Inhibitors are the most serious problem in the treatment of hemophiliacs because the ordinary replacement therapies are essentially ineffective for hemostasis in those patients with inhibitors. Our recent prospective and controlled study revealed that the average medical cost for inhibitor cases are about 2.5 times that for noninhibitor patients. However, the indicators of QOL (quality of life) of the inhibitor patients are significantly worse than those without inhibitors. To try to improve the QOL of inhibitor patients, ITI therapy (immune tolerance induction therapy) has been tried in many countries, but the high dose schedules represented by the so-called Bonn protocol are very expensive. Moreover, the superiority of these schedules shown by the International Immune Tolerance Registry has recently been questioned by the North American Immune Tolerance Registry. An international, randomized, controlled study will be started in autumn this year to make clear which treatment plan, the high dose schedule or the low dose one, is better in respect to efficacy and cost effectiveness. In Japan, we started low dose ITI therapy in 1983. Since then at least 25 inhibitor cases have been on the ITI therapy in Japan. The success rate has been around 67%. It is very important to establish the most appropriate methods for ITI therapy on inhibitor patients.

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We previously reported the first known human case of heme oxygenase-1 (H0-1) deficiency and included information about the patient's family. The proband was a compound heterozygote for a complete loss of exon 2 (the maternal allele) and a two-nucleotide deletion within exon 3 (the paternal allele). In this report, we demonstrate a large genomic deletion (1, 730 bp), including the entire exon 2 in this family by genomic PCR amplification and Southern blot analyses. A sequence analysis of the deletion junction revealed the fusion of a 5' portion of Alu-Sx element with a 3' portion of Alu-Sq element. The junction contained sequences with high homology to the recombinogenic Alu “core” sequence. These structural features of the HO-1 gene suggest a homologous recombination associated with the Alu element as a specific mechanism for the genomic deletion generating exon 2 deficit observed in the HO-1 mRNA. This study presents the initial characterization of the HO-1 gene defect, causing a human case of HO-1 deficiency, and provides the molecular basis for understanding this genetic disease.

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We evaluated sepsis in children with chemotherapy of malignancies from 1987 to 1997. Staphylococcus was the most isolated species from 1987 to 1991, and after 1992, although Pseudomonas decreased to 8.2%, from 27.8%, Streptococcus and Escherichia coli increased to 10.3%, from 6.9%, and to 8.9%, from 2.8%, respectively. After 1992, the strains not isolated from 1987 to 1991, such as Klebsiella, Xanthomonas and Acinetobacter, had increased. Furthermore, the drug-resistant strains had increased among the Staphylococcus and Pseudomonas. These results indicate that the isolated strains become more various and more resistant. Staphylococci were much more isolated in cases in which a central venous catheter was used than when a peripheral venous line was used. It seems very important to use the appropriate antibiotics following the sensitivity of species, and also strict line management.

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Since patients suffering from infantile leukemia are reported to have a poor prognosis, we have been treating them with intensified chemotherapy and various forms of blood stem cell transplantation (SCT). From December 1992 to October 1998, fifteen patients with infantile leukemia were treated ; 9 ALL (6 had a chromosome 11q23 abnormality or MLL gene rearrangement), 5 AML, and 1 NK cell leukemia. All but two patients with AML received SCT. In the beginning we employed autologous BMT (ABMT) following a preconditioning regimen consisting of busulfan and melphalan for the treatment of 5 consecutive patients (4 ALL and 1 AML). Because of a high relapse rate after ABMT in this setting (4 out of 5 patients), we used allogeneic SCT (allo SCT) with an intensified preconditioning regimen, including TBI for the remaining 8 patients and the 4 relapsed patients. At this writing (April 2000), 6 of 13 patients receiving SCT continue in remission (20-88 months after diagnosis), and 5 of 8 ALL patients are still in remission (20-75 months after diagnosis). Thus allo SCT with an intensified preconditioning regimen including TBI seems to be a feasible method for the treatment of infantile ALL.

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A two-month-old girl with Kasabach-Merritt syndrome (KMS) and giant hemangioma from the head to the cervical area was treated with a conventional dose and a pulsed high-dose of methylprednisolone without improvement. She was treated effectively with a three million unit/m² daily subcutaneous infusion of interferon α2a. The side-effects were fever during the first five days and neutropenia, but they were tolerable. Coagulopathy restoration and tumor regression were observed within three days after interferon administration, and thrombocytopenia improved slowly after two months. The tumor disappeared and the treatment was stopped after 7.5 months, and no relapse has been observed for seven months. Although interferon was an off-label drug for KMS, it was safe and useful.

