Tadami Nagao

Efficacy of granulocyte colony‐stimulating factor in the treatment of acute myelogenous leukaemia: a multicentre randomized study

Summary. To investigate the efficacy and safety of granulocyte colony‐stimulating factor (G‐CSF) in patients with acute myelogenous leukaemia, a multicentre randomized study was performed. From October 1993 to September 1996, 270 patients with newly diagnosed acute myelogenous leukaemia were randomized to G‐CSF or control groups after remission induction therapy. The G‐CSF group received G‐CSF (Filgrastim) from 48 h after the completing chemotherapy until the absolute neutrophil count exceeded 1·5 × 109/l. The control group did not receive G‐CSF unless severe infection occurred. There were 245 evaluable patients (120 and 125 in the G‐CSF and control groups respectively). The complete remission rate was similar in the G‐CSF and control groups (80·8% versus 76·8%), as was the 5‐year probability of disease‐free survival (34·5% versus 33·6%) and overall survival (42·7% versus 35·6%). Neutrophil recovery was significantly faster in the G‐CSF group than in the control group (12 d versus 18 d, P = 0·0001). The median duration of febrile neutropenia was significantly shorter in the G‐CSF group than in the control group (3 d versus 4 d, P = 0·0001). In conclusion, prophylactic administration of G‐CSF after remission induction therapy for acute myelogenous leukaemia is safe and useful even in patients without infection on completing chemotherapy.

Increased growth and collagen synthesis of bone marrow fibroblasts from patients with chronic myelocytic leukaemia

Summary. Growth and collagen synthesis were measured in human bone marrow fibroblasts derived from patients with chronic myelocytic leukaemia (CML) and normal individuals. The 3H‐thymidine uptake, growth rate and collagen synthesis of fibroblasts from patients with CML were significantly greater than those from normal subjects. Thus, there is increased proliferation and collagen synthesis of fibroblasts in patients with CML. These findings show that CML fibroblasts may display a greater sensitivity to stimulator contained in the fetal calf serum used for the cultures, and they are relevant to the myelofibrosis by bone marrow fibroblasts in this disease.

Flow cytometric analysis of cell-surface antigen expressions on acute myeloid leukemia cell populations according to their cell-size

Acute myeloid leukemia (AML) cells which expanded from a single leukemic cell show certain degrees of morphological and biological heterogeneity. In the present study, we determined cell-surface antigen expressions (CD13, 33, 34 and 38, and HLA-DR) on AML cells based on their cell-size (large vs small cells) by flow cytometry. We found that the cell-surface antigens were more strongly expressed on the large leukemic cells than the small cells, regardless of FAB subtypes. Furthermore, our preliminary study demonstrated that AML patients who showed a relatively small difference in antigen expression between large and small leukemic cells had longer remission durations and survival periods, compared with those with a more prominent difference in antigen expression. Thus, the heterogeneity of AML cells determined by the combination of cell-surface antigen expressions and cell-size may be associated with clinically important biological behaviors.

Gallium-67 uptake in the salivary glands in chronic graft-versus-host disease after bone marrow transplantation

Ga-67 citrate scans were performed in a 17-year-old female patient after bone marrow transplantation for acute lymphoblastic leukemia. Ga-67 accumulated in salivary glands in which chronic graft-versus-host disease (GVH) was demonstrated pathologically. Ga-67 scan may be a sensitive and noninvasive test for detecting and monitoring the Sicca syndrome induced by chronic GVH.

Platelet volume and intraplatelet adenine nucleotides in various hematologic disorders

By recent advanced techniques, blood platelets have proved to be varied in size and metabolism in various hematologic disorders. We examined platelet volume and intraplatelet adenine nucleotides in 36 patients with various hematologic disorders in order to clarify the quantitative platelet abnormalities. Platelet volumes were smaller in patients with acute leukemia and aplastic anemia, and larger in patients with immune thrombocytopenic purpura (ITP). The amount of intraplatelet ADP was decreased and ATP/ADP ratio was increased in acute leukemia, aplastic anemia and myeloproliferative disoders (MPD), which strongly suggested the presence of storage pool deficiency in these patients. Intraplatelet ADP per volume was decreased in acute leukemia, aplastic anemia and MPD, and ATP per volume was decreased in aplastic anemia. ATP content was increased in ITP in proportion to the increased platelet volume. These parameters were examined in 36 patients with the following hematologic disorders: 7 acute leukemia treated with cytotoxic chemotherapy, 5 aplastic anemia, 3 paroxysmal nocturnal hemoglobinuria (PNH), 9 immune thrombocytopenic purpura (ITP), 5 hypersplenism and 7 myeloproliferative disorders (MPD).

