TPO induces tyrosine phosphorylation of numerous signaling molecules and activates the Ras/MAPK and JAK/STAT signal pathways through its Mpl receptor. TPO specific signaling is as yet unknown. Serum TPO levels may be regulated by bone marrow megakaryocytes and platelets through binding to the Mpl receptor expressed on their surface membrane. But the expression of murine and human TPO mRNA is increased in bone marrow and not the liver under thrombocytopenic conditions, indicating that there is another mechanism for the regulation of TPO. Pegylated TPO (PEG-rHuMGDF) and full-length glycosylated recombinant TPO were used in clinical applications. The patients with cancer who received TPO showed an increase in platelet count or shortening of the duration of platelet recovery in a dose-dependent manner and without apparent side effects. The functions of the platelets were normal. These results indicate that TPO might be useful in clinical applications.

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We review our experience with BMT for ALL in children. Ninety-six patients aged 1 to 18 years underwent BMT. The allogeneic (Allo) BMT group consisted of 65 patients, including 8 with matched unrelated donors; 31 underwent autologous (Auto) BMT. Thirty patients received transplants during first complete remission (CR), 41 during second CR, and 25 during other stages. Conditioning regimens consisted of cyclophosphamide (CY) plus total body irradiation (TBI) ±otheragents (n=22);melphalan (L-PAM) plusTBI ± other agents (n=60); and L-PAM and busulfan (n=14). Prophylaxis for graft-versus-host disease (GVHD) consisted of methotrexate (MTX) alone for two months (n=40) or short-term MTX with cyclosporine (n=23). Two patients received cyclosporine alone. When hematopoietic recovery was compared, allo-BMT and autoBMT had similar granulocyte engraftment, but the recovery of platelets and reticulocytes was significantly faster in allo-BMT. Acute GVHD exceeding grade 2 was documented in 13% of allo-BMT and chronic GVHD was observed in 29%. Thirty-eight patients (40%) died; 16 patients died of relapse. The 5-year disease-free survival (DFS) rate for all patients and that for transplantations in first CR, second CR, and other stages was 59.6%, 83.3%, 61%, and 24.6%, respectively. DFS rates were not different between allo-BMT and auto-BMT in each group. When patients receiving L-PAM were compared with those receiving CY, more patients receiving transplantations in second CR who were conditioned with a regimen including L-PAM had prolonged DFS (71.4%) as compared With the CY group (40%).

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We previously reported that alloantigen-specific cytotoxic T lymphocytes (CTL) could be induced similarly in both cord and adult blood mononuclear cells. Here, we report the kinetics of IL-2 production of cord blood mononuclear cells and the effect of immunosuppressants on IL-2 production. A mixed lymphocyte culture was set up, using cord blood mononuclear cells as responders and irradiated allogeneic mononuclear cells of a healthy adult as stimulators. IL-2 concentration was serially determined from day 1 to day 6. There was no significant difference in IL-2 production in cord and adult blood mononuclear cells. Immunosuppressants, cyclosporin A and FK506, significantly inhibited IL-2 production. These in vitro results, together with our previous observation, suggest that IL-2-dependent CTL may cause graft-versus-host disease and also graft-versusleukemia effect in cord blood stem cell transplantation.

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We report the results of a regimen of mitoxantrone on days 1 to 3, etoposide on days 8 to 10 and cytarabine on days 1 to 3 and 8 to 10 (EMA) in six children with AML. Of the six patients, three were resistant to induction therapies (IF : induction failure), two initially showed relapse and one was initially in complete remission (CR). After one course of EMA, four of the five patients who received EMA as an induction therapy achieved CR. Three patients received autologous (one) or allogeneic (two) bone marrow transplantations (BMT). These three patients have survived without disease for 20 to 60 months. One patient who could not achieve CR with EMA underwent transplantation with positively selected CD34⁺ cells from HLA-mismatched donor's peripheral blood after EMA. However, he died after bone marrow relapse. One patient who was treated with consolidation therapy has shown disease-free survival (DFS) for 63 months. The period that neutrophil count was under 500/μl continued for 28-58 days (mean : day 35.4± 10.7). Sepsis and pneumonia were seen in two patients and one patient, respectively. Thus, four of five patients who had been resistant to (re) -induction chemotherapy achieved CR. This result suggests that EMA is useful for previously treated patients with refractory AML despite extensive therapies.

