The cause of bone marrow failure in aplastic anemia is still unknown despite more than two decades of research. Although clinical and laboratory investigation have suggested several possible mechanism, including (a) proliferation defect of hematopoietic stem cells, (b) deficiency of hematopoietic growth factors, (c) abnormal bone marrow microenvironment and (d) immunological inhibition of stem cells, no single mechanism can explain bone marrow failure in aplastic anemia. Two major factors seem to be involved in the pathogenesis of aplastic anemia. An intrinsic derangement of stem cells by noxious agents such as virus and drugs can lead to the destruction of primarily diseased tissue by immune mechanisms. Therefore, immunosuppressive therapy can restore hematological function, but leaves the patients with a poorly proliferating bone marrow that is prone to late complications such as myelodysplasia and paroxysmal nocturnal hemoglobinuria.

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A questionnaire survey was physicians caring for hemophiliacs in Japan about their opinions on the implementation procedures of switching from the U.S.-based products derived from paid plasma to domestic products from donated blood by the Blood Coagulation Factor Products Committee and the Ministry of Health and Welfare. The main results of this survey are as follows : 1. Almost all physicians agreed to the so-called self-sufficiency program to supply factor products harvested from voluntarily donated blood. 2. As for the supply methods, physicians caring for 10 or more patients mostly agreed that products from donated blood should be supplied by each manufacturer and imported products by importers, while those treating less than 10 mostly agreed that all products should be supplied by the Japanese Red Cross Society.

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To define the clinical and biologic significance of myeloid-associated antigens (My) expressed on acute lymphoblastic leukemia (ALL) cells, We studied 40 cases of My-positive ALL. These cases represented 15.2% of 264 consecutive children with ALL. The antigens expressed comprised CD 15 (24 cases of the total series), CD 11b (19 cases), CD 13 (10 cases), CD36 (4 cases), CD14 (3 cases), CD33 (2 cases) and CD11c (2 cases). Cytogenetic studies of leukemic cells from 22 ceses showed various chromosomal alterations including hyperdiploidy (4 cases), t (9 ; 22) (3 cases), t (4 ; 11) (1 case), t (11 ; 19) (1 case), other chromosomal aberrations (7 cases), and normal karyotype (2 cases). Complete remission was achieved in 39 of 40 cases (97.5%), in which 26cases subsequently relapsed and only 13 cases remained in complete remission. Furthermore in 15 cases of My-positive ALL with favorable prognostic features (age 1-10 yrs, initial leukocyte count <50, 000/mm³ and non-T, non-B phenotype), 9 cases have already relapsed. Thus myeloid-antigen expression appeared to be an important predictor of a poor response to chemotherapy in childhood ALL.

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Double stem cell autografts (DSCA) utilizing two different types of cytoreduction regimens with a 1-2 month interval were applied to the treatment of childhood acute lymphoblastic leukemia (ALL) with very high-risk features. Four patients, from whom sufficient progenitors were collected from the peripheral blood, were planned to receive one-third of the collected cells at the first transplant, and the remaining two-thirds at the second transplant. For two other patients, autologous bone marrow transplantation (ABMT) was planned at the first transplant and PBSCT at the second one. A combination of high-dose melphalan (L-PAM; 120-180 mg/m²) and etopside (200 mg/m²×8) was the cytoreductive regimen for the first transplant and the MCVAC regimen was used for the second transplant. Six patients were scheduled to undergo DSCA, but one patients subsequently was excluded due to early relapse and an other died from veno-occulusive disease after the first transplant, leaving us four patients for DSCA, However, all patients developed relapse 2-12 months after the 2nd PBSCT. DSCA could be performed safely in children with very high-risk ALL, but its efficacy to induce a long-term remission was questioned. A further trial will be required to address this.

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Production of interleukin-1 (IL-1) by leukemic cells, expression of IL-1 receptor (IL-1R) on leukemic cells and proliferation of leukemic cells cocultured with IL-1 were studied in order to clarify whether IL-1 might act as a leukemia growth factor. Acute lymphoblastic leukemia (ALL) cells coexpressing myeloid-associated antigens and newborn/infantile ALL cells produced a small but distinct amount of IL-1. In acute non-lymphocytic leukemia (ANLL), a significantly larger amount of IL-1 was produced by leukemic blasts from 1 of 3 cases of ANLL-Ml, all of ANLL-M2 (3 cases), ANLL-M4 (4 cases), and ANLL-M5b (4 cases). The receptor specific for IL-1 was strongly expressed on ALL cells, but weakly on ANLL cells. DNA synthesis was not induced by IL-1 in ALL excepting one case with T-cell ALL coexpressing myeloid-associated antigens; whereas, IL-1 could induce DNA synthesis in all ceses of ANLL-M2 tested. These data suggest that IL-1 might act as an autocrine/paracrine growth factor in certain cases of ANLL (M2), but other growth factor might function in ALL.

