Cellular levels of asparagine synthetase (AS) correlated with resistance to L-asparaginase therapy. With regard to L-asparaginase sensitivity of human leukemia cells, there is a tendency toward an inverse relation to the degree of AS expression. We established a qualitative immunohistochemical method to detect intracellular AS protein. Leukemia cases with low AS protein expression seem to be sensitive to L-asparaginase treatment. There are increasing numbers of reported cases sensitive to L-asparaginase with low AS expression determined by this method. This method would broaden the spectrum of the possible L-asparaginase-sensitive leukemia-e.g. acute monocytic leukemia, acute megakaryocytic leukemia, myeloid/NK precursor cell leukemia, and nasal/ nasal-type NK/T lymphoma-, but also the possibility of L-asparaginase treatment of malignant melanoma and multiple myeloma. The proposal and the preliminary result of a prospective clinical study of an L-asparaginase-based regimen for leukemia cases with low AS expression was discussed.

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Good indications of splenectomy in childhood hematological diseases are chronic idiopathic thrombocytopenic purpura (ITP), hereditary spherocytosis (HS), and autoimmune hemolytic anemia (AIHA). Urgent splenectomy is rarely warranted for emergency treatment. Other indications are, congenital hemolytic anemias, juvenile myelomonocytic leukemia (JMML) and hypersplenism, etc. There are fewer splenectomized patients with Wiskott-Aldrich syndrome (WAS) or Gaucher disease because of newer treatment with stem cell transplantation and gene therapy. Splenectomy brings superior patient's QOL than long term treatment with medication. Laparoscopic splenectomy is a safe and minimally invasive method and reduces the patient's pain. We should give attention to infections after splenectomy and can decrease the risk of sepsis with indication age of splenectomy more than 5 years old, vaccination of pneumococcus, prophylaxis with antibiotics and prompt management of fever. We should reconsider the optimal timing of splenectomy from the viewpoint of the patient's QOL. We would like to propose the nation-wide registries of splenectomy and its indicative childhood chronic diseases.

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May-Hegglin anomaly (MHA) is one of the inherited platelet disorders characterized by thrombocytopenia, giant platelets and Döhle body-like leukocyte inclusions in peripheral blood. Recently gene mutations in MHA and MHA-related diseases have been identified. We report a 10-day-old male infant with thrombocytopenia, which was not improved with high-dose γ-globulin administration or platelet transfusion. When he was referred to our hospital bleeding tendency was not seen. There were giant platelets in peripheral blood and small immature megakaryocytes in bone marrow. The function of platelets and bleeding time were normal. Anti-platelet antibodies were not detected. Giant platelets made the dissociation of platelet count between microscopic examination and blood cell counter (Coulter model JT). We suspected inherited thrombocytopenia including MHA. It was diagnosed as MYH9 disorder with the gene analysis of MYH9 (287 ; C → T). The patient has been well without any further treatment. In conclusion, it is important to check the smear for the differential diagnosis of inherited platelet disorders in the case of thrombocytopenia without bleeding tendencies.

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We report a seven-month old boy with N-myc amplified neuroblastoma (NB) detected by mass screening (MS). He was pointed out by the high levels of urinary VMA and HVA by MS and diagnosed as having stage 1 NB after detailed examinations. After complete excision of the tumor, we planned to treat with chemotherapy because N-myc amplification was over 40 copies which indicated poor prognosis. But we followed him without any treatment by reason of parental refusal. Four months after discharge, right side exophthalmus, high levels of urinary VMA and HVA, and bone marrow metastasis were recognized. Recurrence of NB was diagnosed. We started chemotherapy and stem cell transplantation (SCT) is planned. There are few cases of N-myc amplified NB detected by MS. In such cases, intensive treatment including SCT should be considered.

