Patients with chronic granulomatous disease are “experiments of nature.” An abnormality of genetic coding of a small part of a protein (cytochrome b) in the membrane of phagocytic cells results in abnormal oxidative metabolism of these cells. The metabolic defect is critical for production of reactive oxygen radicals, which are necessary for efficient intracellular killing of catalase-positive bacterial and fungal species within phagocytic vacuoles.
Patients with CGD suffer recurrent severe and often life-threatenting infections with these same species of bacteria and fungi. Thus clinical evidence is provided for the importance of a normal oxidative response of phagocytic cells during the engulfment process for normal host defense against bacteria. Investigators, intrigued by this remarkable biochemical clinical correlation, have studied human granulocytes with the tools of modern molecular genetics. The abnormal gene has been located and defective-gene products have been identified in CGD patients. This knowledge has provided a basis for therapy of CGD patients with human recombinant interferon gamma, an immunomodulator which stimulates NADPH-oxidase activity in the abnormal granulocytes.
Other treatment and replacement modalities are anticipated but most importantly these CGD patients have provided insights into the usually hidden mysteries of nature. We are very grateful to these patients as our teachers.

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Phorbol ester is synergistic with dexamethasone to cause cytotoxicity to CEM-C7 T-leukemia cell line. Saturation of the specific binding by using [³H] phorbol 12, 13-dibutyrate occurs at a concentration (approx. 100 nm/l) consistent with causing maximal cytotoxicity. The number of binding sites is 194, 000 sites per cell. Phorbol ester has synergistic cytotoxicity to CEM-C7 cells in the presence of 30 nm/l dexamethasone. The synergism of phorbol esters and dexamethasone on CEM-C7 cells is reversible by 1- (5-isoquinolinyl-sulfonyl) -2-methylpiperazine (H-7). However, by treating CEM-C7 cells with TPA for 2 days there is not any increase in the affinity or glucocorticoid receptor levels. It is concluded that phorbol esters may play an important role linked to the glucocorticoid-induced cytotoxicity to CEM-C7 T-leukemia cell line.

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Thirty-two children with acute nonlymphocytic leukemia (ANLL), acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia (CML) were studied by chromosomal banding techniques, and hematologic and clinical evaluations. Nine of 11 children with ANLL showed abnormal karyotypes. A relationship was noted between chromosome patterns and morphologic classes of leukemic cells. In bone marrow cells, t (8 ; 21) was observed in three children with M2-type leukemia, all ofwho m had tumor formation. One patient with M2 exhibited a t (16 ; 21). One child with M3 ANLL had a t (15 ; 17) and one with M4Eo ANLL had an inv (16). One child with M6 had trisomy 8. An abnormal karyotype was found in 10 of 19 children with ALL. Three cases had hyperdiploid. The prognosis of ANLL patients with abnormal karyotypes seemed poorer than that of those with normal karyotypes. The prognosis of ALL patients with hyperdiploid karyotypes appeared better than that of those with other karyotypes. In some cases, serial cytogenetic analysis revealed a relation between the clinical courses and the karyotypic changes, and it was useful for detection of minimal residual disease.

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From December 1976 through December 1988, 29 episodes of septicemia occurred in 65 children with hematological diseases (45 patients with leukemia, 12 patients with malignant lymphoma, and 8 patients with aplastic anemia) at Asahikawa Medical College Hospital. Among 29 episodes of septicemia, 14 occurred in children receiving long-term (more than 3 weeks) oral trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis. Gram-negative rods were isolated from 11 of 14 episodes (79%). Susceptibility test was performed in 10 strains of 11 gram-negative isolates using the disk diffusion method on Muller-Hinton agar plates, and 7 strains were resistant to TMP/SMX. All of the 3 E. coli isolates were resistant to TMP/SMX. In our hospital, TMP/SMX prophylaxis was started in 1979. Septicemia due to TMP/SMX-resistant organisms increased from 1981. Our experience demonstrates that fatal septicemia with resistant gram-negative rods can occur in children with hematological diseases even during long-term oral TMP/SMX prophylaxis.

