The study group has been sponsored by the Ministry of Health and Welfare of Japan. 2, 659 new cases of leukemia in childhood have been registered with the group since 1986 and followed up. The actuarial event-free survival rate (EFS) of ALL is 60.7 ± 1.4% and that of AML is 44.1 2.7%. For AML, a prospective study named Protocol ANLL91 was started in 1991 and was completed in 1994. The protocol was designed to compare the overall results of allo-BMT and non-allo-BMT groups after natural randomization, and was analyzed according to the intent-to-treat principle. 157 new cases of AML have been registered. The overall remission rate is 91.1% and EFS is 62.7 ± 8.4%. So far, there is no statistical difference between the two groups in terms of EFS. A nationwide survey on secondary leukemia was conducted. Fifty seven cases of secondary hematological malignancies were registered. Translocation involving 11q23 and/or MLL gene (mixed lineage leukemia gene) rearrangement were found frequently in VP-16-related secondary leukemia. MLL gene rearrangement and/or t (11q23) were also found in 72% of the cases of infant leukemia. Analysis of p53 gene mutation was done, and the functions of p53 gene products were studied. Other valuable studies have been done on t (1 ; 19), t (16 ; 21), AML1-MTG8 gene, TAM (transient abnormal myelopoiesis), HPS (hemophagocytic syndrome), cytokines, and so on.

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We treated 18 children, of whom 9 had B-cell lymphoma (B-NHL) and the other 9 had B-cell acute lymphoblastic leukemia (B-ALL), with an intensive short-term chemotherapy regimen “B-88 protocol”. This protocol consisted of high-dose fractionated cyclophosphamide and high-dose methotrexate. Sixteen of 18 patients (89%) achieved complete remission (CR), two of whom relapsed within 5 months. One patient who had completed chemotherapy developed a second leukemia. However, the other 13 patients were maintained their initial CR, and their event-free survival, caluculated by Kaplan-Meier's method, was 72% overall (mean follow-up of 51 months), 58% for stage IV-NHL/ALL, 80% for stage III-NHL and 100% for stage I/II-NHL. We conclude that the B-88 protocol is effective for B-NHL/B-ALL and more than a half of such patients may be curable by treatment with chemotherapy alone. We designed a new “B-93 protocol” involving a lower dose and a shorter duration of chemotherapy for the favorable stage I/II-NHL, and the introduction of high-dose cytosine arabinoside for stage III/IV-NHL/ALL in an attempt to achieve a better prognosis.

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We examined the combined effects of granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) on CPU-GM colony and recovery of granulocyte count after allogenic bone marrow transplantation. Admixture of G-CSF and M-CSF increased the number of CFU-GM colonies (139 ± 61.7) to a greater extent than admixture of G-CSF (66.7 ± 38.8) or M-CSF (64.6 ±27.9) alone. Moreover, the numbers of CPU-GM stimulated by G-CSF and M-CSF together were greater than the sum of CFU-GM stimulated by G-CSF and M-CSF alone. When G-CSF and M-CSF were administered together after allogenic bone marrow transplantation, the granulocyte count recovered by day 11. These data suggested that G-CSF and M-CSF may be administered simultaneously when prompt recovery of granulocytes is required.

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It has been reported that a consistent increase in the numbers of _γδ T cells can be seen within the first 4 months after bone marrow transplantation (BMT), but its mechanism has not been elucidated so far. We serially analyzed the immunophenotype of T lymphocytes of peripheral blood from 7 allogeneic BMT patients (5 with aplastic anemia, 1 with immunodeficiency and 1 with acute leukemia) and 3 autologous BMT patients (2 with brain tumor and 1 with teratoma). The percentage of _γδ T cells in CD3⁺ lymphocytes was increased at days 100-140 after allo-BMT and peaked at 22-28%, then started to decrease at day 160-200. In auto-BMT cases, the same course was observed. Most of the _γδ T cells were CD4^-/CD8^- double negative T cells. In cases of chronic graft-versus-host disease complicated with measles infection, the percentage of _γδ T cells was decreased.

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The increase in the cytosolic free calcium concentration, [Ca²⁺] _i, in activated T cells obtained from healthy children was investigated using flowcytometry. The level of [Ca²⁺] _i in activated T cells, which was increased by cross-linking of CD3 molecules, was found to be significantly higher than that in resting T cells. Interestingly, a similar increase in [Ca²⁺] _i was also induced in peripheral T cells from patients at 2-6 months post-bone marrow transplantation. The analysis of surface phenotype clearly revealed a decrease of CD 45RA₊ cells and conversely an increase of CD45RO₊ cells, both in T cells cultured with phorbol 12-myristate 13-acetate (PMA) plus ionomycin and in T cells from bone marrow-transplanted patients. The proliferative response of T cells stimulated with anti-CD3 monoclonal antibody was normal in transplanted patients. However, stimulation with PMA plus ionomycin significantly reduced the response of T cells in patients, while T cell proliferation was clearly enhanced in healthy children.

