation within populations of megakaryocytes and is fully compatible with historical data supporting the stochastic nature of hematopoietic stem cell regulation and with modern molecular concepts about control of the cell cycle.

The authors have developed a murine monoclonal antibody, RC-82.4, against an antigen expressed by a human erythroleukemia cell line OCI-MIR. The antibody reacts with an antigen expressed by proerythroblasts, normoblasts, and some reticulocytes but not expressed in erythrocytes, granulocytes, monocytes, megakaryocytes, plasma cells, or lymphocytes. The authors have established an immunocytochemical method for studying bone marrow smears with RC-82.4. By studying bone marrow smears from 11 patients with M-6 erythroleukemia and 104 patients with various other hematologic and nonhematologic malignancies, the authors have found that RC-82.4 has great sensitivity and specificity in recognizing erythroid differentiation in blasts. The authors have used RC-82.4 and antihemoglobin antibodies to identify erythroblasts in acute and secondary acquired cases of erythroleukemia that would have been unclassifiable by morphologic and all other conventional cytochemical and immunocytochemical criteria.

Specific monoclonal and polyclonal antibody reagents and a double antigen indirect immunofluorescence microscopy technique were used to visualize coagulation factor V in human bone marrow. Marrow aspirates were smeared directly on glass slides, or washed and cytospun onto glass slides, or processed and plated into a plasma/methylcellulose cell culture system. Morphologically identifiable colonies of megakaryocytes, erythrocytes, granulocytes, or monocytes/macrophages were removed from 14- to 18-day marrow culture dishes by micropipette and streaked onto glass slides. Smears of marrow cell preparations were air-dried, fixed, washed, and incubated sequentially with primary IgG antibody reagents and with secondary anti-IgG antibody reagents conjugated with either fluorescein or rhodamine. Preparations were examined and photographed through a microscope suitably equipped for two-color fluorescence and phase contrast analysis. Cells of megakaryocytic lineage were identified by their immunofluorescent reactivity with murine monoclonal antibody HP1-1D, specific for human platelet plasma membrane glycoprotein IIb/IIIa (GP IIb/IIIa), or by their immunofluorescent reactivity with monoclonal or polyclonal antibodies specific for von Willebrand factor (vWF) or for platelet factor 4 (PF4). Coagulation factor V in bone marrow was detected by simultaneous immunofluorescent staining with polyclonal burro anti-human factor V antibody or with a panel of murine monoclonal anti-human factor V antibodies. The double antigen immunofluorescence staining technique, incorporating appropriate controls, revealed that coagulation factor V was principally located in marrow cells simultaneously identified as megakaryocytes by antibodies to GP IIb/IIIa, vWF, or PF4. The specific immunofluorescence of factor V in megakaryocytes and platelets was eliminated when excess purified factor V antigen was preincubated with anti-factor V antibody. Our observations establish the presence of human megakaryocyte coagulation factor V, confirm the presence of human platelet factor V, and indicate that human megakaryocyte/platelet coagulation factor V is a lineage-associated protein.

The acute tumor lysis syndrome occurs rarely in nonhematologic malignancies. This patient, a 34-year-old woman with metastatic medulloblastoma, was receiving palliative radiotherapy for a rapidly expanding abdominopelvic mass. After a total of 300 rad, the patient developed the biochemical hallmarks of the acute tumor lysis syndrome, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. This was complicated by oliguria from hyperuricemic acute renal failure. The patient responded well to hydration, alkaline diuresis, phosphate and potassium binders, and allopurinol. The potential for acute tumor lysis syndrome should be anticipated when treating metastatic medulloblastoma.

