Much progress has been made in the therapy of neoplastic patients in this decade. Amongst prognosis of childhood ALL has been improved remarkably. However, some patients recur despite well-programmed therapies. This might be partly due to the abscence of any information for minimal residual disease (MRD). It has been difficult to effectively monitor the MRD because they are extremely small in number once the patients achieve complete remission. Recently polymerase chain reaction (PCR) has opened a new avenue toward much better diagnosis of MRD. Tumor specific sequences derived from chromosomal translocations or recombination of immunoglobulin or T cell receptor genes are PCR-amplified in 10⁴ to 10⁶ folds in several hours. Currently we are examining MRD in the ALL patients who are treated under the protocols of Children's Cancer and Leukemia Study Group (CCLSG) using TCR δ gene recombination as a clonal marker. The details of the system and part of the results are mentioned in this article.

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By means of a novel method, indirect immune-rosette method, leukocytes obtained from cerebrospinal fluid (CSF) in patients, six common acute lymphoblastic leukemia (ALL), one T-ALL and one T-non Hodgkin's lymphoma, who exhibited pleocytosis during complete remission were evaluated for cell surface antigen expression, together with ten aseptic meningitis with no malignancy as a control. In six out of the eight patients, antigen expression patterns of leukocytes in CSF were coincident with that of lymphoblasts at onset. In these cases cell number was promptly reduced after intrathecal administration of methotrexate. In the remaining two patients, the leukocytes in CSF demonstrated different patterns from those of the lymphoblasts at onset, and they were eventually diagnosed as having aseptic meningitis by their clinical course. The leukocytes in CSF of the two patients revealed multi-clone pattern with CD2, CD3, CD13 and CD14 positive which was exactly identical to that of aseptic meningitis of the control. This indirect immune-rosette method has a great advantage for identification of central nervous system infiltration of malignant cells or viral infection, in that a small number of cells, approximately 100 cells for one antibody respectively, is sufficient for each antigen analysis.

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Proliferating cell nuclear antigen (PCNA) is a nuclear protein associated with the cell cycle. Nuclear PCNA immunoreactivity is found in the proliferative compartment of normal tissues and cells. In these studies, there has been a positive linear relationship between the number of cells with PCNA expression and the number of S-G₂/M phase cells in phytohemagglutinin-stimulated umbilical cord blood mononuclear cells. Human umbilical cord blood mononuclear cells and CD34 cells which are semi-purified hematopoietic progenitor cells showed only very rare (<5%) PCNA immunoreactive cells. After phytohemagglutinin stimulation, PCNA-positive cells were increased in the majority of cells by 72 hours. PCNA-positive cells of cord blood mononuclear cells and CD34-positive cells were increased during 7 to 10 culture days when these cell were stimulated by rhIL-3. Nuclear PCNA immunoreactivity has been expressed also in the proliferative compartment of hematopoietic stem cells. These results appear to be a new method enabling analysis of the proliferative compartment of hematopoietic stem cells.

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A survey was performed to clarify epidemiologic, clinical and pathological features of childhood hemophagocytic syndrome (HPS) in Japan. Over the past 3 years, 98 pediatric patients with HPS (VAHS : 72; MH : 20 ; FEL : 6) were collected from 66 hospitals. In VASH consisting of 40 males and 32 females, a peak age was under 2 years old. Among VAHS cases, Epstein-Barr virus was involved in 28 of the 38 virus infection-proved patients (73.8%). Thirty-one percent (22/72) of the VAHS cases were fatal, with higher mortality for males. In MH consisting of 10 males and 10 females, a peak age was similar to those of VAHS. Seventy-five percent (15/20) of the MH cases were fatal. In MH studied immunohistochemically, pan T-cell markers were highly positive simultaneously with histiocytic markers such as a 1-Antitrypsin, lysozyme, and S 100, indicating that MH is often accompanied with possible neoplastic T-cell proliferation. We assume that the incidence of HPS in childhood in Japan was about 50-70 cases/year, 41% of which were fatal. It was found that the differential diagnosis of VAHS, MH and FEL were difficult even if age at onset, clinical features and laboratory data were taken into account. One problem is that we still do not have any useful methods demonstrating the clonality of histiocytes. To find out the most appropriate therapy for patients with HPS, it is necessary to establish better diagnostic methods that distinguish neoplastic HPS from reactive HPS.

