Drug resistance is one of the main causes of the ultimate failure of chemotherapy in childhood leukemia. I summarize the development and the results of a literature review on in vitro sensitivity in childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), focusing on studies using the 3- (4, 5 dimethylthiazol-2-yl) -2, 5-diphenyl-tetrazolium bromide (MTT) assay. Cell biological features and clinical response to chemotherapy are related to in vitro drug sensitivity. In ALL in vitro sensitivity to prednisolone, L-asparaginase and vincristine are significantly related to the clinical response to combination chemotherapy. In AML, however, an extensive study is required to establish the clinical value of drug sensitivity testing. Possible clinical applications of MTT assays include risk-group stratification, individualized tailored therapy, and rational improvements of current treatment for subgroups of patients with infantile ALL and with Ph₁-positive ALL. The resistance profiles obtained by in vitro testing may be helpful in the rational design of further treatment protocols.

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In Japan, informed consent is obtained in a clinical setting from adult patients or parents of pediatric patients, and pediatric patients rarely receive sufficient explanations about their disease and the treatments to be given. Medical professionals, especially physicians, should respect the rights of pediatric patients. When a pediatric patient is considered able to give informed consent, the medical professional should make every effort to obtain informed consent from the patient by fully explaining the disease and treatments to be given, requesting the understanding and cooperation of the parents. Even if the patients appears to have only limited ability to give informed consent, medical professionals should provide explanations using simple terms and pictures to inform the patient about the disease. Informed consent of pediatric patients is especially important in cases of leukemia, hemophilia, or other intractable hematological/oncological diseases for which a wide range of treatment options are available, some of which often have significant late effects.

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In the Japan Association of Childhood Leukemia Study (JACLS), 177 patients with newly diagnosed non-Hodgkin's lymphoma (NHL) from January 1991 to September 1997 were retrospectively enrolled to analyze their clinical and biological characteristics. They were 0 to 15 years of age (9.14±3.78 years), and the male-to-female ratio was 2.6. Eighty one percent of the disease originated in the neck, thorax, or abdomen. Seventy-three percent of the patients were in an advanced stage. B lineage immunophenotype was identified in 55% of the patients. Histological types include Burkitt's lymphoma in 25.4%, lymphoblastic lymphoma in 24.9%, and diffuse large-cell lymphoma in 20.9%. The probabilities of 5-year overall and event-free survival were 77.1% and 68.1%, respectively. The unfavorable factors for survival included male ; T-cell immunophenotype ; stage III, lymphoblastic histology; and failure of induction therapy.

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A 13-year-old ABO-O Rh D positive girl with ALL received a bone marrow transplant from her HLA genotypically identical, but ABO-A Rh D positive, brother. Short-term methotrexate and cyclosporine were administered for prophylaxis of graft-versus-host disease. Engraftment of myeloid and megakaryocytic lineages was normal, but erythroid engraftment was merely postulated. Anemia did not improve even with the administration of prednisolone. On day 87 bone marrow aspirate revealed that erythroid precursors were markedly decreased, hemoglobin was decreased to 5.3 g/dl, and reticulocyte was 3‰. On day 95, methyl-prednisolone (m-PSL) was administered intravenously at a dose of 20 mg/kg. The next day, her liver function was worse and m-PSL was discontinued. On day 124 reticulocyte was 94‰, on day 138, hemoglobin was increased to 11.8 g/ dl. On day 87 her anti-A agglutinin titer was 1 : 128, and on day 138 it decreased to 1 : 1. These observations suggest that anti-A agglutinin correlated with a risk factor for the development of pure red cell aplasia (PRCA). In conclusion, in consideration of the possibilities of PRCA after major ABO-incompatible allogeneic BMT, a study is needed to determine an appropriate treatment for PRCA.

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We had a rare case of a 13-year-old girl with an acute myelogenous leukemia (FAB : M2) of 8 ; 21 chromosome translocation who had an intermittent extramedullary relapse on breast and uterus. She received allogeneic bone marrow transplantation (allo-BMT) from her HLA-matched sibling at first remission. Twenty-three months after the allo-BMT, she had an extramedullary relapse on her breast. The second remission was induced by reinduction chemotherapy and donor leukocyte infusion (DLI) therapy. But 37 months after the allo-BMT, she had a second relapse on her extramedullary site of the uterus. We started reinduction chemotherapy to do a second allo-BMT. Unfortunately, she died 68 days after her last admission because of an uncontrollable infection. We chose reinduction chemotherapy and DLI at the first extramedullary relapse, but she could not sustain long-term remission. For this reason, therapy at the first relapse may have been insufficient. In conclusion, we believe that the extramedullary relapse, as in our case, needs more aggressive therapy, which may include a second BMT.