We analyzed the clinical and laboratory features of eight children (median age, 20 months; range, 13 months to 11 years) with acute megakaryocytic leukemia (M7) and compared the findings with those reported in the literature. The diagnosis was supported by ultrastructural examination for platelet peroxidase or immunophenotyping for glycoprotein IIb/IIIa or the von Willebrand factor protein. Two patients had Down's syndrome. Initial findings included anemia (in all patients), thrombocytopenia (in six), myelofibrosis (in three), lytic bone lesions (in two), and pronounced leukocytosis (in one). Stem cell culture studies of peripheral blood specimens revealed an aberrant phenotype of the megakaryocytes in one patient and reversal to a normal pattern after successful therapy. Remission was achieved in seven of the eight patients after aggressive chemotherapy, and four patients remained in remission 27 to 57 months after diagnosis. Three of these four patients underwent allogeneic bone marrow transplantation. M7 leukemia is not infrequent in children younger than 3 years of age, especially in those with Down's syndrome. The availability of monoclonal antibodies specific to restricted antigens of the megakaryocytic lineage has made the diagnosis of M7 leukemia both possible and practical.

Abnormal thrombopoiesis has been described in acute leukemias associated with inv(3) (q21q26.2) or t(3;3)(q21;q26.2). We reviewed 13 patients seen at the Mayo Clinic since 1979 with inversions of chromosome 3 or related abnormalities; 12 acquired and one constitutional. The patient with the constitutional abnormality had an inv(3)(p21q29) and mild leukocytosis and thrombocytosis. Among the 12 patients with acquired abnormalities, five had inv(3) (q21q26.2), three had t(3;3)(q21;q26.2), one had del(3)(q12q21), one had ins(6;3) (p21;q21q26.2), one had inv(3)(p21q12), and one had r(3)(p?21q?21). Each of these patients developed acute leukemia; eight had antecedent myelodysplastic syndrome, eight presented with platelet counts greater than 100 x 10(3)/microliters, and six had atypical megakaryocytic hyperplasia. Five patients had ringed sideroblasts in their marrow, an antecedent refractory anemia with ringed sideroblasts, or erythroleukemia. Seven patients received chemotherapy but showed no response. From the time of chromosome study, the median duration of survival was 4 months. Our results suggest that 1) although abnormal megakaryocytopoiesis is observed in patients with inv(3)(q21q26.2), multiple hematopoietic lineages are also involved in the neoplastic process; 2) an antecedent myelodysplastic syndrome is common in acute leukemia with inv(3) or related abnormalities; 3) affected patients have a poor survival and are resistant to conventional chemotherapy; and 4) abnormal megakaryocytopoiesis in acute leukemia may also be associated with pericentric inversions of chromosome 3.

Plasma samples were obtained from 34 bone marrow transplant (BMT) recipients before and after administration of the preparative regimen and tested for their ability to promote and/or support growth of hemopoietic colonies. The ability of plasma samples to promote colony formation on their own was tested on normal nonadherent target cells without addition of exogenous growth factors. The growth-supporting activity was examined in the presence of medium conditioned by phytohemagglutinin-stimulated leukocytes (PHA-LCM) and/or erythropoietin (EPO). A series of kinetic changes was routinely observed. Pretransplant samples rarely gave rise to colonies without addition of exogenous growth factors. Plasma samples obtained after completion of the preparative regimen demonstrated increments of growth-promoting activities for megakaryocyte and granulocyte-macrophage progenitors (CFU-Meg and CFU-GM), respectively, that peaked between 7 and 21 d after transplantation. By day 30, activity levels of some patients had returned to pretransplant values, whereas in other patients, activities remained elevated. Persisting activity levels were associated with delayed engraftment. In contrast, activities for progenitors committed to erythropoiesis (BFU-E) and pluripotent precursors (CFU-GEMM) were only rarely observed. The activities were independent of febrile episodes. Their growth-promoting influence on CFU-GM could be neutralized completely by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. These data suggest that at least some of the observed activities in post-BMT plasma are related to GM-CSF. The growth-supporting activities of pretransplant plasma samples are lower than normal plasma when tested on CFU-Meg and CFU-GM. The growth-supporting activities improved transiently within the first month after BMT. A decline during the second and third month was followed by a gradual return to activity levels that were comparable to normal plasma. The effects of these plasma samples on BFU-E and CFU-GEMM were assessed with PHA-LCM and EPO. Similar to CFU-Meg- and CFU-GM-supporting capabilities, they improved transiently after BMT with a return of normal support function after 5-6 mo. The observed endogenous production of growth-promoting and growth-supporting activities for hemopoietic progenitors may serve as a background to design clinical trials for the timely administration of recombinant hemopoietic growth factors to BMT recipients.