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Thyroid cancer in children is a rare disease. Papillary carcinoma is the most common histologic type, most patients have good prognosis. We report a case with pulmonary and cervical lymph node metastases at the time of initial presentation. In February 1999, a 10-year-old girl with wheezing and dyspnea visited a hospital. A chest X-ray examination revealed multiple bilateral nodules, and multiple lymphadenopathies of the neck were shown. After admission to our hospital for further examination, the pathological findings of lymph node biopsy led to a diagnosis of papillary thyroid carcinoma. Since chemotherapy treatment was not effective, she received ¹³¹I therapy after a total thyroidectomy and lymph node dissection. Multiple lung nodules now remain unchanged in size, and thyroglobulin concentration in blood has not decreased much. Although ¹³¹I therapy is effective in most cases of differentiated thyroid cancer, this treatment was not effective in ours.

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A 14-year-old male was admitted to our hospital because of general malaise. He had massive splenomegaly and high WBC count (25×10⁴/μl). The patient was diagnosed with accelerated phase chronic myelogenous leukemia (CML). He was treated with Interferon α (IFNα) (600×10⁴IU×6 times/week) and hydroxyurea (HU), which induced complete hematological response and a partial cytogenetic response. After 10 months of this therapy, he developed proteinuria and showed elevated serum creatinine, after which doses of IFNα were reduced. About a year later, he developed proteinuria (1.5g/day) and progressive renal failure (Ccr : 16 ml/min). Discontinuation of IFNα led to a gradual improvement in renal function, but a small amount of proteinuria persisted along with a slightly high serum level of creatinine. A percutaneous kidney biopsy was performed. Light microscopy showed global glomerular sclerosis in half the glomeruli with an atrophy of tubules and a sporadic infiltration of mononuclear cells into the interstitial area. The remaining glomeruli demonstrated an irregular thickening of the capillary walls. Immunofluorescent microscopy showed deposits of C_3c and IgM in the epithelial cells and mesangial area. This suggests that deposits of immune complexes may be involved in the pathogenesis of the renal injury.

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A 15-year-old girl with hypoplastic myelodysplastic syndrome, who had been treated twice with antithymocyte globulin (ATG), underwent unrelated allogeneic bone marrow transplantation. The preparative regimens consisted of ATG (2.5mg/kg/day×4 days), cyclophosphamide (50mg/kg/day×4 days) and total lymphoid irradiation (4Gy/day×2 days). Showing no signs of acute GVHD, the patient, developed significant nasal obstruction and cervical lymph node swelling on day 58. This was diagnosed as Epstein-Barr virus associated lymphoproliferative disorder (EBV-LPD). She underwent donor leukocyte transfusion (DLT) on day 64, with an infused T cell count of 1.39×10⁶ cells/kg. The LPD disappeared 20 days after DLT; however, she developed GVHD on the skin and liver and subsequently died of uncontrollable gut GVHD on day 160. Caution must be exercised that repeated usage of ATG could be a risk factor of EBV-LPD after bone marrow transplantation and that DLT may result in fatal GVHD.

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We reported the case of a 13-year-old male who developed immunodeficiency during the course of chronic idiopathic thrombocytopenic purpura (ITP). In May 1993, the patient, who was then 9 years old, had purpura present in the lower extremes. ITP was diagnosed by means of a platelet count of 0.3×10⁴/μl, a megakaryocyte count of 193.8×10⁴/μl in the bone marrow, and a platelet-associated IgG level of 1, 470ng/10⁷ cells. Remission was initially achieved by treatment for ITP, but the patient became steroid-dependent, and Chinese herbal medicine was used in combination. Splenectomy was performed in November 1996, after which the platelet count increased transiently, but it then decreased again after 11 months. Immunoglobulin tests showed a transient decrease in IgG in October 1994 and again in June 1996 and further decreases of IgG and IgA after splenectomy. The patient developed interstitial pneumonia in July 1997. After a period of remission, he redeveloped interstitial pneumonia as a result of cytomegalovirus in May 1999, and later on intracranial hemorrhage. He died on December 22, 1999. The clinical course leading to immunodeficiency and the possible cause are discussed.

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