The development of coagulation factor VIII or factor IX inhibitor remains a major serious complication of treatment in patients with hemophilia. The incidence of the factor VIII inhibitor is 20-30%, according to the recent prospective studies. Major factor VIII gene defects, such as large deletion, intron 22 inversion, and nonsense mutation that result in no detectable circulating antigen, are potential risk factors. However, no exact explanation is available for why some hemophiliacs. develop inhibitors. The treatment of hemophiliacs with inhibitors are divided into two groups. One is the hemostatic treatment. Replacement therapy may be effective in some patients with a transient or low responder inhibitor. (Activated) prothrombin complex concentrates are mainly used in Japan, but long-term usage of the products is limited because of anamnestic response, thrombotic complications, and economic issues. Recombinant factor VII product was recently introduced to Europe and North America, and it is expected to be approved soon in Japan. The other is immunological therapy for the reduction of inhibitor. The most reliable immunological therapy is immune tolerance treatment (ITT). Overall, the efficacy of ITT is 60-80%. Several ITT trials have been conducted in Japan by using mainly moderate to low-dose protocol. The establishment of Japanese protocol of ITT is urgently needed.

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The population of patients with von Willebrand disease (vWD) in England, Italy, and Canada were 9.3, 3.6, and 3.1/10⁵ persons, respectively, in 1998. In contrast, the number in Japan has increased gradually up to 735 cases (0.56/10⁵ persons), possibly, in parallel with the extent of concern about vWD. To normalize criteria for a diagnosis of vWD worldwide, the ISTH/SSC introduced a guideline for Type 1 vWD that consists of significant bleeding symptoms, laboratory findings, and inheritance. The significant bleeding symptoms include frequent and severe nose bleeding, menorrhagia, and abnormal bleeding after tooth extraction and operations. The laboratory finding shows low vWF under <2 SD from mean values of vWF : Ag and vWF : RCo, corresponding to blood groups. Then, positive family history requires at least one first-degree relative or at least two second-degree relatives who have significant bleeding symptoms and compatible laboratory data to vWD. The treatment of mild vWD involves an administration of the synthetic vasopressin analog DDAVP. On the other hand, in severe cases, including Type 3, 2B, and 2N vWD, FVIII/vWF complex concentrate would be required for the replacement therapy. Especially, at delivery, the preventive administration of FVIII/vWF for after-bleeding or hematoma should be recommended in Types 2 and 3 vWD.

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In leukemic blasts of childhood T-cell acute lymphoblastic leukemia/non-Hodgkin's lymphoma (13 cases of T-ALL/ 3 cases of NHL), we studied the expressions of CD3 antigen and of T-cell receptor (TCR) by using the flow cytometric assay and TCR gene rearrangements with Southern analysis. Data were evaluated in relation to the clinical features. CD3 was positive in 7 cases (5 ALL/2 NHL) and negative in 9 (8 ALL/1 NHL). WBC counts (median 152, 100/μl) at onset of the disease in the CD3-group were significantly higher than those (6, 400/μl) of the CD3 + group (p=0.016). The TCR was expressed in 6 (4 αβ, 2 γδ) of the 7 CD3 + patients. On the other hand, no TCR was expressed in the CD3-patients studied (6/7 vs. 0/3, p=0.01). The genotypes of TCR were compatible with phenotypes showing rearrangements of γ and β genes in the αβ type and those of the _γ gene only in the γδ type in the CD3 + patients. Including the 3 cases in which the TCR was not phenotypically expressed, both γ and β genes were rearranged in 7 of 9 CD3-patients. Clinically, relapses were noted in only one case in the CD3+ group and in 5 cases in the CD3-group (1/7 vs. 5/9, p= 0.09). It seems that the leukemic blasts at different differentiation stages estimated from CD3 and TCR expressions may have an effect on the clinical features including prognosis in pediatric patients with T cell malignancy ; however, further studies with a large number of patients are required to confirm our observation.

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When collecting peripheral blood stem cells (PBSCs), it is important to reduce not only the number of apheresis, but also the volume of blood processed because the procedure is uncomfortable for pediatric patients. We monitored peripheral blood CD34⁺ cell count (pbCD34⁺) to optimize the collection method. Twenty-one mobilization courses were done with chemotherapy plus G-CSF (18 courses) and G-CSF alone (3) in 13 patients. Apheresis was started when pbCD34⁺ was above 10/μl, and the volume of blood processed was set based on the preapheresis pbCD34⁺ as 100-300 ml/kg. In 2 courses, apheresis was abandoned because of poor mobilization. The other 19 courses were grouped by pbCD34⁺ into 3 groups (Group A : pbCD34⁺ > 60/μl, B : 10-60, C : <10). In each group, the mean number of CD34⁺ cells collected (volume of blood processed) was as follows. A : 7.61 × 10⁶/kg (148 ml/kg), B : 3.52 (340), C : 2.61 (517). As a result, 16 of 19 courses successfully collected more than 2.0 × 10⁶ CD34⁺ cells/kg. Our method, with monitoring of pbCD34⁺ and setting of the volume of blood processed, proved useful for collecting PBSCs in pediatric patients.