Anagrelide is a member of the imidazo (2,1-b) quinazolin-2-one series of compounds, with a powerful antiaggregating effect on platelets. During studies in humans, anagrelide in small doses has produced thrombocytopenia. We therefore evaluated it in the treatment of thrombocytosis, and to date, platelet levels in 15 of 17 patients with primary thrombocythemia, 2 patients with polycythemia vera and thrombocytosis, and 1 patient with chronic granulocytic leukemia and thrombocytosis have been well controlled with the use of this agent. Induction doses of 1.0 to 1.5 mg given orally every six hours have produced a decrease in the platelet count, starting on day 5 and reaching a normal level by day 12. Side effects of anagrelide have been minimal. Maintenance therapy with 1.5 to 4.0 mg a day has continued to control the platelet count in patients for up to 28 months. This new agent appears promising in the treatment of thrombocytosis in patients with chronic myeloproliferative disease.

This is the first report of doxorubicin (Adriamycin) interacting with whole-body electro-beam irradiation to produce generalized toxic epidermal necrolysis. The patient was a 32-year-old woman with acute myelomonocytic leukemia and leukemia cutis. The severe dermatitis obscured clinical recognition of concomitant pseudomembranous colitis and contributed to the patient's death during management of toxic megacolon. Suggestions are made for minimizing this occurrence in future patients treated in a similar fashion.

We have analysed the contribution to megakaryocyte colony formation in methylcellulose made by human plasma, serum, media conditioned by phytohemagglutinin (PHA) stimulated leukocytes (PHA-LCM), erythropoietin (EPO) preparations, and platelets. The culture system was used as a bioassay for megakaryocyte colony stimulating activity (Meg-CSA) in plasma samples of patients with perturbed megakaryocytopoiesis. Preparations of heparinized platelet-poor plasma yielded the most consistent results. Platelet-poor plasma of normal subjects will at best facilitate the occasional growth of small megakaryocyte colonies. Colony frequency and size are reproducibly enhanced in the presence of PHA-LCM as a source of exogenous Meg-CSA. Commercially available EPO preparations may vary in their content of activities that influence megakaryocyte colony formation. Addition of these preparations to cultures that contain plasma and PHA-LCM usually does not enhance colony formation. In contrast to platelet-poor plasma, platelet rich plasma and serum are less supportive of megakaryocyte colony growth. It is suggested that this loss of activity may be related to the release of inhibitors by activated platelets or alternatively caused by absorption of activities by platelets. Plasma samples from patients with megakaryocytopoietic dysfunction may contain components that promote colony formation without addition of PHA-LCM or EPO. This phenomenon is consistently observed for patients with severe aplastic anemia and bone marrow transplant recipients after completion of their ablative preparative regimen.

Bone marrow from a normal male pig was transplanted into a related female pig with severe homozygous von Willebrand's disease (vWd). After engraftment the circulating leukocytes were of the male karyotype, and the platelets were strongly positive for von Willebrand factor (vWF) by indirect immunofluorescence. The average level of vWF was 1.96 U/dl and of ristocetin cofactor was 2.8 U/dl. The ear immersion bleeding time before transplantation was consistently more than 15 min and afterwards varied between 5 min and more than 15 min. Transfused vWF corrected the bleeding time at a level of 10 U/dl, which is lower than that required for a von Willebrand pig. We concluded that: the plasmatic compartment is only minimally replenished by the vWF from platelets and megakaryocytes; and the platelet vWF alone only partially corrects the abnormal tests of the hemostatic mechanism in severe vWd.

A unique case of adult-onset synchronous cyclic neutropenia and thrombocytopenia occurring at six-week intervals is presented. Periods of cytopenia were associated with fever, myalgias, gastrointestinal symptoms, and mild mucocutaneous bleeding. Alternate-day steroid treatment failed to correct the periodic fluctuations in peripheral blood counts but ameliorated symptoms during cytopenia. The treatment of cyclic hematopoiesis is reviewed.