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Biomedical subjects

J Akatsuka

Publications and source records attributed to J Akatsuka.

At least 19 recordsLinked to original sources
PubMed1997

Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia.

The improved outcome of acquired aplastic anemia (AA) has revealed later complications, such as myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). We retrospectively analyzed 167 children with severe acquired AA. Eleven of 50 children treated with cyclosporin (CSA) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) developed MDS/AML; 8 of these were within 36 months of the diagnosis of AA, much earlier than previous reports. Six of the 11 children received rhG-CSF exceeding 10 microg/kg/d, and 9 received rhG-CSF therapy for over 1 year. Ten children showed monosomy 7 at diagnosis of MDS. All of the 11 children were administered both CSA and rhG-CSF. There was no development of MDS/AML among 41 children treated with either CSA or rhG-CSF or among 48 children who underwent bone marrow transplantation. A well-controlled clinical trial is warranted to determine whether therapeutic modalities affect the development of MDS/AML in children with severe acquired AA.

Acute Disease↗
PubMed1996

Recombinant human interferon alpha-2b (rh IFN alpha-2b) therapy for steroid resistant idiopathic thrombocytopenic purpura (ITP).

The efficacy of recombinant human interferon alpha-2b (rh IFN alpha-2b) in the treatment of steroid resistant idiopathic thrombocytopenic purpura (ITP) was studied in 50 cases. Forty-one patients treated with rh IFN alpha-2b three times a week, six of 18 (33.3%) in the low dose group (150 x 10(4)IU: 3 MIU) and four of 20 (20.0%) in the high dose group (300 x 10(4)IU: 3 MIU) responded with platelet counts increasing to above 50 x 10(9)/L. Because of the exacerbation of thrombocytopenia and nasal bleeding, treatment was discontinued within 2 weeks in three patients out of 41 cases. On the other hand, six of nine patients (66.7%) treated with 3 MIU of IFN alpha-2b once a week for 8 weeks showed satisfactory response. Treatment with either administration schedule did not result in sustaining platelet counts above 50 x 10(9)/L for a long time after treatment. The results indicate that once a week administration schedule of rh IFN alpha-2b is more efficacious for platelet counts increasing for short period in patients who failed to respond to steroid and other medications than other schedules. The maintenance of this treatment schedule will allow sustained increased platelet levels, resulting in relief of bleeding tendency, while also being cost effective in comparison with other IFN treatment schedules and achieving better patient compliance without flu-like symptoms.

Adolescent↗
PubMed1996

Testicular morphological changes in children with acute lymphoblastic leukemia following chemotherapy.

Morphological changes in the testis induced by chemotherapy given according to the Tokyo Children's Cancer Study Group (TCCSG) regimens were studied in children with acute lymphoblastic leukemia (ALL). After informed consent, testicular biopsies were performed 14 times in 12 patients at the end of treatment. The testicular morphology in all cases had sustained a degree of damage. The tubular fertility index (TFI), calculated as the percentage of seminiferous tubules containing identifiable spermatogonia, was from 0 to 42.8% (mean 33.4%) below the normal value. Infiltration of leukemic cells was the most significant factor contributing to the decrease in TFI. There were no differences in the TFI among the TCCSG protocols. Formation of sperm was recognized in six cases, whose ages were 7, 8, 9, 10, 15 and 19 years. In two children, testicular biopsy was performed twice. In the second biopsy, TFI was elevated and sperm formation with the maturation of Leydig cells was observed. A number of other pathological changes were observed: modification of spermatogonia, Sertoli cells and inclusion bodies in spermatogonia, abnormal maturation of Leydig cells, evidence of interstitial fibrosis and thickening of the basement membrane. These results suggest that recent strong chemotherapy for the treatment of ALL might cause severe but not fatal damage to children's testicular tissue. As chemotherapy escalates, more investigation of testicular function will be necessary.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

[Glutathione synthetase deficiency].

