Prospective randomized control studies have been playing a crucial role in the treatment progress of childhood acute lymphoblastic leukemia around the world. Beginning from the Total Therapy Series of St. Jude Children's Research Hospital, Children's Cancer Group, Pediatric Oncology Group, St. Jude, Dana-Farber Cancer Institute in North America, and Berlin-Frankfurt-Münster (BFM) Study Group in Germany have been leading this field. Since the 1980s, the BFM protocols, their strategy by multi-agent intensive induction and reinduction in particular, have been accepted by many European and developing countries worldwide because of their consistent remarkable improvement in the treatment results of childhood ALL. It seems likely that there will be many modification studies and comparative studies on the basis of BFM protocols in the near future. By reviewing past and current strategies of the study groups overseas, we learn the necessity of consistent efforts to make optimal plans and maintain large-scale highly qualified patient registration and follow-up to produce reliable conclusions.

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The relation between erythropoietin (Epo) and erythropoietic capacity was examined in 11 cases with hemolytic anemia (HA), 12 cases with aplastic anemia (AA), 30 cases with iron deficiency anemia (IDA) and 5 other cases, including 1 case with Dubowitz syndrome (DS). Plasma Epo, various hematologic parameters and peripheral blood erythroid progenitors (BFU-E and CFU-E) were assayed to assess correlation among them. As has been previously reported, a significant reverse correlation between Hb and plasma Epo level was obtained in respective anemic conditions. However, AA showed a higher Epo level as compared to other anemias with compatible lowering of Hb. Furthermore, a significant reverse correlation between Epo and peripheral CFU-E was observed only in the AA cases. With much interest, Epo increased to significant levels (more than 50 mU/ ml) in 3 of 4 HA cases, 3 of 7 AA cases and 1 of 5 IDA cases, in which the subject showed not so marked anemia (Hb≥11 g/dl) and a concomitant increase of peripheral BFU-E was observed, suggesting some stimulus to erythropoiesis was present. A patient with DS, a non-anemic case (Hb =12.5 g/dl) and also without abnormal Hb, showed a marked increase in Epo level (206 mU/ml) which was not associated with any increase of peripheral BFU-E. Theses findings indicate the possibility of an Epo stimulating mechanism beside tissue hypoxia. To understand the mechanism, additional experiments using animals were conducted for this study. Intraperitoneal injection of hemin to rats resulted in a marked increase in plasma Epo levels and a significant increase in reticulocyte counts. The degradating products of hemoglobin such as hemin may contribute to stimulating Epo secretion in various non-anemic condition.

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Thrombomodulin (TM), which is mainly present on the surface membrane of endothelial cells, plays an important role in the prevention of thrombosis. It is also present in a free form, named soluble TM (sTM), in circulating blood and urine. Plasma sTM has recently attracted considerable attention as a marker of protease damage to endothelium. We previously reported the plasma and urine levels of sTM in neonates, infants and children, and showed a good correlation between plasma and urinary sTM levels in healthy children. In this study, we investigated sTM levels in newborns with respiratory distress syndrome (RDS) and chronic lung disease (CLD). Plasma and urinary sTM levels in patients with RDS at birth were not significantly elevated as compared to those in healthy neonates. They were found to be remarkably higher in patients with CLD (plasma sTM 1-6 Ms : CLD ; 21.7 ± 7.2 TU/ml, nonCLD ; 14.9± 3.5 TU/ml p< 0.001, urinary sTM 1-6 Ms : CLD ; 280.3 ±126.3 TU/mgCr, nonCLD ; 132.8 ± 37.3 TU/mgCr p< 0.05). These data suggest that CLD in newborns may be evaluated with serial measurements of plasma and urinary sTM.