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Five children with B cell lymphoma were treated with the short-term intensive therapy and two of them are still in continuous complete remission for more than two years. Our protocol was based on the strategy of the European and American protocol of B cell lymphoma, that is (1) intensification of early phase of the treatment, (2) intensified central nervous system (CNS) treatment, and (3) shortening of the duration of chemotherapy. Complications were well tolerated, but intensification of CNS treatment introduced the problem of leukoencephalopathy. Because the survival of children with CNS involvement was still poor, bone marrow transplantation needs to be devised for such patients.

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In 29 children with idiopathic thrombocytopenic purpura (ITP), lupus anticoagulant (LAC) and antiphospholipid antibody (APA) were examined to clarify their effects on the bleeding symptom and platelet-associated immunoglobulin G (PAIgG) levels. Our results were as follows. 1) LAC was detected in 15 of 29 patients (19 of 55 samples) with ITP : in 5 of 13 samples obtained from acute ITP, 11 of 32 samples obtained from chronic ITP, 3 of 8 samples obtained from recurrent ITP and 0 of 2 samples obtained from Evans syndrome. 2) The PAIgG levels in LAC-positive samples were significantly higher than in those of LAC-negative samples, and LAC disappeared when the PAIgG levels were normalized in almost all patients whose serial determinations of both LAC and PAIgG were carried out, indicating that LAC influenced the PAIgG levels in patients with ITP. 3) There was no correlation between LAC and APA levels. 4) No correlation was also seen between the severity of bleeding and LAC in their plasmas.

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We evaluated the treatments of aplastic anemia in children with some immunosuppressive agents such as prednisolone (Pred), anabolic steroid (AS), high-dose methylprednisolone (HDMP), antilymphocyte globulin (ALG; Ahlbulin, Green Cross Co., Osaka, Japan), cyclosporin A (CyA) and 7-globulin. Thirteen children with aplastic anemia (6 severe, 7 moderate) were treated in our hospital between 1977 to 1991. Eleven were male and 2 were female and aged from 1 year to 15 years and 5 months (median of 8 years and 6 months). Five cases were treated with combination of Pred and AS. Three of them were effective and achieved complete remission. HDMP was effective in 25% of 8 cases and CyA in 50% of 2 cases. But both ALG and high dose γ-globulin had no hematologic response. Six died, three of them died of infection and the others died of intracranial bleeding. The survival rate was 42.2%. We conclude that it is not enough to achieve the complete remission by the immunosuppressive therapy alone, so bone marrow transplantation will be necessary for the improvement of the therapeutic results of the childhood aplastic anemia.

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A 12-year-old boy was admitted because of persistent fever and tumor of left chest wall. Computed tomography revealed osteosclerotic degeneration of the left 6th rib and swelling of anterior mediastinal lymphnodes. ⁶⁷Ga-scintigram showed accumulation in the left lower chest. The patient was diagnosed as having Hodgkin's disease (lymphocyte depletion type, Clinical Stage IIE-B) based on pathological findings of tumor in the rib. After 3 cycles of COPP therapy, the tumor disappeared but unremitting high fever continued. Instead of COPP therapy, he was treated with ABVD therapy. He has been free from any relapse signs and symptoms for 22 months.

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Forty-eight children underwent peripheral blood stem cell autografts or allogeneic bone marrow transplantation fifty times in total and three patients developed syndrome of inappropriate secretion of antidiuretic hormone (SIADH). We thought that high-dose regimen using 6- [3- (2-chloroethyl) -3-nitrosoureido] -6-deoxy-α-D-glucopyranoside (MCNU) or cyclophosphamide under over-hydration may have caused SIADH. Both serum sodium level and plasma osmolality should be examined frequently during high-dose chemotherapy because of the occurrence of SIADH.

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An 11-year-old boy with T-cell non-Hodgkin's mediastinal lymphoma (T-NHL) was conditioned with marrow ablative chemotherapy without total body irradiation (MCNU 600 mg/m² plus busulfan 16 mg/kg) in the first remission, and subsequently was reinfused with cryopreserved autologous peripheral stem cells containing CFU-GM of 32 × 10⁴/kg (day 0). Prompt reconstitution of hematopoiesis followed and the absolute granulocyte count exceeded 0.5 × 10⁹/l at day 14, and no serious adverse effect was recognized during the hematopoietic recovery phase. The patient suffered with MCNU-induced interstitial pneumonitis at week 7 of transplant, but this was successfully treated with prednisolone therapy. Additional complication of transplant was a minor case of reactivation of herpes zoster virus. He has remained disease-free for 44 months after transplantation. This case illustrates that peripheral blood stem cell transplantation can be an effective therapeutic option in the treatment of T-NHL, allowing curtailment of treatment period.