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For the purpose of investigation of in vitro drug resistance in infant acute lymphoblastic leukemia (ALL), we examined the drug sensitivity of fresh and relapsed leukemic cells in 9 infants (median age 8 months ; range 0-10 months) by using the methyl-thiazol-tetrazolium (MTT) assay. The immunophenotypical examination of leukemic cells revealed negativity for CD10 in 6 infants ; this negativity was found in all 4 infants less than 6 months old (<6 mo.). The event-free survival (EFS) in infants <6 mo. was significantly worse than that in infants 6 mo.-1 year old (p = 0.011). When we classified the infants into two groups according to their sensitivity to prednisolone, L-asparaginase, and vincristine (PAV), four infants belonged to the three-drug sensitive group (SS) and five to the resistant group (RR). All infants < 6 mo. belonged to the RR group. Fifty percent EFS in the SS group was 8.4 months, which was significantly longer than 2.5 months in the RR group (p = 0.0045). In comparison of leukemic cells from infants aged 6 mo.-1 year and > 1 year, cells from infants aged < 6 mo. were more resistant to prednisolone and dexamethasone. Interestingly, leukemic cells from infants <6 mo. were more sensitive to 4-hydroperoxy-cyclophosphamide, cytarabine, and etoposide without any statistical significance. No increased resistance was found in relapsed leukemia compared with fresh leukemia. We suggest that cellular drug-resistance patterns of infant ALL might be divided into three groups according to their sensitivity to PAV and cytarabine.

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We reviewed growth and endocrine functions in 29 patients who underwent stem cell transplantation (SCT) at the Kanagawa Children's Medical Center and survived without disease for more than 1 year after their SCT. In our study, the more severe decrease of height standard deviation score (SDS) was observed in children who had undergone SCT at an earlier age, using total body irradiation (TBI). The risk factor of hypothyroidism after SCT was the cranial irradiation before SCT. Gonadal dysfunction occurred frequently in both boys and girls regardless of preparative regimen before SCT. It is important to observe carefully the effect of SCT on growth and endocrine function, and to consider whether the hormonal therapy is indicated.

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We reported two relapsed cases with leukemia/lymphoma syndrome (LLS) and non-Hodgkin's lymphoma (NHL) during chemotherapy, including cyclophosphamide and/or ifosfamide. After a second relapse, they received L-phenylalanine mustard with doses of 80 mg/m² and achieved their third complete remission. Grade IV myelosuppression was a major toxicity in both cases. One patient with LLS relapsed four months later. This case underwent allogeneic bone marrow transplantation (BMT) from an unrelated donor after conditioning with busulfan, total body irradiation, and L-PAM in her third bone marrow relapse. She is still in complete remission three years after BMT. These results indicate that L-PAM has a strong antitumor activity for childhood lymphoid malignancies.

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We report a 4-year-old boy with idiopathic pneumonia syndrome (IPS) developing at day 200 post-transplant. He was diagnosed as severe aplastic anemia (SAA) at 2 years and 6-months. He developed myelodysplastic syndrome (MDS) at 3 years and 6-months ; therefore we performed allogeneic bone marrow transplantation (alloBMT) from an HLA-B locus mismatched sibling donor after preconditioning with cyclophosphamide (CY), etoposide (VP-16), and total body irradiation (TBI). Cyclosporine (CSA) and short-term methotrexate (MTX) were used for graft-versus-host disease (GVHD) prophylaxis. He developed grade III acute GVHD, but improved with methylprednisolone (mPSL), antithymocyte globulin (ATG), and tacrolimus at day 120. He was discharged at day 170. He presented cough and wheezing at day 200, and was readmitted at day 207. Chest X-rays showed a bilateral diffuse interstitial shadow. He received mechanical ventilation for rapid evolution of respiratory failure. He was treated with mPSL pulse therapy (20 mg/kg/day), but it produced an insufficient effect, so we performed mega-dose mPSL pulse therapy (100 mg/kg/day) for a long duration. We rescued him without serious complication, and quit steroids. Rapidly progressive respiratory failure in IPS after BMT indicate a higher mortality rate ; therefore mega-dose mPSL pulse therapy in these patients is considered to be worth further investigation.

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We report a case of a 2-year-old boy with Noonan syndrome (NS) complicated by an abnormality of chromosome 7 after treatment of acute lymphoblastic leukemia (ALL). The boy was admitted to our hospital with fever and gingival bleeding. Laboratory findings showed anemia and thrombocytopenia. Bone marrow findings were proliferation of abnormal lymphoblastoid cells (FAB L1), and surface markers were positive for CD10, CD19, and HLA-DR. Both bone marrow and peripheral blood karyotypes were 46, XY. He also had typical phenotypes of NS, including multiple congenital heart disease (atrial septal defect, hypertrophic obstructive cardiomyopathy, and peripheral pulmonary stenosis), hyperterolism, thoracic malformation, left testicular agenesis, and mild mental retardation. He was diagnosed as ALL and was treated with chemotherapy. He entered complete remission (CR), which is currently maintained. But chromosomal analysis of bone marrow during maintenance chemotherapy showed abnormal karyotype, 46, XY, add (7) (q11). The morphological findings of this marrow showed dysplasia of myeloid cells. It was suspected that he also had myelodysplastic syndrome (MDS). Although it is unclear whether his MDS was related to chemotherapy or NS, recently some reports have shown an association between MDS and NS. Further studies are required to examine the cytogenetic background in hematological disorders associated with Noonan syndrome.

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