Bone marrow transplantation (BMT) has been increasingly and successfully applied to the treatment of children with potentially fatal leukemias, aplastic anemia, congenital immunodeficiencies, and some forms of inborn metabolic error. Current indications of allogeneic or autologous BMT, recent advances in this treatment, and unsolved problems are reviewed in this article. The biggest difficulty that we are facing is the lack of HLA-identical sibling donors in otherwise eligible patients. Several possible solutions in future may include allogeneic BMT from unrelated histocompatible volunteer donors, autologous transplantation using (un) purged bone marrow, peripheral blood stem cells or in vitro expanded pluripotential stem cells, and gene therapy.

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The hypothalamic-pituitary function in eighteen children aged 1 to 13 years old with acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL), who had received cranial irradiation (XRT) as central nervous system prophylaxis, was evaluated. Pharmacologic stimulation tests with insulin, TRH, and LHRH were performed to investigate secretory function of the anterior pituitary gland, before and after XRT, and at completion of 3 years maintenance chemotherapy. GH responses to insulin-induced hypoglycemic stimuli were subnormal in 3 of 11 patients before XRT, and 4 of 18 after XRT. Pituitary GH secretion after pharmacologic stimulus was little affected by XRT. TSH responses to TRH were decreased in 6 of 11 patients before XRT, 14 of 18 after, and 2 of 7 at completion of chemotherapy. PRL (prolactin) responses to TRH were excessive in 4 of 7 (before), 13 of 18 (after), and 2 of 7 (completion). Impaired secretions of TSH and PRL were found in the majority of patients before irradiation. Therefore endocrinological abnormalities in TSH and PRL secretion after XRT were considered to be caused not only by XRT but also other factors-i.e., TSH suppression by corticosteroid, stress-induced hyperprolactinemia. Gonadotropin secretions were normal after XRT in all patients excent two.

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The present study was carried out to identify the constitution and distribution of the polyamine family in peripheral blood of growing children. Free and conjugated polyamines were investigated in erythrocytes and plasma from 103 healthy children. As a reference, the same amines were also determined in 9 adult volunteers. In summarizing the results of this study, the following evidences were elucidated as characterizing polyamine metabolism in growing children : (1) free polyamines, especially free spermidine in circulating blood, mostly compartmentalized in erythrocytes; (2) higher amount of total polyamines in whole blood, free putrescine in erythrocytes and plasma, free and conjugated spermidine in erythrocytes in the circulating blood. These results of distibution of polyamines in peripheral blood indicated that erythrocyte polyamine levels are mainly related to the fluctuation of polyamine levels in circulating blood. The present evidence also suggests that the enhanced polyamine synthesis in children derives from a large amount of free putrescine from ornithine de novo, as well as that reproduced from N¹-acetylspermidine via the degradation pathway.

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The measurement of Normotest (Hepaplastintest, Eisai Co., Japan) values for infants was carried out at 5 days, 14 days, and 1 month of age in 151 healthy infants, each having received 2 mg of vitamin K² orally at first feeding (group A), or at first feeding and 5 days of age (group B). These measurements revealed a rising in the mean Normotest values. There was no significant difference in the Normotest value between breast-fed and mixed-fed infants at 5 days and 1 month of age in these two groups. The breast-fed infants showed a significantly lower Normostest value at 14 days of age in group A than that in group B. The number of infants with a low Normotest value (<40%) was 11 and 4 out of 151 cases at 5 days and 14 days, respectively, but none of the breast-fed infants in group B showed a low Normotest value at 14 days of age. The results show the possibility that repeated oral vitamin K² administration increases the Normotest value, especially in breast-fed infants, and prevents vitamin K deficiency in infants.

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The effects of several hormones on erythropoiesis were studied clinically and experimentally. In 46 cases with various endocrine diseases, hematological state was assessed. Mild to moderate anemia was found in 25% of the patients with hyperthyroidism, in 55.5% with hypothyroidism, in 25% with pitutary dwarfism, and in 60% with diabetes insipidus. The effects of dexamethasone (DXM), methenolone acetate (MA), triiodothyronine (T₃), and estriol (Estr) on the recovery phase of anemia in rat hemolytic anemia model induced by acetylphenylhydrazine (APH) injection were studied in vivo. And the in vivo effects of those hormones on erythropoiesis of rat bone marrow cells were also evaluated according to CFU-E assay, ³H-thymidine uptake, ⁵⁹Fe uptake, and cyclic AMP synthesis. DXM had no effects in vivo, but some enhancement of cyclic AMP synthesis was observed in the liquid culture containing 2×10^-8 M DXM and 1U/ml of erythropoietin, which indicated a stimulatory effect on the priming of erythropoiesis. MA and T₃ showed significant acceleration of recovery from anemia in the hemolytic anemia model. MA promoted the uptake of both ³H-thymidine and ⁵⁹Fe, suggesting an acceleration of differentiation and maturation in erythropoiesis. T₃ also promoted ⁵⁹Fe uptake, suggesting enhanced activity of maturation. Estr had an inhibitory effect on erythropoiesis in vivo and in vitro.