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A case of hepatic angiome-multinodulare that regressed naturally is reported. The patient, a 2-month-old boy, had an abnormal hepaplastin test at the age of 1 month, including systolic murmur on the fourth left sternal border, hepatomegaly, and multiple cutaneous hemangiomas, suggesting hepatic angioma of the liver. Roentgenographic examinations demonstrated multinodular masses in the liver that were enhanced by intravenous contrast with computed tomography and magnetic resonance imaging (MRI). Echoscopic examination revealed blood flow and arteriovenous shunting in these masses, leading to a diagnosis of hepatic angiome-multinodulare. Low-dose prednisolone (0.5 mg/kg/day) was the only medication administered, because of the absence of heart failure. Regression of cutaneous angiomas and improvement of hepatomegaly were simultaneously observed at the age of 6 months, and MRI at 20 months was normal. The patient was considered to have hepatic angioma with natural regression. The clinical features of the disease entity and the problems of the therapeutic strategies are discussed.

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IFN-α has antiviral, immunomodulatory and antitumor activity, and thus can be effectively used for treating viral hepatitis and hematological malignancies. We describe here an 8-year-old boy with symptoms suggestive of chronic active EBV infection treated with IFN-α. He had been suffering from recurrent fever, hepatosplenomegaly and pancytopenia for 3 years and a novel herpesvirus, human herpesvirus-7, was isolated from peripheral blood lymphocytes during the clinical symptoms, but subsequently became ineffective. Recombinant interferon-α (IFN-α) was thus administered in consideration of antiviral activity starting from September 1993. However, unusual and life-threatening side effects of this drug, interstitial pneumonitis and renal disturbance, developed with hypercytokinemia after 2 months. These side effects were eliminated through surfactant replacement and plasma exchange.

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Growth and development in a boy with acute lymphoblastic leukemia (ALL) were studied by comparing with his monozygotic twin brother who has been healthy for the whole observation period. The patient was diagnosed as having high-risk ALL at 10 years of age. Subsequently, he was treated with Childrens Cancer & Leukemia Study Group (CCLSG) High Risk 874 protocol, including 24 Gy cranial irradiation. The therapy was successfully completed when he was 13 years old. Since then, he has been in complete remission and now he is 17 years old. The physical growth of the patient was comparable to the Japanese standard. He was 171 cm tall at 17 years of age, while the brother was 182 cm tall. His testicular volume was 12 ml bilaterally, while the brother showed 27 ml. Pubertal voice change in the patient occurred 1 year later than in the brother. Serum gonadotropin levels in the patient were consistently higher than those in the brother. In contrast to these, there were no differences in their school performance and intelligent quotient. In this patient, physical growth was apparently normal, but was markedly retarded compared with his identical twin brother who seemed to be an ideal control.

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Two young children exhibiting severe dyspnea caused by mediastinal non-Hodgkin's lymphoma (NHL) are reported. Both patients were initially treated for bronchial asthma. A 3-year-old boy (patient 1) was referred to our hospital because of progressive dyspnea and an increase in the size of a mediastinal mass. On admission, superior vena cava syndrome and severe cyanosis were found. NHL was diagnosed by biopsy of a cervical lymph node within 23 hours of admission. Tracheostomy was performed, and induction chemotherapy under the mechanical ventilation for 23 days was successful to achieve a complete remission. A 5-year-old boy (patient 2) was referred to our hospital because of progressive dyspnea and mediastinal shift accompanied by right pleural effusion. NHL was diagnosed by cytology of the tumor cells obtained from the effusion. The symptoms improved dramatically following induction chemotherapy, but he died 6 days after initiation of induction chemotherapy because of the abrupt respiratory distress. Mediastinal NHL among younger childhood is rare, which resulted in delayed diagnosis. Such patients require prompt and accurate diagnosis and should be treated as an “oncologic emergency” case.

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We report a case of 3-year-old girl with common ALL who had osteolytic lesions of the hip joint, femur and tibiae, but no bone lesion of vertebra on X-ray survey at diagnosis. Although complete remission was achieved by remission induction therapy (TCCSG L92-13 protocol), severe back pain and multiple vertebral fractures with osteoporosis was presented 2 weeks after finishing the induction therapy. No changes in the osteolytic lesion at the hip joint, femur and tibiae were revealed. Lumbar spinal bone mineral density (LSBMD) was markedly low (0.271 g/cm²) and levels of osteocalcin, pyridinoline, deoxypyridinoline were high. She was treated with 1α (OH) D₃, calcitonin, physical therapy and an orthopedic corset. Back pain disappeared within 3 months, and LSBMD was improved but was still in the low range at 9 months after diagnosis. This case suggests that osteoporosis and multiple vertebral fractures might occur in children during chemotherapy and bed rest. Skeletal survey and BMD measurement may allow early detection of bone alteration.

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