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We report two patients with aplastic anemia who developed hepatocellular adenoma after long-term therapy with oxymetholone. Patient 1. A 20-year-old male was diagnosed with severe aplastic anemia at 13 years of age. Six years after the start of oxymetholone therapy (total dose 125 g), the patient developed multiple hepatic tumors. These tumors regressed after cessation of oxymetholone, but he died of sepsis. Tumors were confirmed to be hepatocellular adenoma by autopsy. Patient 2. A 22-year-old male was found to be anemic at age 7 and diagnosed as having aplastic anemia. He underwent oxymetholone therapy (226 g) for 14 years. A liver biopsy from the left hepatic lobe was performed. The mass was suspected to be hepatocellular adenoma. A tendency for it to regress was noted after the withdrawal of oxymetholone. The patient underwent bone marrow transplantation from his older brother, and his hematological data recovered. The main cause of death from hepatic tumor occurrence in these cases was sepsis, bleeding tendency, and rupture of the tumors. A follow-up of hepatic tumor by echogram and treatment of the original disorder after the cessation of drugs are important in cases of this kind.

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A radiation-induced osteochondroma (OC) is one of the common complications in long-term survivors of childhood malignancy. It was reported that OC was associated with localized high-dose irradiation to the tumor bed. We experienced four cases that developed OC after bone marrow transplantation (BMT) for childhood malignancy from September 1982 to September 2000. They were all boys and less than eight years old when they received conditioning based on total body irradiation (TBI). In the same period, there were 58 survivors after BMT with TBI-based conditioning. The duration between BMT and the diagnosis of OC was more than 3 years. All four cases presented multiple bone lesions. OC was not observed in patients that received non-TBI conditioning. TBI appears to have an effect on the pathogenesis of OC.

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A 7-year-old girl developed moderate aplastic anemia. Hematological findings were not improved by various types of treatments. There were no HLA-matched donors for the bone marrow transplantation. She required frequent red cell transfusions since 1991. Because the patient complained of general fatigue and edema on the lower extremities in fall 1999, she was admitted to our hospital for further examinations. Thyroid hormone values were below the normal range, and TSH levels were extremely high. Echography showed thyroid gland atrophy. Furthermore her thyroid gland displayed low-signal intensity in both T1- and T2-weighted magnetic resonance imaging (MRI). Coupled with pancytopenia, high values of serum iron and ferritin, frequent red cell transfusions, and abnormal findings of the liver, spleen, and pancreas on computed tomography and MRI, she was diagnosed as having primary hypothyroidism as a result of hemochromatosis. Thyroid function was improved by the treatment with thyroid hormone. Thus it is important to study prognostic factors for the appropriate treatment of moderate aplastic anemia.

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We successfully performed granulocyte transfusions for an 11-year-old boy with acute myeloblastic leukemia who developed cervical phlegmone with profound neutropenia after chemotherapy. Initial induction therapy failed and salvage therapy was then performed. Despite the administration of appropriate antibacterial agents, he developed right cervical phlegmone caused by Pseudomonas aeruginosa. After obtaining an informed consent for G-CSF administration and granulocyte donation from his father, who was ABO compatible, we collected, respectively, 1.2 × 10¹⁰ and 2.2 × 10¹⁰ granulocytes following the second and third doses of G-CSF. Granulocyte concentrates were infused with 15 Gy immediately for 2 hr after irradiation and yielded complete recovery. No adverse reactions were observed. Our findings suggest that granulocyte transfusions are useful for critically ill patients with severe neutropenia.