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For further understanding of the clinical and biological significance of ferritins, intracellular ferritin levels of several kinds of human-derived cells were investigated and some cell lines were analyzed for their ferritin synthesis by radioisotope labeling techniques. Results are as follows : 1) Leukemic cells of acute lymphocytic leukemia showed lower cellular ferritin levels than normal peripheral lymphocytes. 2) Both erythroleukemia cell line (K-562) and monocytic leukemia cell line (THP-1) showed high intracellular ferritin levels, and ferritin was also detected in their tissue culture medium. Other cell lines which showed low ferritin level did not show any ferritin in their culture medium. 3) The level of intracellularly synthesized ferritin was gradually increased in each examined cell line. 4) Release of synthesized ferritin into culture medium was proved only in the high intracellular ferritin group.

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The West Japan Pediatric Oncology Group studied the treatment of pediatric malignant tumors with VP-16 from December 1984 to March 1988. Of 156 cases examined, VP-16 evaluation was possible in 116 cases, including 71 cases of acute non-lymphocytic leukemia, 20 cases of relapsed lymphocytic leukemia, 13 cases of histiocytosis, 7 cases of neuroblastoma, and 5 cases of malignant lymphoma. The efficacy rate was calculated by considering complete and partial remission cases to be effective. The efficacy rates were 87.5% for primary cases of ANLL, 100% for primary cases of histiocytosis, 28.6% for relapsed cases of ANLL, and 40% for relapsed cases of ALL by VP-16 alone. The efficacy rates were 92.6% for primary cases of ANLL, 66.7% for primary cases of histiocytosis, 45.5% for relapsed cases of ANLL, 66.7% for relapsed cases of ALL, and 100% for relapsed cases of histiocytosis by combination therapy with other drugs. Alopecia, gastrointestinal symptoms, and bone marrow suppression were observed, but they presented no significant problems. From our results, we believe that chemotherapy including VP-16 is effective in remission induction therapy for acute nonlymphocytic leukemia.

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We have analyzed the alteration of cyclic nucleotide levels in spleen and bone marrow after acetylphenylhydrazine (APH) -induced anemia. The studies were carried out on male Wistar rats. Rats received an intraperitoneal injection of acetylphenylhydrazine at a dose of 60 mg/kg body weight. Bone marrow and spleen cells were collected daily from the beginning to the recovery stage of anemia. The cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels were determined by radioimmunoassays. The spleen cAMP levels elevated gradually and showed the peak at 6 days after APH injection. The maximum level of bone marrow cAMP was found at 3 days after APH injection. A significant elevation of spleen cGMP level was detected and the maximum was shown at 5 days after APH injection. We have also analyzed the effects of erythropoietin (Connaught, step III) on cAMP levels of rat bone marrow cells suspended with RPMI 1640 medium containing 10% fetal calf serum at different times. Purified erythropoietin produced the increase of cAMP level in fractionated bone marrow cells when incubated with 10^-6 M theophylline (inhibitor to phosphodiesterase). It revealed that the increase of cAMP occurred shortly after adding erythropoietin in vitro. The relation between the initiation of erythropoiesis and increasing intracellular level of cAMP was discussed.

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We investigated the prognosis of 46 children with acute lymphoblastic leukemia who relapsed during or following the initial treatment program of Nagoya Children's Hematology/Oncology Study Group (protocol 7804 and 8104). Overall survival and disease-free survival rates were 24% and 19% at five years, respectively. The prognosis of 34 children in bone marrow relapse was extremely poor, regardless of any other prognostic factors. With regard to the prognosis of 9 children in meningeal relapse, initial remission duration longer than one year was a good prognostic factor after relapse. More intensive treatment including bone marrow transplantation should be employed in patients with bone marrow relapse.

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In October 1987, a 16-year-old female was diagnosed as having an astrocytoma in the left antero-temporal region, 7 years after completing treatment for acute lymphoblastic leukemia (ALL). The patient had been treated for ALL from 1976 when she was five years old, with systemic chemotherapy and central nervous system prophylaxis, consisting of cranial irradiation (1, 920 cGy) and intrathecal methotrexate. When the brain tumor was found, bone marrow and cerebrospinal fluid were negative for abnormal cells. The patient received subtotal resection of the tumor and systemic chemotherapy and attained clinical and radiological improvement for 4 months; however, she eventually relapsed and died in October 1988. A total of 30 glioma cases after treatment of ALL have been collected from the literature, which disclosed very poor prognosis of brain tumors as a second malignancy.

