Recent progress in the study of the genetic basis of cancer, such as genomic stability, DNA repair and cell-cycle control, is changing our insight into how heredity contributes to the risk of childhood cancer. Although familial cancer in children is rare, the role of inherited genes in the etiology of childhood neoplasia needs to be reevaluated. Our progress in understanding the genetic factors predisposing individuals to familial cancer might help to understand the genetic basis of sporadic cases of childhood neoplasia. Recent progress in the study of genetics and hereditary factors of childhood neoplasia is reviewed and discussed.

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An 8-year-old girl with ALL was treated by chemotherapy including L-asparaginase (L-ASP). In the course of the chemotherapy, transient hepatomegaly, fatty liver and type V hyperlipidemia of the Friedrickson classification developed. With the experience of this case, we prospectively measured lipid-related parameters during chemotherapies including L-ASP in 3 ALL cases. Decreased lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activity and apoprotein C-II (apo C-II) were shown in all cases. In one of these cases, a patient eating a sufficient diet, chylomicron and very low-density lipoprotein (VLDL) increased after decreasing LPL and HTGL activity. Low LPL activity resulted from decreased LPL protein and apo C-II protein due to the inhibition of protein synthesis by L-ASP. We confirmed another hyperlipidemia pattern in an 8-year-old girl with ALL. Transient fatty liver and hyperlipidemia with a rapid peak were caused after chemotherapy, while at the same time, increased apoprotein was observed. The results suggest that decreasing LPL and HTGL activity with a protein-synthesis inhibitor by L-ASP causes exogenous hyperlipidemia, accumulation of lipids in the liver with hepatomegaly and transient fatty liver during chemotherapy. Endogenous hyperlipidemia after chemotherapy is caused by the removal of lipids from liver during recovery of the lipid metabolism.

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The incubation of neutrophils with GM-CSF for short time periods at 37°C enhanced their chemotactic activity caused by N-formylmethionyl-leucyl-phenylalanine (FMLP). Longer periods of incubation with GM-CSF diminished the enhancement of stimulated locomotion of neutrophils. Adherence is a fundamental function of neutrophils and should even be important for chemotactic movement. C3bi receptor (CR3), an adhesion molecule, expression was also enhanced with GM-CSF treatment. What mechanism underlies this phenomenon ? It is possible that the best-fit expression of adhesion molecules would enhance neutrophil chemotaxis, and that incubation with GM-CSF for a longer period causes the overexpression of adhesion molecules with a subsequent decrease in neutrophil motility. Actually, the incubation time for the maximal enhancement of the chemotaxis by GM-CSF coincided with the time for the best-fit value of mean fluorescence intensity, and the overexpression of adhesion molecules by phorbol myristate acid (PMA) also showed a biphasic effect on neutrophil chemotaxis in a dose-dependent manner. The augmented expression of adhesion molecules by GM-CSF incubation was largely inhibited by a tyrosine kinase inhibitor. The results suggest that the augmented expression of adhesion molecules on neutrophils by GM-CSF is mediated by tyrosine kinase and affects cellular motility.

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The Bone Marrow Transplantation Committee of the Society has conducted an annual registry of bone marrow transplantations to children in Japan since 1983. As of June 30, 1997, 3, 793 patients had received stem-cell transplantation, an increase of 572 patients from the 1996 registry as registered from 136 institutions. In this paper, the results of the main diseases transplanted between July 1, 1987 and June 30, 1997 were analyzed. The DFS rates of patients with severe aplastic anemia who received an allogeneic bone marrow transplant (BMT) are 86.4±5.8% (mean, 95% CI) for HLA-matched sibling donors and 65.0±17.7% for HLA-matched unrelated donors. The DFS rates of patients with AML who underwent transplants at the time of 1st CR are 65.8±9.3% for HLA-matched sibling donors, 71.3±11.3% for ABMT and 47.9±12.8% for AutoPBSCT. There is a statistically significant difference between the DFS rates of BMT from HLA-matched sibling donors and that of AutoPBSCT (p<0.01). The DFS rates of patients with ALL who underwent transplants at the time of 1st CR are 64.9±9.9% for HLA-matched sibling donors, 57.0±18.5% for ABMT and 58.3± 11.7% for AutoPBSCT. There is no difference statistically among them. The DFS rate of patients with adult-type CML who received BMT from HLA-matched sibling donors at the 1st chronic phase using TBI containing regimens is 86.9 ± 17.1%. The overall DFS rate of unrelated BMT from “donor bank” donors is 50.7±6.8%. Allogeneic cord blood stem-cell transplantation was conducted for 18 children, and 15 of them are alive. Allogeneic PBSCT was performed on 54 children including 35 children treated with CD34-positive selection.

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An eight-month-old boy was admitted to our hospital because of anemia and abdominal distention. Initial laboratory data were as follows ; white blood cell count 23, 890/μl with 90% leukemic cells, red blood cell count 125 × 10⁴/μl, and platelet count 1.3 × 10⁴/μl. The immunophenotype of leukemic cells aspirated from bone marrow was CD 10 (+), CD 19 (+) and HLA-DR (+). The karyotype of leukemic cells was t (4 ; 11) (q21 ; q23) with MLL gene rearrangement. The patient was diagnosed as having infant lymphoblastic leukemia. Chemotherapy was started with VCR, ADR, PRD and L-Asp. Complete remission was obtained 5 weeks after the initiation of induction therapy. Since then, he has been in complete remission for 7 years. Irradiation of the entire brain was performed when he was 27 months old. He developed hypothyroidism 3 months later. The sequential data of serum T3, T4 and TSH levels suggested that thyroid function became defective after the initiation of induction chemotherapy but it recovered during maintenance therapy. It became defective again after irradiation of the brain. Though the prognosis of infant leukemia with MLL gene rearrangement was generally poor, his first remission was maintained over 7 years. We speculated that his favorable clinical course might be related to the positive CD 10 leukemic cells.