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Recent studies have demonstrated that mutations including MLL gene initiating infant leukemia can arise in the uterus during pregnancy. In this study, we performed clinical and epidemiological studies of the patients with infant leukemia who were diagnosed and treated on Kyushu Island between 1990-1994. The proportion of infant leukemia for childhood leukemia was 7.5%; 5.0% in ALL and 13.1% in AML. The incidence of infant leukemia in the same period was 3.96/100, 000 infants/year. However, the proportion and incidence of infant leukemia in the Kyoto area was definitely high ; 12.9% for childhood leukemia and 5.60/100, 000 infants/ year. On Kyushu Island, all but one AML patient who showed 11q2/MLL abnormality were less than 10 months old at diagnosis. Most of the ALL patients with 11q23/ MLL abnormality dieddespite intensive therapy. In a case-control study on risk factors, maternal exposure to organic compounds was found to increase the risk of infant leukemia. In the Kyoto area, other exposures were also found to increaserisk, including antibiotics, herbal medicine or viral infection. These findings suggest some reagents with topoisomerase II inhibiting activity may induce fetal abnormalities or leukemogenesis. An international collaboration study will clarify this hypothesis in the near future.

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We investigated the occurrence of secondary acute myelocytic leukemia (AML) or myelodysplastic syndrome (MDS) in children with acute lymphocytic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) treated with TCCSG protocol. a) ALL : Secondary AML or MDS developed in seven of 1, 209 ALL patients (cumulative risk at seven years, 1.5%). The median time from the initiation of chemotherapy to the development of secondary AML or MDS was 42 months (range, 18 to 79). Four patients developed AML and 3 developed MDS. b) NHL : Secondary AML developed in eight of 38 NHL patients treated with T-8801 (cumulative risk at 70 months, 27.6%). The median time from initiation of chemotherapy to the development of secondary AML or MDS was 29 months (range, 13 to 66). There were no secondary AML patients among the 50 NHL patients treated with other T-NHL protocols or among the 101 NHL patients treated with B-8801 or B-9201. Secondary AML and MDS were resistant to chemotherapy and showed poor prognosis. Chromosomal translocations involving 11q23 were demonstrated in five of 15 patients with secondary AML or MDS.

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The structures of red cell saccharide chain were examined to analyze the abnormal agglutination of red cells in children with congenital chronic pure red cell aplasia (Diamond-Blackfan anemia = DBA) against peanut lectin (PNA, Arachis hypogaea). DBA was diagnosed within one month after birth. It was treated using corticosteroids without blood transfusion. A persistent positive reaction to PNA was seen in the red cells. The abnormal agglutination of the red cells to PNA disappeared after treatment with papain. Therefore, this abnormality may have contributed to sugar chain anomalies. PNA-reactive red cells were also seen in the control cord blood cells and Viblio cholerae (VC) -treated healthy control subjects, but were not observed in children with several types of anemia. The O-glycans were separated from glycoproteins in the PNA reactive red cell membranes by O-glycanase treatment. The O-glycans were subjected to HPLC and a single high saccharide chain peak was eluted after 14 minutes from VC-treated red cells, DBA patients and cord-blood red cells. The peaks in these O-glycans also passed through a PNA-absorbed column, while saccharide peaks were absent in healthy control and anemic patients. The distribution of PNA-reactive red cells in the total red cell population was analyzed by flow cytometry. With VC treatment, most red cells became PNA-positive but only ten percent was positive in DBA patients. The saccharide chain of the red cell membrane in DBA patients showed similar properties to the immature chain of cord-blood red cells or to the loss of sialic acid from O-glycan in VC-treated red cells in which a complete saccharide chain of sialic acid was lost. Therefore, abnormal saccharide chains expressed on red cell membranes may induce anemia in DBA patients.

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Thirty-five children with high-risk leukemia received an allogeneic bone marrow transplantation (BMT) following a pre-conditioning regimen consisting of total body irradiation, thiotepa and melphalan. Twenty-one patients had acute lymphocytic leukemia, 6 acute nonlymphocytic leukemia, 2 acute undifferentiated leukemia, 2 acute mixed lineage leukemia, 2 myelodysplastic syndrome and 2 juvenile chronic myeloid leukemia. Sixteen patients received BMT while in complete remission (CR), but 19 were not in CR. Eighteen patients received transplants from HLA-matched related donors, 15 from unrelated donors and 2 from HLA-mismatched related donors. Cyclosporin ± methotrexate was used for graft-versus-host disease (GVHD) prophylaxis in the BMTs from related donors and tacrolimus ± prednisolone in the BMTs from unrelated donors. Transplant-related death occurred in 12 patients; 5 acute GVHD, 4 infections (3 fungal infections, 1 Cytomegalovirus pneumonia), 1 intracranial haemorrhage and 2 chronic GVHD. Relapses were observed in 6 patients (69, 168, 175, 222, 275 and 609 days post BMT). Event-free survival rate at 2 years is 38.1% in CR patients and 36.9% in nonCR patients.

