Tissue fibrobiasts/myofibroblasts play a key role in growth factor secretion and extracellularmatrix protein production, and therefore regulate the inflammation responses in the processes of wound healing. Once the origin of tissue fibroblasts/myofibroblasts was thought to be local tissues themselves; recently, it was proved that the fibroblasts/myofibroblasts are derived from bone marrow. We have carried out studies of tissue reconstitution by transplanting clones derived from a single hematopoietic stem cell (HSC) expressing transgenic enhanced green fluorescent protein (EGFP). We found that there were EGFP⁺ fibroblasts/myofibroblasts in many organs and tissues which were derived from the HSC, excluding the possibility of cell fusion. Since fibroblasts/myofibroblasts are important in the pathological process and maintenance of steady state, it is of interest for the application of regenerative medicine to clarify the newly identified road from HSC to fibroblasts/myofibroblasts

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Over the past decade, clinical success in the treatment of serious genetic disorders using retroviral vectors was achieved, specifically in patients with serious genetic immunodeficiency diseases. However, this progress was unfortunately tempered by a serious adverse event, leukemogenesis, related to retroviral vector integration into genomes of hematopoietic stem cells or primitive precursor cells in 2003. Here, the encouraging results and the serious adverse event based on the genotoxicity of vector integration will be reviewed, and strategies to decrease the risk of leukemogenesis and adverse events to achieve clinical safe gene therapy using hematopoietic stem cells will be discussed.

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We evaluated the clinical characteristics and the prognosis of infants with acute myeloid leukemia (AML), excluding Down syndrome and acute promyelocytic leukemia, registered in two consecutive multicenter trials, desig-nated TCCSG M91-13 and M96-14, between 1991 and 1998. Among the infants, 80% of the cases comprised FAB type M4/M5 (58.4%) and M7 (25.0%), which was more than twice as high as non-infant cases. In addition, infants had a karyotypic character distinct from older cases, such as higher incidence of 11q23 abnormalities (20.8%), no cases with t (8;21), etc. There was no significant difference in 5-year event-free survival rates for 24 infant cases and 168 non-infant cases, which were 49.4%±20.2% vs. 55.2%±7.5% (p = 0.46), respectively. Among the infant cases, the proportion of fatal infectious complications was high; 60.0% (3/5) of the events during remission inductio and 41.7% (5/12) of the total events. Careful and effective supportive care for infectious complications is required, especially during remission induction, for the treatment of infants with AML.

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In the selection of alternative donors for stem cell transplantation (SCT), if an HLA full-match donor can not be secured, the identity of the most appropriate donor is unclear. We experienced two children with refractory, acute myeloblastic leukemia (AML) who underwent SCT from the non-inherited maternal antigen (NIMA) -mismatched sibling donor linked with long-term feto-maternal microchimerism, with expectation of graft-versusleukemia (GVL) effect. The engraftments were speedy and acute graft-versus-host disease (GVHD) did not occur. But after donor lymphocyte infusion (DLI) or acute tapering of their immunosuppressant, severe lung complication with GVHD occurred in both cases. Our cases suggest the risk of immunotherapy after SCT from a NIMA-mismatched sibling donor.

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We report 2 cases who were successfully treated with multi-antifungal agents including voriconazole (VCZ) for severe aspergillus infection after bone marrow transplantation (BMT). Case 1 is a 4-year-old girlwith ALL who showed a relapse after BMT. Marked elevation of, β-D-glucan and Aspergillus antigen were observed during low-dose chemotherapy despite the anti-fungal treatment with micafungin (MCFG) and amphotericinB (AMPH-B). Theaddition of VCZ resulted in prompt improvement of the infection. Case 2 is a 15-year-old boy with chronic granulomatous disease who received donor lymphocyte infusion for graft rejection. He developed aspergillus pneumonia during the treatment for acute GVHD with tacrolimus and methylprednisolone. Treatment of MCFG and VCZ resulted in the decrease of β-D-glucan within 3 months accompanied with an improvement of lung lesions. In both cases, multiantifungal agents were very effective without any severe side effects. Monitoring the hemoconcentration of VCZ was very useful for hematopoietic stem cell transplantation recipients who received various drugs that have interactions with VCZ.