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We report on an eight-year-old boy with acute lymphoblastic leukemia who developed pulmonary aspergillosis associated with chemotherapy. He complained of chest pain and dyspnea during prolonged granulocytopenia after high-dose Ara-C, VP-16 and L-asp for peripheral blood stem cell harvesting. Fever and hemoptysis were observed. C-reactive protein and β-D-glucan were elevated. A chest X-ray tomography revealed a fungus ball at the right upper lobe. On the basis of these findings, he was diagnosed as having aspergilloma. He was treated with itraconazole (orally 6 mg/kg/day) and amphotericin B (intravenously 0.5 mg/kg/day). Three months after the start of treatment with itraconazole, the fungus ball had almost disappear-ed. After five months, he received an autologous stem cell transplantation without surgical resection. Plasma concentrations of itraconazole and hydroxy-itraconazole were 250-1, 100 ng/ml after a dose of 6 mg/kg, a higher level than MIC for Aspergillus. Itraconazole can be considered to be a useful oral agent for aspergillosis in children.

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A 4-year-old boy with juvenile chronic myelogenous leukemia (JCML) received an unrelated donor allogeneic bone marrow transplantation. While cyclosporine A (CsA) and short-term methotrexate were given for GVHD prophylaxis, an acute GVHD of grade III and disturbance of consciousness occurred on day 40. The latter was recovered soon after conventional treatments without any abnormality as shown by brain magnetic resonance imaging (MRI). However, the GVHD worsened further, and thus tacrolimus (FK506) was substituted for CsA and methylprednisolone pulse therapy was administered on day 53. His consciousness again began to deteriorate. A brain MRI disclosed a scattered, abnormally high signal intensity on T2-weighted image in his cortex and subcortical white matter areas. On day 93, he suddenly had a convulsion and became unconscious and oliguric. Considering that the condition was an encephalopathy side effect due to FK506, it was dis-continued and CsA was again administered. Thereafter, his condition improved and finally recovered without leaving any abnormality in neurological and MRI findings. It should be stressed that FK506 may have an adverse effect not only on renal function but on the central nervous system as well.

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A 16-year-old girl diagnosed as having a primitive neuroectodermal tumor was treated with New Al protocol and underwent a purified CD34-positive cell autograft derived from peripheral blood after high-dose chemotherapy. The hematological recovery was compared to that of five patients who underwent conventional peripheral blood stem cell transplantation. The number of CD34-positive cells and CFU-GM infused was 1.4× 10⁶/kg and 1.0×10⁵/kg, respectively. G-CSF was administered from day 1. Neutrophils and reticulocytes recovered in a short time, and no significant delay was observed when compared with the PBSCT group. The recovery of platelets and lymphocytes was delayed. The times to a platelet count of 20, 000/μl and lymphocyte count of 500/μl were 112 days and 215 days, respectively. (In the PBSCT group, the means were 11 days and 24.8 days, respectively.) In the PBSCT group, the patient requiring the longest time (61 days) for her platelet count to reach 50, 000/μl was treated with new Al protocol. The time for her CD4-positive cell count to reach 200/Ail was 328 days. Her serum IgG level began to increase after day 200. She developed varicella zoster on day 265. Serum anti-varicella zoster antibody increased significantly at the convalescent phase. Thus, immunological recovery was obtained by day 300. The delay of platelet recovery may have been caused by the New Al protocol and that of lymphocyte recovery by CD34-positive cell purification.

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Two cases with acute leukemia secondary to the chemotherapy for non-Hodgkin's lymphoma (NHL) are reported. One case involved an 11-year-old girl. She has suffered from acute monoblastic leukemia (M5a) six years and seven months after the diagnosis of NHL. The other case is a 5-year-old boy. He has suffered from acute lymphoblastic leukemia seven years and four months from the diagnosis of NHL. It is noted that bothpatients have received LSA₂-L₂ protocol, both had a period of MDS (myelodysplastic syndrome) that developed into acute leukemia, and both had the same chromosomal abnormality of -7. It is suggested that the leukemia of these cases is associated with alkylating agents that were given for treating NHL. Secondary leukemia associated with etoposide is well described, but few leukemia cases secondary to alkylating agents have been reported in Japan.

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We report a case of refractory t (16 ; 21) -acute myelocytic leukemia (AML) with a submandibular tumor formation. The t (16 ; 21) (p11 ; q22) genotype is a rare chromosomal abnormality, and shows no specific tendencies with regard to leukocyte count, age distribution, or gender. Additionally, no t (16 ; 21) cases involving tumor formation have previously been reported. Our patient achieved complete remission by ANLL-91 protocol, but relapsed 11 months after diagnosis during post-remission intensive chemotherapy. After the relapse, he was refractory to all chemotherapy and died at approximately 2 years after diagnosis. Recent reports of t (16 ; 21) -AML cases have also shown poor prognosis. We recommend that a new therapeutic strategy for t (16 ; 21) -AML that includes bone marrow transplantation should be employed.

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