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Growth in height was surveyed in 180 patients with acute lymphocytic leukemia in continuous first complete remission, who were registered in the Children's Cancer & Leukemia Study Group (CCLSG) from 1981 to 1987. Central nervous system prophylaxis consisted of cranial irradiation at a total dose of 18 Gy or intravenous high-dose methotrexate. Chemotherapy was given for 3 years. More intensive chemotherapy including cyclophosphamide and Adriamycin was given for children in the high-risk group. One of 125 children in the standard (low & intermediate) risk group and 12 of 55 children in the high-risk group showed a decrease in the rate of growth in height, which was less than -2SD. Age of onset in the 13 children was more than 9 years old and growth failure was recognized during prepubertal periods. Moreover, 12 of 13 children showed a tendency towards delayed pubertal development, but 6 of 12 children had later catch-up growth with pubertal maturation after completion of chemotherapy. Thus, chemotherapy temporally contributed to growth failure and gonadal impairment during prepubertal periods. Although, there was no relationship between cranial irradiation (18 Gy) and growth failure, further study is necessary to determine the long-term effects of irradiation on growth.

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We analyzed multidrug-resistance gene (mdr-1 gene) expression in 56 children with leukemia. The mdr-1 gene encodes P-glycoprotein whose expression correlates with resistance to multiple antineoplastic drugs. Two onset samples, one from a patient with common acute lymphoblastic leukemia and the other from a patient with myeloid blast crisis of chronic myelogenous leukemia, demonstrated mdr-1 gene expression. The former case achieved complete remission but the duration of remission was very short and the patient died 9 months after onset. The latter case did not respond to chemotherapy and the patient died 8.5 months after onset. These two patients may be examples of multidrug resistance associated with overexpression of the mdr-1 gene. The other 54 patients, comprising 31 patients analyzed at the time of onset and 23 patients at relapse, did not show detectable mdr-1 gene expression. These data suggest that childhood leukemic cells infrequently express the mdr-1 gene and it may not be involved in relapse of these diseases.

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The biological characteristics and prognosis of childhood extra-nodal non-Hodgkin's lymphoma (NHL) were analyzed during the period from 1974 to 1985. Out of 408 cases with NHL, 139 cases were diagnosed as the primary lesion on extra-nodal. The primary sites of extra-nodal NHL were 53 cases on the head and neck, 35 on the abdomen, 14 on the skin, 10 on bone, 8 on the central nervous system, and 19 on other tissues and organs. The ratio of male to female was 2.2. The average age at onset was 7.1 years old. The pathologic type was 95% diffuse type [lymphoblastic (27%); large cell (25%); medium-size cell (22%); undifferentiated, Burkitt's/non-Burkitt's (16%); miscellaneous (5.7%)]. The phenotype was 11% T-cell, 59% B-cell, and 26% non-T and non-B cell. The clinical stage, which was determined by Murphy's criteria, was 13% at stage I, 34% at stage II, 27% at stage III, and 27% at stage IV. The remission induction with initial treatment was achieved in 79%, and leukemic conversion and CNS invasion during the course of disease occurred in 9.2% of all cases. The 7-year survival rate, which was estimated by Kaplan-Meier's method, was 59%. The survival rate in the cases presenting on bone was poorest. The major biological characteristic of extra-nodal NHL in Japan was a lower incidence of abdominal Burkitt's lymphoma.

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The Bone Marrow Transplantation Committee of the Society has conducted an annual registry of bone marrow transplantation in children in Japan since 1983. As of June 30, 1989, 540 patients had received transplants and were registered from 52 institutions. Bone marrow transplantation was performed in 136 cases of acute lymphoblastic leukemia (58 alive), 113 cases of acute nonlymphoblastic leukemia (74 alive), 33 cases of chronic myelocytic leukemia (27 alive), 5 cases of juvenile-type chronic myelocytic leukemia (4 alive), 39 cases of non-Hodgkin's lymphoma (22 alive), 97 cases of malignant solid tumors (46 alive), 71 cases of aplastic anemia (64 alive), 26 cases of severe combined immune deficiency (9 alive), and 20 other cases (16 alive). The details are reported in this paper.