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Fluconazole is a rather newly invented drug for treatment of fungal infection. It is believed to have a better antifungal effect and fewer important side-effects. An 8-year-old boy with chronic granulomatous disease (CGD) was admitted to hospital for treatment of generalized infection. He had been given various antibacterial agents including sulfamethoxazol/trimethoprim (s/m), since h was 6 years old when diagnosed as having CGD. We started to give him fluconazole because of the probability of fungal infection. About 8 weeks later, we noticed his pancytopenia : Hb 4.4 g/dl; RBC 1.59 × 10/td; MCV 88.7 fl; MCH 27.7 pg; MCHC 31.6%; reticulocyte 6%; WBC 1, 900/id (12% neutrophils ; 86% lymphocytes ; 2% monocytes ; 0% eosinophils); platelets 1.0 × 10/, u, l. Bone-marrow examination revealed normo-cellularity with nuclear-cytoplasmic dissociation and megaloblastic change of erythroid cells. Hypersegmented neutrophils and giant metamyelocytes were also seen. We diagnosed him as having a folate-deficient megaloblastic anemia because his serum folate level was 1.3 ng/ml. His hematological abnormalities recovered to previous levels two weeks after administration of folate (5 mg/day) and discontinuation of fluconazole and s/m. S/m is well known as a causative drug of megaloblastic anemia, but, in this case, re-administration of it did not induce such anemia any more. These findings suggested that fluconazole was the most suspicious drug. We recommend a careful hematological monitoring of patients receiving fluconazole.

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An 8-year-old boy was admitted in February 1990 with a diagnosis of AML (M2). By two courses of BHAC, THP-ADR, VP16 and PSL regimen, complete remission was induced after two months, while marked pyrexia persisted. An ultrasonography (US) and computed tomography (CT) revealed multiple abscesses and suggested mycotic etiology. Splenectomy was done and diagnosed candidiasis. He was also treated by administration of amphotericin B (AMPH) and fluconazole (FCZ) through catheter-inserted portal vein and hepatic artery and 5-fluorocytosine. AMPH was administrated at the total dose of 1, 484 mg from portal vein and 1, 395 mg from hepatic artery. Catheter was inserted in portal vein for 136 days, and to hepatic artery for 87 days. A side effect by AMPH was tolerable. On this therapy, the abnormal low density findings in CT and US disappeared and his condition improved. After discontinuence of AMPH and FCZ from catheter-inserted line, he received bone marrow transplantation (BMT) from HLA-matched family donor. In spite of severe bone marrow suppression, he has been well without recurrence of fungal infection. He has now bee well for one and a half years after BMT.

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Recombinant human erythropoietin (Epo) was administrated to an anemic infant with severe heart failure. He had heart failure due to ventricular septal defect since his birth, and developed anemia during his course. Instead of blood transfusion, Epo was given with a treatment for congestive heart failure. Then heart failure was improved with erythropoietic response.

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We collected umbilical cord blood at the delivery of a baby girl whose elder sister was suffering from a severe type of juvenile chronic myelogenous leukemia and for whom there were no human leukocyte antigen (HLA) -matched relative donors available. Blood from the umbilical cord and placenta was obtained by needle aspiration immediately after the delivery, frozen in a programmed freezer without red blood cell depletion, and preserved in liquid nitrogen. The cryopreserved cord blood contained 0.79 × 10⁸ nucleated cells/patient's body weight (kg), 2.12 × 10⁴ burst-forming uniterythroid (BFU-E) /kg and 2.41 × 10⁴ colony-forming unit-granulocyte-macrophage (CFU-GM) /kg. These numbers were within the reported range associated with successful allogeneic umbilical cord blood transplants. Because HLA typing showed 2 locus mismatched, the baby was not appropriate for a bone marrow donor. Thus, the possibility exists that umbilical cord blood may be a potential source of pluripotential hematopoietic stem cells for allogeneic bone marrow transplantation instead of harvesting bone marrow cells from an HLA-identical sibling in the neonatal period.

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