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The Aplastic Aemia Committee has undertaken three nationwide surveys of children with aplastic anemia (AA) since 1993. The clinical characteristics and outcome of patients diagnosed between 1988 and 1995 were summarized for this report. As of June 1996, 425 patients with idiopathic AA, 50 with posthepatitis AA, 35 with Fanconi anemia and 32 with Diamond-Blackfan anemia have been registered. Idiopathic AA was diagnosed in an average of 60 patients a year, and half of the cases were severe. Eighty-six of the 218 severe AA patients were classified as very severe. The survival rate in the 425 idiopathic AA patients was estimated at 77±4.0% (±SE) by the Kaplan Meier method. The survival rate in 294 patients who had not undergone transplantation was estimated at 74.8±5.1% (very severe : 42.9±13.5%, severe : 78.4±5.4%, moderate : 86.5±6.1%, mild : 84.2±13.1%). Fifty-five of the idiopathic patients died, of which 23 patients died due to severe infection and hemorrhage within 6 months. The estimated survival rate of the 55 posthepatitis AA patients was 71.2±7.1%.The estimated survival rate of the 35 Fanconi anemia patients was 53.3±11.9%. Of the 7 Diamond-Blackfan anemia patients who have been followed over 5 years, 5 still require treatment. Twenty-six MDS/AML-developed patients were registered and reported in this study. Twenty-two of them were diagnosed within the survey period. Of the 22, 18 developed from idiopathic AA and 4 from posthepatitis AA. Twenty of the 26 MDS/AML patients were diagnosed with severe AA. MDS/AML developed between 7 months and 7 years 2 months (median 3 years 2 months) following the time of diagnosis of AA. The majority of those patients were treated with immunosuppressants and rhG-CSF. Monosomy 7 was a prominent chromosome abnormality in the MDS/AML patients.

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We report on a 14 year-old girl with T-cell ALL who developed brain infarctions associated with receiving G-CSF. G-CSFs were administered intravenously for 15 days after induction of chemotherapy. When it was found that she had leukocytosis (predominantly neutrophilia) with a leukocyte count of 39.3×10³/μ1, G-CSFs were continued. On the same day, she had a generalized tonic clonic seizure probably caused by her brain infarction. Her brain CT, MRI and single-photon ECT (SPECT) showed figures compatible with transient brain infarctin. One month after the convulsion, she received high-dose Ara-C and G-CSF for three days, when the leukocyte count rose to 2, 800/μl from 300/μl. At that time, her brain CT and SPECT revealed figures of infarction without neurological abnormalities. The repeated figures of SPECT suggested that her infarctions were related to the administration of G-CSF. It is possible that hyperviscosity, caused by rapidly developed neutrophilia induced by G-CSF, caused her brain infarctions. We think that the use of G-CSF during chemother-apy needs to be watched carefully for possible neurological abnormalities.

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A 3 year-old boy, who had received blood coagulation examinations before induction therapy for acute lymphocytic leukemia, was found to have a dysfibrinogenemia characterized by a reduced fibrinogen level by the thrombin time method despite a normal level being determined by the nephelometry method. This abnormality was observed in his mother and the mother's father. We identified a substitution of arginine by cysteine at position 275 of the gamma chain in the patient's fibrinogen. This abnormal fibrinogen was designated “fibrinogen Asahikawa II”. The patient did not recognize clinically apparent bleeding or thrombosis during the course of acute lymphocytic leukemia.

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We describe a 12 year-old boy with acute promyelocytic leukemia (APL, M3) who showed pseudotumor cerebri after administration of all-trans retinoic acid (ATRA). He wasadmitted to our hospital with anemia and thrombocytopenia. On admission, increased abnormal promyelocytes and PML-RARa chimeric mRNA were detected in bone marrow aspirate and laboratory tests. He was diagnosed as APL and the administration of ATRA 45 mg/m²/day was started immediately. He showed the complication of disseminated intravascular coagulation (DIC). On the second day after starting the therapy, he experienced severe headache and frequent vomiting. Intracranial hemorrhage was suspected, but a brain CT scan revealed no sign of intracranial hemorrhage. We induced relief for his headache after the administration of hydrocortisone to prevent allergic reaction to the administration of platelet transfusion. We diagnosed this episode as pseudotumor cerebri caused by treatment with ATRA. Thereby he received hydrocortisone as a prophylaxis for headache and his episode of headache diminished after that. Some investigators have reported that pseudotumor cerebri is one of the dose-limiting factors of ATRA administration. Our results suggest that steroid hormone is effective to control pseudotumor cerebri due to ATRA. Co-administration of steroid hormone withATRA may be an efficient strategy for induction therapy with ATRA for APL.

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We report on a 5 year-old girl who suffered from Epstein-Barr virus-associated hemophagocytic syndrome (EB-VAHS), accompanied by non-convulsive status epileptics and transient organic mental disorder as central nervous system complications. Disseminated intravascular coagulopathy was observed in the acute phase. Based on EEG, CT and MRI studies, symptoms of the central nervous system were thought to be caused by intracranial hemorrhagic infarction due to circulatory insufficiency and microthrombosis. Chemotherapy using HLH-94 protocol was introduced and remission has been maintained for the past 1 year. Although the mental disorder was spontaneously resolved in about two and a half months, epilepsy focused on the left occipital lobe and visual dysgnosia have persisted as late sequelae.

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A three-month-old female infant was admitted for an evaluation and treatment of central nervous system infiltration, hepatosplenomegaly and eruption. With the diagnosis of non-lymphocytic leukemia (FAB M0), she was treated with chemotherapy. At 3 months after admission, she developed abdominal distension, vomiting and bloody stool. We performed a laparotomy twice for intestinal obstruction. Cytomegalovirus was detected from a specimen of excised small intestine. Despite antiviral therapy, she died from malnutirition. Cytomegalovirus infection may have occurred during the perinatal period. Care sould be taken to watch for primary cytomegalovirus infections in infants with leukemia.

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