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An 11-year-old girl presented with a history of a pale face and easy fatigability. Physical findings showed no hepatosplenomegaly and lymph adenopathy. Examination of peripheral blood showed severe anemia with no thrombocytopenia and normal counts and differentiation of leukocytes. Bone marrow aspiration was unsuccessful. Trephin biopsy revealed marked myelofibrosis with deeply suppressed erythropoiesis, slightly increased megakaryocytes, and normal differentiation of myeloid series. Immature blasts were detected below five percent. Another notable examination was trisomy 8, which was observed in all the metaphases analyzed from unstimulated peripheral blood. Under the diagnosis of acute myelofibrosis she was mainly observed conservatively. Treatment with corticosteroid and anabolic steroid was of no benefit. Ten months later, immature blasts appeared in the peripheral blood. A diagnosis of acute myelomonocytic leukemia was made by cytochemical, immunological, and electron microscopic studies of the blasts.

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Combination therapy with high-dose methylprednisolone (m-PSL) and irradiation was performed in an infant with Kasabach-Merritt syndrome. She was a two-month-old infant with a giant hemangioma-29 cm in diameter-around her left thigh. After open biopsy in the center of the tumor, the size of the tumor increased up to 40 cm in diameter. Abnormal findings of blood coagulation data and thrombocytopenia appeared at the same time and showed DIC. Initial treatment for DIC and hemangioma consisted of heparin, gabexate mesilate (FOY), antithrombin III (AT-III) and irradiation however, all proved ineffective : the size of the hemangioma remained the same and frequent transfusions including platelet and fresh frozen plasma (FFP) were necessary. There was quick response to high-dose m-PSL therapy combined with irradiation as the second treatment. The tumor decreased and no transfusion was necessary. The combination of high-dose m-PSL and irradiation therapy thus proved to be a useful treatment for life-threatening DIC complicated with bleeding after performing the biopsy in the hemangioma.

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A 13-year-old girl with T cell ALL with hyperleukocytosis, tumor lysis syndrome, intracranial hemorrhage, and diabetes mellitus was reported. She presented anemia, bleeding tendency, hepatosplenomegaly, and lymphadenopathy. The white blood cell count was 730, 000/μl with 90% leukemic cells. The bone marrow contained 95% leukemic cells which were considered to be T cell ALL morphologically, cytochemically, and immunologically. Serum creatinine was 5.8 mg/dl and uric acid 17 mg/dl. Leukapheresis was performed three times during the chemotherapy (HEX, TCLSG-11-protocol). First leukapheresis lowered the blood viscosity from 9.72 to 6.06 and the white blood cell count from 770, 000 to 640, 000/μl. Insulin in therapy was initiated because of diabetes mellitus induced by prednisolone and L-asparaginase. Intracranial hemorrhage was judged by computed tomography without neurologic symptoms. Although she achieved a complete remission, she died of pneumonia and leukemic relapse, 13 months after diagnosis.

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We report a Pakistani boy with severe congenital factor V deficiency with abnormal factor V protein. He was born in Berlin as a first child of Pakistani parents with consanguinity. He has suffered from mucocutaneous bleeding since his neonatal period. He was diagnosed as congenital factor V deficiency (severe form) because of extremely low level of plasma factor V activity. Since the age of ten he has had three attacks of intracranial hemorrhage, and each of them was successfully treated with fresh frozen plasma. His plasma factor V activity was less than 1 % that of normal, whereas factor V antigen measured by enzyme immunoassay was 21 % that of normal. From these data, we diagnosed him as having severe congenital factor V deficiency with abnormal factor V protein. Coagulation study of all family members revealed that factor V antigen and activity were moderately decreased in his parents and brother, who were thought to be heterozygous carriers. This mode of inheritance was compatible with that of autosomal recessive trait.

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A 14-year-old boy with acute nonlymphocytic leukemia (ANLL) having t (7;11) (p15 ; p15) is reported. The patient had hepatomegaly and right knee joint swelling, and showed WBC 117, 500/μl (blast 47%, Auer rod positive), Hb 8.5g/dl, and platelet count 12.8 × 10⁴/μl. The bone marrow findings, NCC 40 × 10⁴/μl (blast 36.5%), were compatible with M2 by the definition of FAB (French-American-British). A chromosomal analysis of both his peripheral blood and bone marrow before treatment revealed t (7; 11) (p15 ; p15). The patient received systemic chemotherapy including high-dose Ara-C (cytosine arabinoside), attained a complete remission 2 months later, and was in remission for 8 months. Subsequently he relapsed and died of respiratory failure. He had been alive for 13 months after the initiation of induction therapy. A survey of the literature, including this case, demonstrated a total of 19 leukemia cases with a reciprocal translocation t (7p-; 11p+).