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We report a case study of a boy, aged 1 year and 7 months, with a reduced level of CD20 antigen in B cell malignant lymphoma, especially during clinical manifestations and immunological findings. Malignant cells, namely giant atypical lymphoid cells from the abdominal tumor, resembled matured B cells without CD20 antigen ; positive CD79a, negative CD20, CD3 and CD99. A surface marker analysis of 3days' culture of malignant cells also showed reactivity for CD10, CD19, CD21, surface immunoglobulin and HLA-DR with low reactivity for CD20. Ligation of CD20 with monoclonal antibody failed to induce apoptosis in the tumor cells. The lymphoma cells exhibited invasive and destructive features : bone destruction at recorded, apparent central nerve system invasion under intrathecal treatment, reflecting considerable disease activity and rapid growth rate of the malignant cells. The patient showed long-term bone marrow hypoplasia after remission induction chemotherapy along with recurrent varicella-zoster virus infection. He was unsuccessfully treated and expired due to DIC and bronchopneumonia. A B cell malignant lymphoma with a negative or low presence of CD20 such as in our case was likely to be invasive and highly pervasive, and its clinical features suggest a poor prognosis for the patient.

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We report a one year and ten months old boy who had folic acid deficiency megaloblastic anemia caused by poor diet. Anemia can result from deficiency of folic acid, one of the important dietary nutrients. In typical cases of megaloblastic anemia, megaloblasts appear in the bone marrow due to impaired DNA synthesis, thus resulting into megaloblastic anemia. However, our patient who was already put on folic acid-rich diet by his previous physician did not show these typical bone marrow features but his serum folic acid concentration (before folic acid administration) was low. We made a diagnosis of nutritional folic acid deficiency megaloblastic anemia. Adherence to a well balanced diet and regulated life style during the period of hospitalization resulted in improvement of his anemia.

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We report a boy of autoimmune lymphoproliferative syndrome (ALPS) type Ia presenting hemolytic anemia and thrombocytopenia in early infancy. He suffered from hepatosplenomegaly, hemolytic anemia and thrombocytopenia at the age of one month. His anemia and thrombocytopenia was improved with steroid, but recurred with infections. He then received splenectomy, and his hemolytic anemia and thrombocytopenia have been improved. At the age of eight years, genetic examination revealed that he and his mother had heterozygous Fas mutation. We emphasize that it is important to diagnose ALPS in case of infants with hepatosplenomegaly, hemolytic anemia and thrombocytopenia.

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An 11-year-old girl with prolonged cough was diagnosed as having acute lymphoblastic leukemia. After induction therapy, she showed recurrent attacks of severe cough with marked sputum production. Following first consolidation therapy, she had high fever with an elevated serum CRP level. Chest X-ray films disclosed cavities with a fungus ball-like shadow over the left lung field, and a computed tomography scan of the chest showed the stenosis of left bronchus and the cystic lesions associated with consolidation and shadows like a fungus ball in S3 and S6 of left lung. Interactions of the cystic lesions to segmental bronchi were also noted, indicating the characteristics of central bronchiectasis. With a combined administration of anti-fungal agents, amphotericin B and itraconazole, fever and radiographic abnormalities such as consolidation and fungus ball-like appearance rapidly subsided, but the respiratory symptoms responded poorly to therapy until oral corticosteroids were administered. Since evidence for immunological hypersensitivity to aspergillus was not obtained, this case did not meet the criteria for allergic bronchopulmonary aspergillosis (ABPA). However, her clinical course, existence of central bronchiectasis, history of asthma in her mother, and HLA-DR2 serotype that is common in the patients with ABPA, suggest the contribution of allergic bronchopulmonary mycoses in this unusual respiratory complication.

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The advances in treatment outcome of childhood leukemia/lymphoma have been obtained with the multi-center trials performed by the pediatric leukemia study groups, which have been developed in our country since the 1970's. However, scientific and ethical considerations of clinical trials have not been sufficiently provided because the pediatricians in our country confound them with guideline therapies. At this time, a new research project supported by the health and labor science research grants has started to establish a research basis for multi-center clinical trials for promoting evidence-based medicine in pediatric hematologic malignancies. Therefore, cooperating activities to improve the quality of clinical trials, such as providing objective evaluation to the trials and the projects by itself will be expected of the Japanese Society of Pediatric Hematology.