Pulmonary fibrosis with megakaryocytoid cell infiltration in accelerated phase of chronic myelogenous leukaemia

Summary. We report a patient in the accelerated phase of Philadelphia‐chromosome‐positive chronic myelogenous leukaemia who developed fibrosis in lungs, spleen and bone marrow. In the lungs, fibrosis was demonstrated in the alveolar septa which had been infiltrated by giant, bizarreshaped cells resembling the megakaryocytes in the bone marrow. The relationship between the fibrosis and megakaryocytoid cell infiltration in the lungs is discussed.

Granulocyte colony‐stimulating factor production by human bone marrow fibroblasts stimulated with interleukins

Granulocyte colony‐stimulating factor (G‐CSF) is a cytokine that mediates the clonal proliferation and differentiation of progenitor cells into mature granulocytes. The kinetics of G‐CSF production by human bone marrow fibroblasts (BMF) were investigated by quantitative immunoassays. The spontaneous production of G‐CSF by BMF was below the detectable level. Interleukin‐1 (IL‐1) induced a dose‐dependent production of G‐CSF, and the production reached a plateau at 50 U/ml of IL‐1. G‐CSF production by BMF stimulated with IL‐1 was cell concentration dependent. Detectable G‐CSF was produced by 5 × 102 BMF in a 35 × 10‐mm plastic dish. The optimal range was 1 × 104−5 × 104 BMF. Production of newly synthesized G‐CSF was detectable 6 hr after stimulation and continued for approximately 48 hr. A 6‐hr pulse exposure to IL‐1 was necessary to induce production of G‐CSF, and after 48 hr, the adherent BMF could not be restimulated. IL‐2, IL‐3, IL‐4, IL‐5, and IL‐6 were unable to induce G‐CSF production. However, IL‐4 promoted G‐CSF production after stimulation with IL‐1. These results provide useful data with regard to the mechanism of G‐CSF production by human BMF.

Increased Collagen Synthesis of Bone Marrow Fibroblasts by Materials Released from Platelets of Chronic Granulocytic Leukemia and Polycythemia vera

Collagen synthesis stimulated by materials released from platelets (MRFP) of patients with chronic granulocytic leukemia (CGL) and polycythemia vera (PV) was measured in human bone marrow fibroblasts derived from normal individuals. The MRFP of patients with CGL and PV stimulated normal fibroblast collagen synthesis significantly compared to the response from normal MRFP. Platelets derived from patients with CGL and PV may have some factors that dramatically stimulate collagen synthesis which is relevant to the frequently observed myelofibrosis in these diseases.

Identification of circulating micromegakaryocytes in a case of erythroleukemia

A 26‐year‐old man with erythroleukemia was found to have circulating micromegakaryocytes. Megakaryocytic features were defined by morphologic and cytochemical studies using light and electron microscopy with platelet‐megakaryocyte peroxidase staining. This appears to be the first reported instance of erythroleukemia with circulating micromegakaryocytes.

Upregulation of cell surface expression of T-lymphoid antigens and adhesion molecules on acute myeloid leukaemia cells after in vivo administration of granulocyte colony-stimulating factor.

We herein report a case of acute myeloid leukaemia (AML, FAB:M0) who showed upregulation of T-lymphoid antigens (CD2, CD7) and adhesion molecules (CD11a, CD11b, CD18) on leukaemic cells after in vivo administration of granulocyte colony-stimulating factor (G-CSF). To our knowledge, this is the first report which describes in vivo changes of cell surface antigen expression on AML cells after the administration of G-CSF.