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We report a case involving a 13 year-old-boy who first presented with severe abdominal pain and convulsion. He was ultimately diagnosed with varicella-zoster virus (VZV) reactivation following bone marrow transplantation (BMT). At 12 years of age, the patient was diagnosed with acute lymphoblastic leukemia. He underwent treatment with BMT from an HLA-matched related donor during the first complete remission. As chronic graft-versus-host disease occurred, treatment with cyclosporin and prednisolone was initiated. Six months after BMT, the patient complained of severe upper abdominal pain, which did not improve with the administration of H₂-blocker or pentazocine. Three days after the onset of abdominal pain, the patient developed general convulsions. Magnetic resonance imaging (MRI) of his brain detected an abnormal T2 high-intensity lesion in the region surrounding the falxus cerebri. Upper gastrointestinal endoscopic findings suggested erosive esophagitis/gastritis. On the fourth day after symptom onset, vesicular rash covering his entire body was observed. A reactivation of VZV was diagnosed, and he was started on acyclovir therapy. Soon after the start of therapy, abdominal pain and skin rash improved. No recurrence of convulsion was detected. High anti-VZV antibody titers were observed, and VZV DNA was detected by an endoscopic biopsy probe (by polymerase chain reaction). The presenting symptoms of visceral VZV reactivation may lack skin rash. Early precise diagnosis is needed because of the high mortality associated with this disease.

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A one-year-old boy with juvenile myelomonocytic leukemia underwent bone marrow transplantation from an unrelated female donor. The conditioning regimen included busulfan, cyclophosphamide, cytarabine (Ara-C) and GVHD prophylaxis short-term methotrexate, and cyclosporine A (CsA). On day 22, engraftment was observed, and a previously detected huge splenomegaly was shown to have improved. On days 28, 43, and 69, the male karyotype was detected at a rate of 12/1, 000, 12/1, 000, and 34/1, 000, respectively, by the FISH method, and splenomegaly was increased. After the patient was diagnosed as being in relapse, CsA was discontinued to induce the GVL effect. Rash with itching and severe diarrhea were noted, and the patient was diagnosed as having GVHD (grade III). GVHD improved in response to administration of prednisolone and CsA. After GVHD, no male karyotype was detected, and splenomegaly again improved. The present case suggests that the GVL effect occurs in JMML and that induction of GVL by a cessation of immunosuppressant may be effective in cases showing relapse after hematopoietic stem cell transplantation.

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We report a male infant with acute lymphoblastic leukemia (ALL) who received hematopoietic stem cell transplantations (HSCTs) three times. At the age of seven months, he was diagnosed as having ALL with t (9 ; 11) (p22 ; q23) and MLL rearrangement. At his initial presentation, a cutaneous invasion of leukemic cells and marked hepatosplenomegaly were observed as an extramedullary manifestation. Both his first and second bone marrow transplantations were performed from an HLA-identical sibling. Preconditioning regimens consisted of busulfan (BU) + cyclophosphamide (CY) + etoposide (VP-16), and CY + 12 Gy total body irradiation in the first and the second HSCT, respectively. Testicular relapses occurred at 6 and 4 months after each HSCT. HLA-matched unrelated cord blood transplantation was performed as his third HSCT with a preconditioning regimen of BU + CY +thiotepa. At the time of each HSCT, his bone marrow was in complete remission (CR). Although grade I acute graft-versus-host disease was positive after the third HSCT, no other severe treatment related toxicity was observed. He remains in CR at 8 months after the last HSCT. Although repetitive HSCTs are considered to be a therapeutic option for intractable infant ALL, a preconditioning regimen including prophylactic testicular irradiation may be necessary for a male patient with an initial extramedullary disease.

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We report a 4-year-old boy with fasciitis of musculus platysma as a manifestation of chronic graft-versus-host disease (GVHD). He underwent allogeneic bone marrow transplantation from an HLA 1-locus mismatched mother for myelodysplastic syndrome. The prophylaxis for his acute GVHD consisted of short-term methotrexate and cyclosporin A. On day 72, he developed thrombocytopenia and liver dysfunction corresponding to grade II acute GVHD. These findings resolved in response to prednisolone and tacrolimus, which were discontinued on day 139. However, bilateral neck swelling, generalized skin rash, and photophobia with keratoconjunctivitis sicca developed on day 182. Laboratory examination revealed eosinophilia, liver dysfunction, and elevation of serum aldolase. A T2-weighted MR image showed hyperintensity of the fasciae of bilateral musculus platysma and the surrounding subcutaneous tissue. A full-thickness skin-muscle-fascia biopsy taken from the right leg showed chronic GVHD and early signs of fasciitis. After treatment with prednisolone and tacrolimus, the patient's skin rash, eosinophilia, and liver dysfunction rapidly disappeared, and the fasciitis of musculus platysma improved four months later. This is the first case report of fasciitis developing on the neck as a manifestation of chronic GVHD.

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