Today about 70% of the children with leukemia are cured by intensive therapy. Therefore, how to deal with the children and their families before, during, and after the treatment has become a major concern for caregivers. This kind of problem should be considered from an ethical and socio-economic viewpoint as well as from the psychological aspect. We have been trying to establish a good total-care system that fits our society. We have formed medical teams which consist of doctors, nurses, and caseworkers. From our experience, we think the most important principle for the caregivers is frankness. Sometimes this is very difficult. Other important points of total care are mentioned.

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The effect of a recombinant human granulocyte colony-stimulating factor (rhG-CSF, KRN 8601) was studied on 23 pediatric cases (17 boys ; median age, 3 yr) comprising 9 Kostmann, 8 chronic benign, 3 hypogamma-globulinemia-associated, 1 glycogen storage disease Ib-associated, and 2 drug-induced neutropenic patients. rhG-CSF was administered subcutaneously at doses of 50-300 μg/m² or intravenously at doses of 100-200 μg/m², over the periods of 1-10 weeks. Twenty (87.0%) of the 23 patients who had neutrophil counts less than 500/mm³ before therapy, demonstrated significant increase of neutrophils. Patients with Kostmann-type neutropenia responded poorly compared with patients with chronic benign neutropenia. Twenty (80.0%) of the total 25 cases showed no side effects, while 5 cases showed minor side effects, which included 1 case with skin rash at the injection site, 1 case with vomiting, and 3 cases with transient increase of laboratory data ; no interruption of therapy was necessary. Considering both the neutrophil-increasing effect and safety, rhG-CSF is useful for childhood neutropenia.

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We evaluated the clinical usefulness of recombinant human granulocyte colony-stimulating factor (rhG-CSF : KRN8601) in children with neutropenia induced by cancer chemotherapy. In the first course, only chemotherapy was given to observe the degree of neutropenia, and in the second course, rhG-CSF was administered at the dose of 50 μg/m² subcutaneously or 100 μg/m² intravenously once a day for 10 days starting 3 days after completion of chemotherapy. In total, 105 children were treated with rhG-CSF, but 17 were excluded from the evaluation of efficacy and 2 from the evaluation of safety for various reasons. Nadirs of neutrophil and leukocyte number were significantly higher in the rhG-CSF courses than in the controls and the days required to attain neutrophil counts over 500/μl from the start of chemotherapy were significantly shortened by rhG-CSF. Episodes of infection were less frequent in the rhG-CSF phase (26 cases, 29.5%) than in the control phase (42 cases, 47.7%). Thus, rhG-CSF administration was considered to be effective in 64 of 88 cases (72.7%). As side effects of rhG-CSF administration, bone pain (4 episodes), fever (2), and diarrhea (1) were observed in 6 cases (5.8%), but these were not severe and were tolerable. We concluded that rhG-CSF was useful in children with neutropenia induced by cancer chemotherapy.

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The method for detection of TdT-positive cells by flow cytometry and the relation of immuno-logical phenotype in childhood hematopoietic tumor with TdT were investigated. Comparing the levels of TdT in Molt-4 culture cells (T-cell lineage), formalin-methanol fixation was the best method to fix single cells in suspension. In total, 105 patients with leukemia or lymphoma in children were examined for TdT. In ALL, 33 cases of common ALL and 8 cases of T-ALL were all positive for TdT ; out of 13 cases of pre-B ALL, 12 patients were positive for TdT and 1 patient was TdT^-; out of 9 cases of unclassified ALL, 6 patients were positive for TdT and 3 patients were TdT^-. Among 26 cases of ANLL, only 1 patient was positive for TdT. In malignant lymphoma, out of 5 cases with T-cell type lymphoma, 4 cases were TdT positive and 1 case was TdT^-; the 3 cases of B-cell type lymphoma were all TdT^-. These data suggested that the TdT level is important for diagnosis and classification of leukemia and lymphoma.

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The West Japan Pediatric Oncology Group studied the treatment of malignant histiocytosis (MH) and Letterer-Siwe disease (LS) with etoposide (VP16) from November 1985 to May 1988. Seven children with MH and five children with LS ranging in age from 4 months to 14 years old were treated with single VP16 course (4 children) or with VP16 combination chemotherapy (8 children) at the initial phase or at the relapsed phase. Clinical complete remission was achieved in 8 (four single courses, four combination courses) of 12 patients (66%). Partial remission (PR) was achieved in two patients (17%) and nonresponse effect (NR) was seen in two patients (17%). The efficacy rate was 83% for 12 patients. Disease-free survival was 67% from 22 months to 53 months (median, 41 months) after the VP16 therapy. There were no relapsed children who were treated with VP16 alone from the initial phase. Our observation showed that VP16 alone or in combination chemotherapy induced a high response rate and prolonged survival in MH and LS.

