Eutherians and marsupials have particular kinds of genes, which are contradictory to Mendel's law and show parent-of-origin-specific expression. This phenomenon is called genomic imprinting. Most imprinted genes are involved in development of the placenta and the individual. Abnormalities of imprinted genes, such as a disruption of the imprinting system or gene mutations, cause several congenital diseases and cancer. Beckwith-Wiedemann syndrome (BWS) is a well-known imprinting-related disease characterized by macrosomia, macroglossia, and abdominal wall defects. The BWS locus is 11p15.5, which is one of the well-studied imprinted regions. Here, we describe the mechanisms of imprinted gene regulation and imprinting disruptions leading to BWS, different frequencies of some alterations between Japanese and other peoples, and the relation between assisted reproductive technology and BWS.

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The literature review of cumulative survival and cause-specific mortality revealed that the mortality of childhood cancer survivors has been significantly high even after 5 years have passed (the standardized mortality ratio was 4-17). The 5-year survivors of childhood cancer have also a high rate (60-70%) of chronic burden of disease from various late effects. The cumulative incidence of second malignant neoplasmas was 3.5-4.7% at 25 years and the standardized incidence ratio was 3.6-6.38. These results confirm the requirement of life-long follow-up of children with cancer. I introduced the models of long-term care for childhood cancer survivors (advantages and disadvantages of various types), and explained the follow-up programs which were proposed in the United States of America, the United Kingdom, Germany, Italy and so on. Lastly I discussed the issues about long-term follow-up for childhood cancer in Japan.

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Chronic active EBV infection (CAEBV) is a poor prognostic disease, and allogeneic stem cell transplantation (allo-SCT) is one of the curative treatments. We report a boy with T cell-type CAEBV, who was successfully treated with reduced intensity stem cell transplantation (RIST). A 9-year-old boy was suffering from fever and hepatosplenomegaly, and was diagnosed with CAEBV based on a high level of EBV DNA in his plasma (1.5 ×10⁶ copy/ml). Allogeneic bone marrow transplantation (BMT) from his HLA-matched mother was performed after a preconditioning regimen consisting of Fludarabine (30 mg/m²/day × 4 days), Melphalan (70 mg/m²/day × 2 days), and horse antithymocyte globulin (10 mg/kg/day × 2 days). He received an infusion of BM containing 3.3 × 10⁸ mononuclear cells/kg. Cyclosporine A and short-term Methotrexate was used for prophylaxis against graft-versus-host disease (GVHD). He was engrafted with neutrophil > 5 × 10²/μl on day 17, reticulocyte > 1.0% on day 21, and platelet > 5 × 10⁴/μl on day 24, and complete chimera was confirmed by FISH analysis of sex chimerism on day 105. He developed grade II acute GVHD, and his hepatosplenomegaly subsided subsequently. EBV DNA became undetectable in the plasma after BMT. This outcome suggests that RIST could be a safe and effective treatment for the patients with CAEBV.

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Epstein Barr virus-lymphoproliferative disease (EBV-LPD) is a complication of primary immunodeficiency and it has a very poor outcome. We report a case of EBV-LPD complicating primary immunodeficiency which had successful treatment with rituximab after induction therapy. The patient received reduced intensity stem cell transplantation (RIST) after rituximab, and maintains complete remission. Primary immunodeficiency often complicates severe infection, and intensified chemotherapy leads to treatment-related mortality for such patients. In this case, EBV infected B cells, and she received intravenously administered rituximab. Rituximab induced a rapid improvement in the clinical symptoms without adverse events. Rituximab may benefit the management of other disorders with EBV-LPD complicating primary immunodeficiency.