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Despite the advance of treatment and biologic analyses in pediatric hematology, the quality of clinical study and its monitoring system have been low in Japan. In 1996, an intergroup collaborative study of infant leukemia was organized ; the event-free survival of infant ALL with positive MLL rearrangement has been improved with the combination of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) (MLL96/MLL98 study). The data was analyzed in a research center, and the follow-up of each patient was performed by regional investigators and the managing office. However, the variation of treatment was large among patients, because the exact follow-up system was not organized in these studies. In the next study (MLL03), therefore, all patients will use identical protocol regimens to clarify the prognostic factors in infant ALL. In addition, supporting systems by several specific committees have been organized. These systems will help us to perform high-quality clinical trials for infant ALL.

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We have established a clinical research review board in the Japanese Society of Pediatric Hematology, to review and approve clinical research in pediatric hematology/oncology. The purpose of this committee is to protect human rights and the safety of patients recruited in the clinical research and to certify the quality of clinical research, by objective review and discussion of ethical, scientific and medical appropriateness. Furthermore, by notifying the researchers of the decision of review board, we expect that this will help to improve the quality of clinical research and the knowledge of researchers. We hope that this committee will positively contribute to the progress of clinical research in the field of pediatric hematology/oncology.

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Although immune mechanisms play an important role in the pathogenesis of bone marrow failure syndrome including aplastic anemia and refractory anemia, there is no good marker for diagnosing immune pathophysiology. When peripheral blood granulocytes and red blood cells of bone marrow failure patients were examined for the presence of minor populations of CD55^-CD59^- (PNH-type) blood cells using two-color flow cytometry with anti-CD 11 b antibodies for granulocytes or anti-glycophorin A antibodies for red blood cells, patients with PNH-type cells (PNH⁺ patients) showed a higher rate of response to cyclosporine, higher incidence of HLA-DR antigens, and lower incidence of karyotypic abnormalities compared with those without increased PNH-type cells (PNH^- patients). The HUMARA assay revealed lower incidence of clonality in granulocytes in PNH⁺ patients than in PNH^- patients. Most patients who later developed RAEB or AML had been PNH^- with clonality. These findings suggest that detecting a minor population of PNH-type cells as well as clonality in granulocytes is useful in differentiating pathophysiology of bone marrow failure.

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The aplastic anemia committee has undertaken annual nationwide survey of children with aplastic anemia (AA). As of 2002, 760 idiopathic AA patients (diagnosis year 1988-2000) have been registered and followed up. Numbers of newly diagnosed patients in each year ranged from 45 to 82. Severe AA patients accounted for 53% of these patients. Over 80% of patients who were diagnosed after 1994 underwent bone marrow cell chromosomes analysis, and 9 of 336 patients showed abnormalities at their presentation. The survival rates of very severe and severe patients who were diagnosed after 1994 improved (Kaplan-Meier [KM] survival 86.7 ± 5.3%, 87.5 ± 3.8%); however that of moderate and mild patients did not. It should be of concern that some of the mild patients died over 5 years later. Prognosis of allogeneic bone marrow transplantation from HLA matched siblings was good. If patients received HLA matched unrelated bone marrow transplantation within 2 years, the prognosis was fair (KM survival 86.4 ± 6.3%). The number of MDS/ leukemia transfbrmation decreased after 1994. This annual nationwide survey is expected to provide useful information for every clinician and patient.