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We analyzed the expression of the immunoglobulin p, heavy chain (Cμ) gene and the T cell receptor βchain (Tβ) gene in 24 children with acute lymphoblastic leukemia (ALL). All four T-lineage ALL patients, including two with rearrangement of the immunoglobulin heavy chain (IgH) gene, had abundant 1.3 kb Tβ transcripts and low Cμ gene expression. In contrast, among the 17 B-lineage ALL patients, only six showed high levels of Cμ gene mRNA : two of the eight with Tβ gene rearrangement and four of the nine without Tβ gene rearrangement. The expression levels of the Tβ gene were low or undetectable in all but one B-lineage ALL patient. These data indicate that the detection of gene expression may be a sensitive marker for T-lineage ALL but less sensitive for B-lineage ALL. Three acute undifferentiated leukemia patients displayed rearrangement of both IgH and Tβ genes, but the expression levels of the two genes were low or undetectable. Therefore, determination of the cellular origin of leukemic cells, which display dual rearrangement and lack lineage-associated surface antigens, seems to be ambiguous even when Northern blot analysis of the antigen receptor genes is performed.

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Surface antigens on 227 cases of acute lymphoblastic leukemia (ALL) and 32 cases of non-Hodgkin's malignant lymphoma (NHL) in children were analyzed using a panel of monoclonal antibodies. By immunological criteria, ALL cases were subdivided into 4 major subgroups : common ALL (176 cases); T-cell ALL (14 cases); B-cell ALL (4cases); undifferentiated-type ALL (33 cases). T-cell associated antigens (CD3, CD5, and CD7) were exclusively expressed on T-cell ALL/NHL. On the contrary, B-cell associated antigens (CD19, CD20, and P20 antigen) were demonstrated on the cell surface of common ALL, undifferentiated-type ALL, and B-cell ALL/NHL but not on T-cell ALL/ NHL. Both common ALL cases and undifferentiated-type ALL cases could be subdivided into phenotypically defined subgroups on the basis of CD9, CD10, P20 antigen, and HLA-DR antigens. Cytoplasmic μ chain and CD20 were positive in 16 of 78 cases (20.5%) and 17 of 133 cases (12.8%) of common ALL, respectively. However, no positivity was noted in a group of undifferentiated-type ALL.

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Twenty-three children with acute nonlymphocytic leukemia (ANLL), ranging in age from 1 to 16 years, were treated with the DCVP regimen (DNR, Ara-C, VCR, Pred) or the ACMP 2 step regimen (ADR, Ara-C, Pred, 6-MP) as the induction therapy, and with the modified VAPA therapy as the postremission induction therapy between March 1983 and December 1988. Twenty-two of the 23 patients entered complete remission (CR) (95.7%) after 5 to 7 courses of the DCVP regimen (5 patients) or 1 course of the ACMP 2 step regimen (17 patients). Four patients received allogeneic bone marrow transplantation (BMT) in the first CR; they were regarded as not eligible for entry in the study of our ANLL protocol at the time of BMT. The life table analysis revealed a probability of 44.0% for continuous CR after 80 months and 59.0% for survival. Nine patients relapsed. Four of the 9 patients relapsed under this protocol therapy, and 2 relapsed soon after and 3 about one year after completing the therapy (off therapy). We conclude that more intensive chemotherapy and adequate supportive treatment will be necessary for the improvement of the therapeutic results of childhood ANLL.

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A nontransfused 10-month-old female infant was admitted for recurrent infections and fever. On admission, absolute neutrophil counts ranged from 112 to 998/μl. Antibodies against neutrophils were examined with an indirect immunofluorescence test (GIIFT) and a microleukocyte agglutination test (MLAT). The patient's sera reacted with neutrophils from normal donors on GIIFT and MLAT. The results of a leukocyte cytotoxicity test were negative. These findings suggest that her neutropenia was caused by the autoantibody against neutrophils. Trimethoprim-sulfamethoxazole was given orally at a dose of 6 mg (trimethoprim) /kg/day every other day. Although the neutrophil counts did not increase after the treatment, the frequency of infections remarkably decreased. We conclude that oral administration of trimethoprim-sulfamethoxazole every other day was effective for the prophylaxis of infections of in our patient with autoimmune neutropenia.

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There are some reports describing preleukemic patients with monosomy 7. Recently we had an interesting patient with monosomy 7 who developed erythroleukemia after 1 year and 9 months since the initial presentation. The patient, a 4-year-1-month-old boy, was diagnosed as myelodys-plastic syndrome because of blast cells in both peripheral blood and bone marrow. At this time, chromosome analysis of blast cells showed 45XY, -7 and he was diagnosed as monosomy 7 syndrome. He developed erythroleukemia (FAB; M6) after 1 year and 9 months. At this time, chromosome analysis also showed 45XY, -7. He was treated with low-dose Ara-C but died of aspergillus pneumonia. It is well known that monosomy 7 syndrome is a preleukemic state which develops ANLL on its course, but it is rare that this syndrome terminates in erythroleukemia.