CASE REPORT: The patient was a boy born in June, 1990. The proband's father had a history of nonspherocytic hemolytic anemia. The patient was anemic at birth (Hb 11.9 g/dl) and had a hemolytic attack on postnatal day 2. His hemolysis became well compensated, and his second hemolytic episode occurred at three years of age. CLINICAL AND LABORATORY FINDINGS: The patient's mental development had so far been normal and he has no neurological symptoms. His only clinical manifestation has been compensated hemolytic anemia with a hemoglobin concentration of about 11.0 g/dl and a reticulocyte count of 3-6%. He was positive on the Heinz body formation test, and target cells were seen on his peripheral blood smear. The osmotic fragility test yielded slightly increased value. Decreased reduced glutathione (GSH) was observed (4.4 mg/dlRBC) (normal range: 63.9 +/- 9.6), and he also had decreased glutathione synthetase (GS) activity of 0.03 U/gHb (0.38 +/- 0.08 U/gHb). A diagnosis of GS deficiency was made. Decreased glutathione S-transferase (GST) activity was also found (0.57 U/gHb) (normal range: 6.65 +/- 1.20). DISCUSSION: GS deficiency has been reported in about 30 families all over the world. This patient was the first Japanese patient with red cell GS deficiency.

Child↗
PubMed1996

[Hereditary elliptocytosis].

Recently a number of different red cell membrane skeletal abnormalities have been identified in patients with hereditary elliptocytosis (HE). In Japanese patients with HE, most of skeletal abnormality was protein 4.1 abnormalities. alpha-spectrin abnormality was found only one lineage in Japan, in spite of these abnormalities were most common abnormalities in western countries. On the contrary beta-spectrin abnormalities were found in two lineages, in spite of these abnormalities were rare abnormalities in western countries. The other abnormalities, such as band 3 abnormalities and glycophrin abnormalities, were found in HE. We described here about clinical features and above mentioned abnormalities of red cell membrane skeleton in HE.

Elliptocytosis, Hereditary↗
PubMed1995

Immunthrombocytopenic purpura as a model for pathogenesis and treatment of autoimmunity.

In honour of Professor Rossi's 80th birthday we review the development of our understanding of the immune and auto-immune nature of the pathogenesis of immune thrombocytopenic purpura (ITP). The immune aspects have been documented by postviral alterations of the cellular and humoral immune system, by new methods of specific auto-antibody detection against platelet glycoproteins and by the therapeutic effect of administering immunoglobulin concentrate from healthy blood donors. The various possible mechanisms of action of immunoglobulin treatment have led to use of this treatment as an alternative for other immune-related disorders. The treatment of severe chronic ITP in children, however, remains unsatisfactory. With a new international clinical and laboratory study of children and adolescents with early chronic ITP we are continuing the investigation of the pathogenesis and treatment of ITP.

Antibody Formation↗
PubMed1995

Ex vivo expansion of umbilical cord blood hematopoietic progenitor cells by combinations of cytokines.

Ex vivo expansion of hematopoietic progenitor cells in the umbilical cord blood mononuclear cells (CB-MNC) was investigated in liquid culture system with various combinations of cytokines (stem cell factor [SCF], interleukin [IL]-3, IL-6, granulocyte-colony stimulating factor [G-CSF], erythropoietin [EPO], and interferon [INF]-gamma). Non-lineage-committed hematopoietic progenitor cells and lineage committed hematopoietic progenitor cells were represented as CD34+CD38- and CD34+CD38+ subpopulations, respectively. Although absolute CD34+CD38- cell numbers decreased even in the presence of multicytokines, the combinations of SCF plus IL-6 and SCF plus IL-3 plus IL-6 plus IFN-gamma were significantly effective in maintaining CD34+CD38- cells than the other combinations (P < 0.05). After 4 weeks of culture. CD34+CD38- cells disappeared in all combinations of cytokines. Absolute CD34+CD38+ cell numbers increased in the presence of cytokines. Maximal expansion of CD34+CD38+ cells were observed in the combinations of SCF plus IL-3 plus IL-6 plus EPO (19.8 +/- 3.3-fold) and SCF plus IL-3 plus IL-6 plus G-CSF (18.3 +/- 2.6). The combination of SCF plus IL-3 plus IL-6 was also effective to expand CD34+CD38- cells (15.8 +/- 3.9). However, the expansion was transient and they decreased to zero within 3 weeks. In the combinations of SCF plus IL-6 and SCF plus IL-3 plus IL-6 plus INF-gamma, maximal expansion was inferior to the others but CD34+CD38+ cells were maintained more than 4 weeks. These results suggested that the indication of CBT can be expanded into older children by ex vivo augmentation of CB hematopoietic progenitor cells using multi-cytokines.