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The combination of immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CyA) with or without granulocyte colony-stimulating factor (G-CSF) has been the treatment of choice for young patients with severe aplastic anemia (SAA) who have no HLA-matched family donors during the last decade. Although the combined therapy has produced complete or partial remission in 50 to 70% of patients, long-term survivors are at risk for relapse or secondary clonal diseases such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Several recent studies have suggested that the cumulative incidence of relapse or developing MDS/AML is 30 to 40% or 5 to 15%, respectively. Allogeneic bone marrow transplantation is another choice for treatment of SAA. The success of bone marrow transplantation is hampered by the high incidence of graft failure and graft-versus-host disease (GVHD). The prospective multicenter trial is indispensable for developing an optimum conditioning regimen and GVHD prophylaxis for patients with SAA.

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The epidemiology and treatment responses of Diamond-Blackfan anemia (DBA) were surveyed, based on the cohort of patients < 16years of age registered by the Japanese Society of Pediatric Hematology from 1988to 1998. The registered number was 54 (M : F=26 : 28), and the annual incidence was calculated to be 4.02 cases/million births. The median age at diagnosis was 60 days, and 59% presented within 3 months of age. Three patients had a familial occurrence. All patients received prednisolone (PSL). Cyclosporine A (CsA) was combined in 17 patients. Forty-seven received transfusions, and 13 underwent hematopoietic stem cell transplantation (HSCT). The cumulative probability of a medication- or transfusion-free state prior to HSCT was 36% or 69% > 5 years after diagnosis. Thirteen patients were weaned from PSL-therapy without HSCT. Adjunct CsA was not associated with weaning from the therapy. Transfusion and medication were stopped at 249 and 933 days after diagnosis, respectively, in 13 patients who achieved a state of independency. No initial findings could predict the treatment dependency. More than 20% of patients sustained hemosiderosis and/or adverse effects of PSL. The ages and reticulocyte counts at diagnosis in patients who underwent HSCT were lower than in those who did not. HSCT lead to the highest success (85%) of all previous reports, despite the fact that 5 alternative donors were included in our results. Two unrelated cord blood transplantations failed. These results suggest the need for developing an integral treatment strategy including selective HSCT for the patients with refractory DBA.

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To clarify the epidemiology and clinical features of Fanconi anemia (FA) in Japan, questionnaires were sent to all centers of Japanese Society of Pediatric Hematology. We analyzed the data from 752 patients with aplastic anemia between April 1990 and March 1999. Of those, 55 cases were registered as Fanconi anemia. Data from further questionnaires were collected in 36 cases. For the overall group, there were 28 boys and 27 girls, aged 0-14 years. Thirteen cases had a family history of FA. Two developed into solid tumors and seven patients had features of Myelodysplastic syndrome (MDS). Twenty five patients were transplanted, and 16 patients died within 8 years after diagnosis. The prognosis was very poor in patients with MDS. In further questionnaires, the extensive malformation syndrome (involving at least 3 of 6 important anatomic sites) were observed in 6 cases and the incidence was very low compared to that in a European group. Chromosomal fragility test was performed in 23 patients and genetic analysis was examined only in 7 patients.

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We retrospectively analysed the clinical outcome of 85 children with hepatitis-associated aplastic anemia (HAA), who were diagnosed between April 1988 and March 2000 and registered by the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology. Twenty-three patients received bone marrow transplantation (BMT) and the other 60 patients were treated with immunosuppressive therapy (IST) as a first-line therapy. Twelve of the 16 nonresponders to IST received BMT as a second-line therapy. The results of viral studies were available in 70 patients, but the pathogenesis of HAA is still unclear. The association with HLA-DR was also examined in 48 HAA and 156 idiopathic aplastic anemia (IAA) patients. The increased presence of HLA-DR9 was more frequent in HAA (54.2%) than in normal populations (27.8%). This was not observed in patients with IAA. The actuarial survival rates at 8 years in patients who were diagnosed between 1988 and 1993 and after 1994 were 70.8 ± 9.3% and 91.9 ± 4.5%, respectively. They were similar between the patients with HAA and IAA. It was concluded that there was no statistical difference in the response rate to IST between the children with HAA and IAA. Further studies are required to clarify the etiology of the preceding hepatitis and the mechanism of bone marrow failure.

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