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We performed a liver biopsy for a case of Down syndrome with transient abnormal myelopoiesis (TAM) and prolonged liver dysfunction. Pathologic findings showed neither hepatic fibrosis nor infiltration by megakaryoblasts, being compatible with TAM, but showed a paucity of interlobular bile ducts and intracellular cholestasis, resulting in the diagnosis of nonsyndromic paucity of interlobular bile ducts (NS-PILBD). If patients with TAM show prolonged hepatic dysfunction, we consider NS-PILBD as one of the differential diagnoses.

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We report a female infant with acute lymphoblastic leukemia who developed severe veno-occlusive disease (VOD) after unrelated cord blood transplantation (UCBT) with buslfan (Bu), cyclophosphamide and VP16 conditioning regimen. Because her Bu clearance had been decreased, blood Bu concentration showed 967 ng/ml, markedlyelevated from the expected average concentration. She showed hepatomegaly, ictelus, thrombocytopenia and severe weight gain (+57.7%) between day 6 and 20 after UCBT. After a six-day course of activated protein C administration with intensive supportive therapy, she completely recovered by day + 60 and has maintained complete remission more than 30 months after UCBT. Activated protein C administration might be useful as one of the treatments for hepatic VOD.

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We described a 13-year-old boy with Klinefelter syndrome associated with a mediastinal germ cell tumor. He initially presented with_ ;a prominent gynecomastia, which might be considered to be a symptom of Klinefelter syndrome. The serum levels of AFP and β-hCG were extremely elevated. The germ cell tumor was treated with chemotherapy and total resection of the tumor. After he achieved complete remission, his gynecomastia was improved. The gynecomastia might be associated with not only Klinefelter syndrome but also the β-hCG-producing germ cell tumor.

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We encountered a child case of low titer cold agglutinin disease (CAD) causing a severe hemolytic attack, though the cold agglutinin titer was extremely low. A 3-year-old boy was admitted to our hospital because of jaundice and drowsiness following fever and diarrhea. Laboratory examinations revealed normocytic normochromic anemia (hemoglobin; 5.7 g/dl), elevated levels of direct bilirubin and LDH, and low haptoglobin concentration, which suggested an acute attack of hemolytic anemia. Direct Coombs tests were strongly positive for C3bC3d, C3d and weakly positive for IgM, but negative for IgG. Although hemagglutination tests using the patient's serum were positive only in low temperature, the serum level of cold agglutinin was very low (1 : 32). After other forms of hemolytic anemia were ruled out, he was diagnosed with low titer CAD. He was kept in a warm room (30 degrees C), and treated with predonisolone and transfusion of warmed red blood cells because hemoglobin concentration was lowered to 3.9 g/dl the next day. He achieved remission, and had no recurrence of the disease for one and a half years.

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The Aplastic Anemia Committee has undertaken an annual nationwide survey of children with hemopoietic disorders such as acquired aplastic anemia (AA). As of 2005, a total of 1, 411 child patients has been registered : 1, 002 idiopathic AA, 129 hepatitis associated AA (HAA), 8 secondary AA, 98 Diamond-Blackfan anemia, 89 Fanconi anemia, 36 severe congenital neutropenia, and 49 other types of congenital hemopoietic disorders, respectively. The 10-year survival rate of 414 idiopathic AA patients who were diagnosed between 1994 and 2000 is estimated as 86.7% (95% confidence interval; 82.6-90.8%). Survival rate differences between disease severities has disappeared due to the development of specific therapies, immunosuppressive therapy and unrelated bone marrow transplantation. Stem cell transplantation-related complications are the main causes of death in long-diseased children. Improvements in survival are also observed in HAA patients and Fanconi anemia patients who were diagnosed after 1994; 92.7% for HAA, 83.8% for Fanconi anemia, respectively. The number of MDS/leukemia developments decreased after 1994. Establishment of a nationwide blood disease registry centralized by the JSPH can improve the precision of the database.

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In Japan, prospective multi-center studies have been conducted for childhood aplastic anemia (AA) since 1993 and data on more than 500 patients have been accumulated. The outcome of both immunosuppressive therapy and allogeneic bone marrow transplantation, particularly in unrelated donor settings, have significantly improved. The long-term survival rate in childhood AA exceeded 90% in the recent decade. Although our previous study reported an extremely high incidence of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) after combination of immunosuppressive agents and granulocyte colony-stimulating factor, the current study revealed a prominent decrease in the incidence of MDS/AML with monosomy 7 after the start of prospective multi-center studies.

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