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The efficacy of high-dose cytosine arabinoside (HDCA) and phenotypic difference in the prognosis were investigated in T-lineage malignancies (ALL and NHL) in children. Twenty-nine patients from July 1984 to December 1991 were included in this study. Ten patients were treated with the regimen without HDCA (Group A), 9 received single HDCA intensification (Group B) and 10 were treated with cyclic HDCA intensifications (Group C). Disease-free survival (DFS) rates at 48 months were 48%, 38.1% and 71%, respectively. Although these values were not significantly different, cyclic HDCA intensifications seem to be effective for T-ALL and NHL in children, because only 2 patients of Group C relapsed. The phenotype of the samples from Group B and C was divided into 3 groups, i.e., CD3 + group; CD3-, CD4+ and/or CD8+group; and CD3-, CD4-and CD8-group. The patients whose leukemic cells expressed CD3 had a favorable prognosis, and the patients with CD3-, CD4-and CD8-had the worst. Further study is needed to clarify whether the phenotype remains a prognostic factor in patients treated with very intensive therapies or not.

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The fluorescence polarization immunoassay method using a monoclonal antibody (m-FPIA) was introduced for the determination of whole blood cyclosporine (CyA) concentration in 96 samples from six children who had received allogeneic bone marrow transplantation (BMT). When steady-state trough levels seemed to be achieved, eight blood samples in each patient were serially collected during 12 hours after intravenous infusion and an oral administration of CyA. CyA levels determined by the m-FPIA method were almost at the same levels (r =0.996, p <0.001) as those determined by the ¹²⁵I-labeled radioimmunoassay (m-RIA) method. There was a linear correlation [slope of 1.04; y intercept (m-FPIA values) =-19] between the m-FPIA and m-RIA methods. Since the m-FPIA method is faster and simpler than other methods, this assay will give us reproducible results for the routine monitoring of CyA in patients who undergo BMT.

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The Bone Marrow Transplantation Committee of the Society has conducted an annual registry of bone marrow transplantation in children in Japan since 1983. As of June 30, 1992, 1, 330 patients had received stem-cell transplantation and were registered from 74 institutions. Among them, autologous bone marrow transplantation and autologous peripheral blood stem-cell transplantation were mainly performed in hematological malignancies or malignant solid tumors, and the former procedure was done in 342 children (183 alive) and the latter one was done in 172 children (113 alive), respectively. Allogeneic or syngeneic bone marrow transplantation including fetal liver cell transplantation (5 cases) were given to 807 children, i.e. 222 cases of acute lymphocytic leukemia (117 alive), 206 cases of acute myeloid leukemia (133 alive), 57 cases of adult-type chronic-myelocytic leukemia (38 alive), 5 cases of juvenile-type chronic myelocytic leukemia (2 alive), 37 cases of non-Hodgkin lymphoma (29 alive), 23 cases of malignant solid tumors (14 alive), 154 cases of severe aplastic anemia (137 alive), 33 cases of severe combined immune deficiency (15 alive), and 62 other cases (46 alive). The total number of transplanted cases has increased from 1, 013 to 1, 330 during the past one year. The details are reported in this paper.

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We report two cases of Ki-1 lymphoma in children. In case 1, enlargement of cervical lymph-nodes was the first clinical symptom. The COMP therapy achieved and sustained remission. A relapse in the primary site of lesion was noted after the therapy-off. However, we have succeeded in inducing the second remission. The first symptoms observed in case 2 were cervical adenopathy, fever, skin erythema, pleural effusion and ascites. Therapy under modified LSA2L2 protocol achieved remission which is still sustaining. Though immunologically and histologically, Ki-1 lymphoma is considered as an independent syndrome, clinically it shows diverse symptoms similar to so-called malignant lymphoma, and currently we are not yet able to find characteristic clinical features of this disease. There seems to be no need to clinically discriminate Ki-1 lymphoma from other malignant lymphoma, and the therapeutic method should be selected according to cell origin and disease stage.