ADP-ribosyl Cyclase↗
PubMed1995

Autoantibodies and CD5+ B cells in childhood onset immune thrombocytopenic purpura.

We evaluated platelet associated immunoglobulin (PIag) G, PaIgM, platelet associated autoantibodies to platelet glycoprotein IIb/IIIa (Pa-GPIIb/IIIa), the percentage of CD5+ B cells and the amount of platelet-bound anti-GPIIb/IIIa monoclonal antibody (mAb) in the peripheral blood of 29 patients with childhood onset chronic immune thrombocytopenic purpura (c-ITP). The percentage of CD5+ B cells ranged from 2 to 8% (4.7 +/- 2.0) in control patients and 1 to 18% (6.2 +/- 4.2) in the ITP patients. There was no overall significant difference between the two groups, but the percentage of CD5+B cells in six of the ITP patients was higher than the mean + 2 s.d. of the controls. There was a significant correlation between the percentage of CD5+ B cells and PaIgM (y = 1.73x + 13.4, r=0.40, P < 0.05). This finding is the basis for the speculation that CD5+ B cells may play an important role in the production of PaIgM in vivo. There was no correlation between the amounts of PaIgG and Pa-GPIIb/IIIa). This suggests that the amount of PaIgG does not accurately reflect of the amount of Pa-GPIIb/IIIa. Furthermore, we have demonstrated that autoantibodies to GPIIb/IIIa are directed to more that one epitope.

Adolescent↗
PubMed1995

Effects of cytokines on hematopoietic progenitor cells in cord blood, in bone marrow, and in peripheral blood mobilized by chemotherapy and G-CSF.

We compared the effects of various combinations of cytokines (stem cell factor [SCF], interleukin [IL]-3, IL-6, granulocyte-colony stimulating factor [G-CSF], erythropoietin [EPO]) among the growth of human hematopoietic progenitor cells from cord blood (CB), bone marrow (BM), and peripheral blood mononuclear cells (MNC) mobilized by chemotherapy and G-CSF (PB) in a semi-solid medium. Macroscopic colonies, that were visible to the naked eye, were formed from PB-MNC within 1 week even without cytokines. They consisted of blasts containing macrophage-like cells with immature nuclei on Wright stain, and were strongly accelerated by IL-3. Macroscopic colonies were also formed from CB-MNC. However, they appeared after 1-3 weeks and synergistic effects of SCF with other cytokines, especially EPO, were prominent. Macroscopic colonies were not formed from BM-MNC. Granulocyte-colony stimulating factor was effective in increasing colony forming units of granulocyte macrophage from BM-MNC and they appeared between 1 and 2 weeks. These results suggested that the quality of hematopoietic progenitor cells was different among blood sources. This might lead to different bone marrow recovery patterns after transplantation of each blood source. The appropriate cytokines should be added to evaluate their exact potential.

Adult↗
PubMed1994

Establishment of a human pro-B cell line (JKB-1) and its differentiation of preestablished bone marrow stromal cell layer.