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Marked advances have been made in hemostatic treatment for hemophilia during the last20 years, owing to a stable supply of safe and effective coagulation factor concentrates. On the other hand, the treatment results in patients who developed inhibitors, particularly high responder type inhibitors after the initiation of the injection of coagulation factor concentrates are considerably poorer than those in inhibitor-negative patients. Therefore, hemostatic treatment in inhibitor-positive patients is a majorproblem in the treatment of hemophilia. To improvethissituation, various approaches have been attempted. We introduce recent topics on inhibitor bypassing agents as follows. 1. Long-term safety and efficacy of rFVIIa (NovoSeven®) in hemophilia patients with inhibitors : Interim marketing study in Japan. 2. Clinical studies for single/highdose treatment of rFVIIa. 3. Clinical studies comparingrFVIIa to APCC. 4. Prophylactic treatment with rFVIIa or APCC. 5. New inhibitor bypassing drugs under clinical investigation.

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A common strategy for replacement therapy in patients with hemophilia is replacement of the deficient co-agulation factor (factor VIII or IX) in the event of bleeding, for a certain period until the bleeding stops, which is referred to as on-demand therapy or episodic therapy. The Scandinavian countries have recently begun toemploy regular replacement therapy (referred to as prophylaxis in the US and Europe), with regular replacement of the coagulation factor over the long term, even in the absence of hemorrhage, in order to prevent bleeding as well as prevent the development and progression of arthropathy, and the usefulness of this strategy in the prevention of arthropathy has been reported. However, as the outcomes of regular replacement therapy are mainly derived from retrospective observational studies, lack of sufficiently strong evidence for the effectiveness and safety of the therapy has been pointed out. Therefore, the Hemophilia Committee of the Japanese Society of Pediatric Hematology has launched a prospective clinical study. With accumulation of further evidence in regard to the effectiveness of regular replacement therapy from progress reports of the ongoing prospective randomized controlled trials in the US and Europe, replacement therapy for hemophilia is now expected to enter a new era.

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The primary approach to the hemostatic management of patients with hemophilia and inhibitors includes treatment with bypassing agents or inhibitor neutralization with high doses of factor VIII (IX) concentrates. The choice of treatment for acute bleeding or surgery in inhibitor patients is dictated by the severity of the bleed, the current inhibitor titer, and the previous anamnestic response to factor VIII (IX). In general, a certain consensus for the choice of treatment has been established in overseas guidelines. Inhibitor neutralization therapy is recommended in low responder patients with a current titer of less than 5 Bethesda units (BU) /ml, while treatment with bypassing agents is recommended in high responders with a current titer of more than 5 BU/ml as the first-line therapy. In high responders with a current titer of less than 5 BU/ml, treatment with bypassing agents is chosen in minor bleeding, whereas the therapeutic choice in severe bleeding or surgery is controversial. Many of the guidelines do not fix an order of priority for the choice of bypassing agent, except for the recommendation of recombinant activated factor VII concentrates on the Australian guideline. These issues have been reviewed in this article for development of a domestic guideline for the treatment of patients with hemophilia and inhibitors.

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Comprehensive care for hemophilia means support by a healthcare team composed of members of various occupations specializing in hemophilia to enable hemophiliacs and their families to go about their lives both physically, mentally and socially in a manner that suits them. The need for comprehensive care has been pointed out for some time, but it has not yet become established as a universal system in Japan. Carrying out comprehensive care not only reduces bleeding and its sequelae, but contributes to improving the QOL of patients and their families. The organization of a comprehensive care system and setting up of a care liaison system in Japan are urgent tasks. The Hemophilia Committee of the Japanese Society of Pediatric Hematology has set up a pediatric hemophilia care network with the aim of exchanging healthcare information and disseminating healthcare information. We hope to construct the comprehensive care system that conforms to Japanese medical system by exchanging views through the network and cooperation with Japanese Nurse Group for Research of Hemophilia Care. The principal objectives of the Hemophilia Patients' Association are encouragement to enable patients and their families to become informed and to provide psychological support, and it made recommendations to the government to improve medical environment. The role of physicians is to transmit knowledge and information at the request of the patient association and to serve as consultants. It is necessary to provide support to enable the patient association to grow stronger.

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