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A 4-year-old girl was diagnosed in June 1990 as having acute lymphoblastic leukemia (ALL) with (1;19) translocation. Complete remission was obtained with TCCSG L84-12 intermediate risk protocol. Seven months after reinduction therapy, 50% of bone marrow cells showed blast-like morphology, with CD 10, 19, 20, HLA-DR antigen expression. In order to clarify whether the blast-like cells represent leukemic relapse or not, E2A-PBX1 chimeric mRNA was analyzed with RT-PCR. It showed only leukemic cell with (1;19) translocation. E2A-PBX1 transcript, which was expressed in the initial presentation sample, was not detected in those blast-like cells. Subsequently the patient was diagnosed as being in complete remisson. In this case, the continuous complete remission has been confirmed by the negativity of a serial E2A-PBX1 expression during treatment period.

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A 13-year-old boy who has had dark brownish urine since 6 years of age came to our hospital due to common cold. Bilirubinuria and mild hemolytic anemia (RBC 416 × 10⁴/μl, Hb 11.6 g/dl, reticulocyte 132‰) were noticed. Bone marrow showed erythroblastic hyperplasia. Isoelectric focusing analysis of hemoglobin revealed an abnormal band near the Hb A₂ fraction. Structural analysis of abnormal hemoglobin showed that valine in position 98 of the β-chain had been replaced by methionine, which led to the diagnosis of Hb Köln.

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We report here secondary acute lymphoblastic leukemia (ALL) in a child previously treated for Wilms' tumor. A 4-year-old female presented in January 1985 with anorexia and a left abdominal mass. The diagnosis of Wilms' tumor was confirmed after total excision. She was treated with radiation and chemotherapy using actinomycin D, vincristine and vindesine for 15 months. In May 1988, the patient developed intermittent fever and hepatomegaly. Bone marrow aspiration was consistent with acute lymphoblastic leukemia. Complete remission occurred after chemotherapy with prednisolone, vincristine, L-asparaginase and daunorubicin, but relapse developed in June 1990. The patient responded well to the second remission-induction therapy, and underwent an allogeneic bone marrow transplantation from HLA identical younger sister in January 1991. She remains free of recurrent disease. While myelogenous leukemia is a common second malignancy following the treatment of Wilms' tumor, ALL is rare. It is said that secondary ALL has poor prognosis. Hence, we believe that bone marrow transplantation should be firstly considered for the treatment of secondary ALL.

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In a 5-month-old boy with infection-associated hemophagocytic syndrome (IAHS) lymphocyte subsets of peripheral blood, serum and cerebrospinal fluid (CSF) cytokines were serially studied. The patient showed markedly increased serum LDH, GOT, GPT, hyperferritinemia and low fibrinogenemia. Marked hemophagocytosis was seen in CSF cells. In acute phase of the disease, peripheral blood B cell increased, associated with low T cell counts. As for cytokines, IL-6 in CSF was found to be elevated. Serum IFN-γ, sIL2-R, IL-6, IL-lβ, and TNF-α were all above normal range. These abnormal findings returned to normal level within a month along with improvement of clinical symptoms.

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A 6-year-old male patient with thrombotic thrombocytopenic purpura (TTP) was reported. The patient presented with typical pentad of fever, microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, and renal involvement. He was initially treated with plasma exchange (PE), but he could not tolerate the procedure because of renal and cardio-vascular insufficiency and failed to respond. Subsequently he was treated with exchange transfusion (ET), which he tolerated well and showed rapid clinical improvement. We concluded that ET would be an alternative choice of treatment for cases of TTP with cardio-vascular insufficiency.

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A 1-year-old boy with myelodysplastic syndrome had been treated with bone marrow transplantation using HLA-non-identical donor after 4 courses of subcutaneous administration of low-dose cytosine arabinoside (Ara-C). His laboratory data on first medical examination showed : WBC 11, 200/μ1; monocytes 2, 100/p1; blasts 1%; Hb 7.3 g/dl ; plt 7.6×10⁴/μl. A bone marrow examination showed normal cellularity with 12% of blasts and trilineage dysplasia. Cytogenetic studies revealed all of the metaphases to be 45, XY, -7. A diagnosis of chronic myelomonocytic leukemia was made. Pre-conditioning regimen consisted of Ara-C, cyclophosphamide, and total body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine, short-term methotrexate, and prednisolone. His peripheral neutrophil count increased to over 500/μl on day +20. But five months later, he relapsed and developed acute leukemia which was refractory to chemotherapies. He died 12 months after BMT. An autopsy revealed generalized infiltration of leukemic cells and aspergillosis of the lung.

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