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A 4-year-old girl developed Epstein-Barr virus (EBV) -associated peripheral T-cell lymphoma (PTCL), showing hemophagocytic lymphohistiocytosis. Bone marrow smears showed an increase of atypical immuno-blasts with mature T-cell antigens and some histiocytic hemophagocytes. Southern blot analyses of bone marrow cells by TCR C-β-1 and EBV terminal probes revealed the monoclonal proliferation of EBV-infected T-cells. The patient received HLH-94 protocol and achieved remission in a month. At 50 days after the onset, however, the disease recurred. Combined chemotherapy with cyclosporin A improved her condition transiently. At the 7th month, she received an allogeneic bone marrow transplantation (BMT) from her HLA-identical brother. She is doing well 6 months after the transplantation. It is suggested that allogeneic BMT is an effective treatment for refractory EBV/PTCL.

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We report the therapeutic results of allogeneic bone marrow transplantations (BMTs) for 4 pediatric patients with refractory leukemia. The conditioning regimen consisted of total body irradiation (TBI), busulfan (Bu) and melphalan (L-PAM). Three recipients received marrow cells from HLA fully matched related donors and one from one locus-mismatched unrelated donor. All 4 cases were given methotrexate and cyclosporinA for graft-versus-host disease (GVHD) prophylaxis. Three of the 4 cases developed gradeIII to IV acute GVHD, 2 of which required FK-506 for disease control. In 2 evaluable cases, chronic GVHD was not noted. Although all cases suffered from severe mucositis mainly due to the adverse effects of L-PAM, none had mortal regimen-related-toxicity. After BMT, no leukemic relapse occurred, and 2 of the cases have continued complete remission for 24 months and 14 months. Two patients died from complications, one on day + 120, from acute renal failure caused by rhabdomyolysis, and the other on day + 56, from cytomegalovirus pneumonitis. These results suggest that the combination of TBI, Bu and L-PAM as a BMT regimen could be effective for pediatric patients with refractory leukemia.

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We report a case involving a 4-year-old boy with osteosarcoma. He failed to respond to chemotherapy according to the Rosen T-12 protocol and to surgical operations, and relapsed. He had multi-relapse in the lung and brain after one year. Therefore he underwent mega-dose chemotherapy followed by 8 autologous bone marrow transplantations. Multidisciplinary treatment included 6 surgeries, radiotherapy of a total 30 Gy and mega-dose chemotherapy with autologous BMT 8 times. The patient obtained disease-free survival for one and a half years, though he later died because of mandibula relapse. Mega-dose chemotherapy followed by plural autologous stem cell transplantation for advanced osteosarcoma will be useful to get complete remission in the future.

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We report a rare case of autoimmune hemolytic anemia (AIHA) with reticulocytopenia and erythroblastosis in peripheral blood. A 9-month-old boy was admitted to our hospital because of a pale face and general malasis. Peripheral blood revealed RBC 168×10⁴/μl, Hb 4.7g/dl, reticulocyte 15‰ (25, 100/μl), nucleated RBC (NRBC) 3/200 WBC, WBC 20, 400/μl and T. bilirubin 2.0mg/dl. Both direct and indirect Coombs tests were positive and anti-e antibody was identified. The patient was diagnosed as having AIHA and treated with prednisolone (2mg/kg/day) and gammaglobulin (400mg/kg/day for 5 consecutive days), but hemolysis with reticulocytopenia and erythroblastosis in the peripheral blood continued in spite of the therapy. These findings suggest that not only mature RBC but also reticulocytes were destroyed. Pulse therapy with methylprednisolone was employed and a dramatic improvement of hemolysis was noted. The boy was in complete remission for two years after onset.

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