Despite recent advances in chemotherapy for childhood acute lymphoblastic leukemias (ALL), Philadelphia chromosome-positive andMLLgene rearranged ALL are still refractory. To overcome the refractory nature of these leukemias, it is important to clarify a vulnerable point (the heel of Achilles) of these leukemias by pursuing biological characteristics in addition to clinical and molecular/genetic features. In this review, an outline of established and recent understandings on chromosomal abnormalities resulting in production of fusion genes/fusion proteins, leukemogenesis, clinical features, antigens expression, tumor suppressor genes, and DNA chip analysis in these refractory leukemias is discussed, and then our data on established cell lines, sensitivity to anti-leukemic agents, expression and function of cytokine receptors, molecule-targeted therapies, and sensitivity to cytotoxic molecules are presented together with reported data with discussion regarding possible clinical applications.

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Endocrine dysfunction is one of the most common and important events as a late effect in survivorsof childhood and adolescent leukemia. In this paper metabolic syndrome (MS), which consists of visceral fat obesity, impaired glucose metabolism, dyslipedemia and blood pressure elevation, is concisely described as a late effect, especially in patients with stem cell transplantation (SCT). Various reports have observed that a higher prevalence of MS developed as a late effect after treatment with SCT, while others reported that MS occurred less often. Though there are some limitations to conclusions based on previous reports, it is possible to show two positive findingsas follows. First, every study suggests that patients after SCT tend to have some laboratory features of MS, especiallythe presence of dyslipedemia. Second, chemotherapy including SCT may induce the development of MS during long-term followup. Irradiation is well known to play an important role in development of many dysfunctions including obesity. Recently, it has been reported to be likely that insulin resistance and obesity are associated with chronicsystemic inflammation, especially hepatic and adipose tissue inflammation, and a paracrine loop involving free fatty acids and TNF-alpha between adipocytes and macrophages infiltrating into adipose tissue establishes a vicious cycle. A number of cytokines secreted on chronic GVHD as the same status of chronic inflammation could induce the development of MS. Conclusively, it is likely that a large cohort with longer follow-up would provide more useful information and that such a study must be planned with a prospective design.

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We analyzed the complications of severe infectious episodes in 223 children with acute lymphoblastic leukemia (ALL) who were treated by the Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol from June 2003 to May 2004. Sixty-two cases were complicated with bacterial or fungal infections. In 49of these patients, infectious episodes occurred during neutropenia (< 500/, u1 of peripheral neutrophil counts).Among causes of infection in the neutropenic patients, gram-negative bacteria accounted for 32.7%, gram-positive bacteria for 59.2%, and fungi for 8.2%. In the patients with complications of bacterial infections of gram-positive or gram-negative pathogens, infectious symptoms disappeared with initial empirical antibiotic therapy. On the other hand, thelesions of fungal infections in three children (two systemic Candidasis and one Aspergillus pneumoniae) did not disappear despite antifungal therapy, so the ALL-02 protocol was discontinued in these patients. In the treatment of ALL, it seemed that prevention and the treatment management of fungal infections were important as well as broad spectrum antibiotic empirical therapy.

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We encountered the case of a 5-year-old boy who developed cerebral embolism 9 months after undergoing a Fontan procedure. No abnormalities were found in the patient's plasma protein C, protein S, antithrombin, heparin cofactor II or plasminogen levels. The coagulation test for lupus anticoagulant (LA) was negative, suggesting that the blood coagulation profile did not reveal any thrombotic predispositions. The development of the thromboembolic episode in this case was considered to be related to characteristic hemodynamic factors associated with the Fontan procedure, and sporadic ventricular extrasystoles were possibly involved as aggravating factors. Thrombosis after the Fontan procedure is an important prognostic factor, and we await the development of evidence-based guidelines for antithrombogenic therapy in such cases.

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We describe umbilical hemorrhage associated with severe hemophilia A in a neonate who required intensive care due to acute progressive anemia. A male neonate was referred to our hospital due to persistent umbilical bleeding uncontrolled by digital pressure or cauterization with silver nitrate, and a pale face after separation of the cord. Normal prothrombin time and prolonged activated partial thromboplastin time (aPTT; more than 180 sec) on admission suggested hemophilia. Further investigation into coagulation factors revealed less than 1% factor VIII activity and 46% factor IX activity. Diagnosis of hemophilia A was made. Infusion of factor VIII concentrates to replacethe defective clotting factor was effective for umbilical bleeding. However, we were compelled to treat the patient in a neonatal intensive care unit with packed RBC because of poor performance status probably due to acute progressive anemia. Since neonates with hemophilia seldom show hemorrhagic manifestations, it is often difficult to make a diagnosis of hemophilia during the neonatal period. Delay in treatment may lead to an increase in severity of symptoms. In a clinical examination of bleeding tendency in the neonatal period, pediatricians should make an early and correct diagnosis with hemophilia in mind, and evaluate the need for replacement therapy.

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Adult respiratory distress syndrome (ARDS) is mainly caused by pulmonary injury by granulocytes. We report a 12-year-old girl with acute lymphoblastic leukemia who developed ARDS. After intensification chemotherapy, she became neutropenic and febrile. α-streptococcus was detected in the blood culture from the central venous catheter. Although her fever subsided after administration of antibiotics, she fevered up again at 3 days after onset ofα-streptococcal bacteremia, and an administration of granulocyte colony-stimulating factor (G-CSF) was started. Herwhite blood cell (WBC) count was 140/μl at 8 days after onset, and increased to 800/μl at 9 days whenshe suddenly developed respiratory arrest with a diagnosis of ARDS based on bilateral pulmonary infiltration in a chest X-ray film. The patient died of multi-organ failure 5 hours after respiratory arrest. It has been reported that approximately 10% of the neutropenic patients with a-streptococcal bacteremia develop ARDS, suggesting that α-streptococcal bacteremia was the main cause of ARDS in the present case. Moreover, the present case possessed HLA-B51, a specific type of HLA strongly correlating to the development of ARDS during administration of G-CSF, which might be associated with the development of ARDS in the recovery phase of WBC count.

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