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A 8-year-old boy with severe aplastic anemia responded to cyclosporin A (CyA) alone. He was admitted to our department, with the complaints of pale face and subcutaneous hemorrhage. Peripheral blood examination showed RBC 128×10⁴/μl, WBC 2, 100/μl, granulocytes 252/μl, platelets 11, 000/μl, and reticulocytes 20, 000/μl. Bone marrow aspiration revealed hypocellularity. Bolus methylprednisolone therapy followed with no hematological improvement. Two months after hospitalization, oral administration of CyA at a dosage of 5 mg/kg/day was initiated without support of any other therapeutic modalities. Since the treatment produced no hematological response, after 5 weeks the dosage was increased to 10 mg/kg/day. Following the increase in dosage, hematological conditions showed gradual improvement but the development of renal dysfunction forced a reduction in dosage back to 5 mg/kg/day after 7 weeks. In spite of the dosage reduction, the tendency toward an increase in blood cells continued. Twelve months after the start of CyA therapy, the following results were obtained : Hb 11 g/dl, neutrophils over 1, 000/, al, and platelets over 30, 000/μl. CyA administration was interrupted after 12 months but at present (8 months since the cessation of drug administration), no pancytopenic tendency was recognized.

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We treated one patient with a variant form of acute promyelocytic leukemia (M3V) and two patients with typical M3 according to the FAB classification. In contrast to the typical M3 cases, the M3V case had unique characteristics as follows : skin involvement at the first visit, elevated initial WBC counts (1.5×10¹¹/l), microgranular leukemic cells with specific nuclear lobulation and weak chloro-acetete esterase stain. The M3V case died from brain hemorrhage following a sudden decrease in the antithrombin-III value during induction chemotherapy. On the other hand, the two typical M3 cases were successfully treated with DCMP (daunorubicin + cytarabine + 6-mercaptopurine+prednisolone) and heparin. At present, one of them continues to remain disease-free 5 years after the diagnosis.

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In order to prevent chemotherapy-induced alopecia, a hair grower, Tetaris (Sankei Pharmaceutical Co., Tokyo) was applied to the scalp. Five girls (from 5 to 15 years old) with localized malignant tumors were selected for this study. Thirty grams of Tetaris was applied the day before administration of anti-neoplastic drugs, and thereafter 6 grams was applied every morning and evening for 3 days. In LSA₂-L₂ protocol for non-Hodgkin's lymphoma, a small amount of hair loss was observed. However, alopecia was hardly noticed in the treatments of osteogenic sarcoma including high-dose MTX, ADM, CPM and CDDP. In all 5 cases, Tetaris was effective and all the patients did not suffer from inconveniences in their lives. Though the prevention was successful even in the cases treated with Tetaris alone, we realized that the effect of Tetaris was reinforced by scalp cooling, and hair loss was considerably reduced. A synergestic mechanism between cooling and Tetaris can be expected.

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A 14-year-old boy with a 4-month history of fever and arthralgia was admitted to D.U.H. Osteolytic degeneration of the pelvis and cranial bone was found on X-ray examination. Collapse of the 7th-8th, 11th thoracic vertebrae and the 4th lumbar vertebra was also noted. The lymphnode biopsy from the right inguinal region revealed infiltration of giant tumor cells accompanied with lymphocytosis. By surface marker analysis, the tumor cells were positive for CD30 (Ki-1), epithelial membrane antigen, HLA-DR and leukocyte common antigen. The patient was diagnosed as having Ki-1-positive malignant lymphoma based on the above clinical and laboratory findings, and was treated with chemotherapy according to TCCSG T8801-protocol in addition to radiation therapy for the relief of arthralgia. He has been free from complaints for eight months.

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A 4-year-old boy was diagnosed as having acute lymphoblastic leukemia (ALL, L1 by FAB) in June, 1982. The immunological phenotype showed CD 10⁺ ALL. The patient received standard combination chemotherapy, prophylactic intrathecal methotrexate, and whole-skull irradiation. The initial complete remission was interrupted by his first hematological relapse in 1984. The patient subsequently relapsed with central nervous system leukemia (CNSL) in 1987, when he was treated with chemotherapy and intrathecal methotrexate and attained the third complete remission. In 1989, the patient relapsed again at the testicles and CNS. Systemic chemotherapy and intrathecal methotrexate were continuously given ; however, the patient complained of headache, vomiting, and gait disturbance 10 months later. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a tumor in his right cerebellar hemisphere with secondary hydrocephalus. The patient was histologically diagnosed as having a tumor which consisted of leukemic cells negative for CD10. This rare complication of ALL indicates that MRI is useful for the diagnosis of intracerebellar infiltration of leukemic cells, and that phenotypic change of leukemic cells may have a relationship with the development of intracranial tumor.

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