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We report herein a case of monozygotic twins suffering from common acute lymphoblastic leukemia (ALL) which developed four months apart in the two infants. The twins were treated by the same therapeutic regimen according to the extremely high risk (Hex) group in the 11 th Protocol of the Tokyo Children's Cancer Study Group (TCCSG). With a lapse of time, a recurrence in the bone marrow was observed in one of the twins. At the initial examination, the bone marrow samples from both twins showed L1 form in the FAB classification by light microscopy, negative peroxidase staining, and diffusely and weakly positive PAS staining. Moreover, almost no differences, including the surface markers, were recognized between the two cases. However, in the electron microscopic study, obvious differences were found in the nuclear chromatin aggregation and glycogen particles which showed positive response against PA-TCH-SP (Periodic acid-thiocarbohydrazide-silver proteinate). These results suggested that leukemia cells in the monozygotic twins, which were thought to have originated from the same stem cells, developed various changes separately in the ultrastructural level by the time of the onset of the illness and that these changes were assumed to have affected the degree of malignancy.

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Three children with severe aplastic anemia (SAA), essentially refractory to conventional therapy with oral steroids, were successfully treated by plural courses of bolus methylprednisolone (M-PSL) therapy. Two patients achieved hematological remission after two courses of therapy and one obtained partial improvement after four courses of therapy. All three became independent of transfusion; therefore, the therapeutic benefit of plural and bolus M-PSL therapy in the treatment of advanced-stage SAA, even in Fanconi's anemia, was confirmed.

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Spinal cord tumor is a rare but serious complication in patients with childhood leukemia. We report the clinical course and pathology in three children with acute leukemia and compared these with 12 similar patients under 20 years old described previously. The tumors extrinsic to but compressing the cord are the most common finding and the thoracic cord is the most common site of involvement. Treatment with chemotherapy and radiotherapy can be effective, but emergency laminectomy should be performed if there is rapid neurologic progression.

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A 3-month-old female infant with agammaglobulinemia developed hypergammaglobulinemia with M-protein. She contracted chronic active Epstein-Barr virus (EBV) infection with generalized lymph nodes swelling and hepatosplenomegaly. Serum IgG antibody to EBV viral capsid antigen was increased, whereas antibody to EBV-determined nuclear antigen was negative during her illness. Lymph node biopsy showed EBNA-containing cells. She died of malignant lymphoma 30 months after the onset of the disease. EBV-DNA was detected in enlarged lymph nodes at autopsy by southern blotting analysis. These data suggest that chronic EBV infection might have a causal relationship to the development of malignant lymphoma. Her elder sister and brother died of malignant lymphoma at the age of 20 months and of pneumonia at the age of 3 months, respectively. From these data, the clinical and laboratory findings in our patient may represent a new variant of hereditary immunodeficiency disease.

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We reported a 2-year-old boy with mosaic Down's syndrome who had megakaryoblastic leukemia (MKBL) 2 years after recovering from transient abnormal myelopoiesis (TAM). At birth, the peripheral white blood cell count was 101, 000/μl with 59.5% blast cells. However, bone marrow examination revealed the presence of only 30% blast cells. From these findings, he was diagnosed as having TAM. The abnormal findings gradually subsided without any medical treatment and he returned to a healthy state within a few months. At the age of 2 years and 5 moths, he developed petechiae due to thrombocytopenia. Bone marrow examination revealed 65% blast cells. They were positive for platelet peroxidase (PPO) on analysis with electron microscopy. Fresh blast cells did not react to monoclonal antibodies recognizing platelet-associated antigens (pl-gp Ib and pl-gp IIb/ IIIa), but blast cells cultured. for 4 days in vitro turned positive. He was diagnosed as having MKBL and treated with low-dose cytosine arabinoside. He has presently remained in complete remission for 1 year.

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