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We describe a 15-year-old girl who was initially diagnosed as having primary aquired sideroblastic anemia (PASA) with chromosome abnormalities and who developed leukemia 6 months later. At the onset of the disease, mild leukopenia and moderate anemia and thrombocytopenia were noted in peripheral blood (PB). The bone marrow (BM) smear exhibited 67 % of ring sideroblasts without excess of blasts, and 3-aminolevulinic acid synthetase (ALA-S) activity of erythroblasts in BM was decreased. Chromosome analysis of BM cells showed-5, -17, -18, -19, +i (17q), +der (19) t (18; 19) (q 11; p13). These findings supported a compatible diagnosis of PASA with chromosomal abnormalities. A T-cell and B-cell line derived from PB of this patient showed normal karyotypes. Transient improvement of pancytopenia was obtained by small-dose Ara-C therapy; however, acute myelomonocytic leukemia developed 6 months after the onset of PASA. The blasts were positive for peroxidase, nonspecific esterase, and chloroacetate esterase, and expressed CD13, CD14, and CD33 antigens. Chromosome analysis revealed increased populations of tetraploid clones with the specific abnormalities observed during the stage of PASA.

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Transient abnormal myelopoiesis (TAM) has been well described in infants with trisomy 21. We report a phenotypically normal newborn infant with hepatosplenomegaly, skin rash, and circulating blastoid cells. Chromosome analysis on peripheral blood cells incubated without PHA revealed 47XY, +21 on all cells.In contrast, peripheral blood cells stimulated with PHA for 72 hours had exclusively 46XY. A biopsy of the skin lesion exhibited infiltration of leukemoid blast cells. Without any anticancer drugs, the skin lesions as well as organomegaly gradually resolved, and leukemoid blasts disappeared from both the peripheral blood and the bone marrow. Subsequent chromosome analysis on peripheral blood cells disclosed normal karyotype. These findings suggest that an abnormal clone with 21 trisomy might be associated with the proliferation of leukemoid blasts in this patient with TAM.

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A case of Castleman's lymphoma in retroperitoneum associated with severe hypoferremic anemia is reported. A 15-year-old boy was admitted to our hospital for further examination of anemia, high level of CRP, and abdominal mass in November, 1987. Laboratory data indicated hypochromic microcytic anemia : (Hb 6.8 g/dl, MCV 53.6 fl, MCH 15.4 pg, Fe 10 g/dl, ferritin 18 ng/ml) Elevated erythrocyte sedimentation rate, high level of CRP over 10 mg/dl, and slight increase of serum IgG were also found. The anemia continued in spite of oral administration of 250 mg/day of ferrous sulfate. Abdominal palpation did not feel any mass but a solid mass was demonstrated in the anterior to the left kidney by abdominal ultrasonography and computed tomography. Angiography revealed a highly vascular mass but ⁶⁷Ga-citrate scintigram failed to demonstrate abnormal uptake. On December 18, a mass measuring 4.0×3.5×3.0 cm was totally resected. It was an enlarged lymph node. Histologically, there were hyperplasia of lymphoid follicles and marked vascular proliferation with thick hyalinized walls. Interfollicular fibrosis and plasma cell infiltration were also shown in some areas. The histological picture was compatible with Castleman's lymphoma, an intermediate type of hyaline-vascular type and plasma-cell type. Anemia and other abnormal laboratory data were normalized after surgery and the patient remains well as of March, 1989.

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Bone marrow transplantation (BMT) was carried out on a 1-year-old boy with congenital pure red cell anemia who did not respond to corticosteroids, cyclophosphamide, and antilymphocyte globulin. Peripheral blood examination at diagnosis showed WBC 6, 900/mm³, RBC 236×10⁴./mm³, Hb 8.3 g/dl, Plat. 62×10⁴/mm³, Reticulo. 0 ‰, and blood type was group O Rh (D) +. He had an HLA identical 4-year-old brother whose blood type was group A Rh (D) +. After he received cyclophosphamide (50 mg/kg for 4 days) and busulfan (3 mg/kg for 4 days) followed by 350 rads of total body irradiation, nucleated marrow cells (2.8×10⁸/kg) were transfused on January 26th, 1987. Short-term MTX and CSA was given to prevent acute GVHD. No evidence of severe complication has developed after transplantation. The recovery of WBC over 1, 000/mm³, neutrophil over 500/mm³, and platelet over 5×10⁴/mm³ was day 19, 28, and 26, respectively. Bone marrow examination on day 58 showed the marked evidence of erythropoiesis and engraftment was confirmed by the blood type on day 120. He has been completely healthy and hematologically normal for more than 2 years. This is the first successful case of allogeneic transplant for congenital pure red cell anemia in Japan.

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