A human pro-B cell line, named JKB-1, was established from the bone marrow of a 16-year-old girl with acute lymphoblastic leukemia (ALL) in relapse. The origin of the JKB-1 cell line was indicated by its chromosomal and immunologic similarity to the patient's fresh leukemic cells. This cell line has been growing for more than 14 months in suspension culture medium and had a doubling time of about 24 hours. JKB-1 expressed terminal deoxynucleotide transferase (TdT) and early antigens (HLA-DR, CD19, CD24) of B cells, with heavy chain gene rearrangement. However, it did not express late antigens (CD10, CD20, CD21, CD22, CD23) of B cells, light chain gene rearrangement, and cytoplasmic mu-chain. These results suggested that JKB-1 is at the stage of "pro-B" cell or early B-cell precursors. This cell line was induced to differentiate after 7 days of co-incubation with irradiated bone marrow stromal cells because of the expression of pre-B cell antigens (CD10, CD20), cytoplasmic mu-chain, light chain gene rearrangement, and disappearance of TdT, JKB-1 cells adhered to a preestablished bone marrow stromal cell layer with string-like processes under scanning electron microscope. When JKB-1 cells were separated from the stromal layer by a cyclopore membrane with 0.45 micron pore size, they did not differentiate. Bone marrow stromal cell conditioned medium could not induce differentiation either. Thus it was suspected that direct contact between JKB-1 cells and stromal cells was required for differentiation. In methylcellulose semisolid medium, the colony size and number of JKB-1 cells were increased by stem cell factor (SCF), or interleukin (IL)-3, or IL-7, but they were decreased by IL-6. Moreover, SCF synergized with IL-3 or IL-7 to stimulate the proliferation of JKB-1 cells. Because there are very few reproducible models for examining early stages of human B-cell differentiation, the JKB-1 cell line would be useful for studying the relationship between human B-cell differentiation and bone marrow microenvironment, as well as leukemogenesis.

Adolescent↗
PubMed1994

Factors affecting the efficiency of peripheral blood stem cell collection in children treated with chemotherapy and G-CSF.

This retrospective study attempts to clarify the optimal timing for peripheral blood stem cell (PBSC) collection after conventional chemotherapy followed by granulocyte-colony stimulating factor (G-CSF) administration. Leukapheresis was performed 32 times in nine children with various cancers during bone marrow recovery phase following transient pancytopenia after chemotherapy. (On two occasions, leukapheresis was excluded because many leukemic blasts were included). When the number of white blood cells (WBC) exceeded 1.8 x 10(10)/L after administration of G-CSF (200 micrograms/m2, continuous infusion), many more CD34+ cells were contained in the collected peripheral mononuclear cells (P > 0.02) and a sufficient number of PBSC for transplantation (> or = 10 x 10(8) CD34+ cells/kg) was obtained after one run in 15 of 17 leukapheresis sessions. In contrast, sufficient PBSC were obtained only in one of 13 runs of leukapheresis when the number of WBC was < 1.8 x 10(10)/L. The number of WBC on the day when PBSC were collected correlated with collected nuclear cell number (r = 0.60), but not with the CD34+ cell ratio. The ratio was higher only when both platelets and reticulocytes increased in parallel with WBC. We conclude that sufficient PBSC collection is possible after conventional chemotherapy using G-CSF, when hematopoietic recovery is parallel, without the use of high-dose chemotherapy.

Antigens, CD↗
PubMed1994

Lymphoma syndrome leukemia revealed interesting finding on brain CT and ultrasound scan of abdomen at the initial presentation.

This paper reports on a patient with lymphoma syndrome leukemia (LSL) who showed interesting findings on brain computed tomography (CT) and ultrasound scans of the abdomen at the initial presentation. The patient was a 5 year old girl. When she was admitted to our hospital, there were many lymph nodes palpable. The abdomen was distended and the liver and spleen were palpable below the umbilicus. Hematologic examinations revealed a leukocyte count of 275,800/microL with 98% lymphoblasts. Chest X-ray film revealed a mediastinal mass. The diagnosis of LSL was made. Her brain CT scan showed a low density area in the right thalamic region without contrast enhancement; infarction was suspected. Furthermore, her abdominal ultrasound scan showed hepatosplenomegaly, kidney swelling with increasing echogenicity and hydronephrosis and stones in the renal pelvis and bladder. These findings are unprecedentedly rare in cases of childhood acute lymphoblastic leukemia (ALL), much less in LSL.

Abdomen↗
PubMed1994

Umbilical cord blood as a rich source of immature hematopoietic stem cells.

To investigate immaturity of hematopoietic progenitor cells in umbilical cord blood mononuclear cells (CB-MNC), the formation of macroscopic colonies and mixed-cell colonies was assayed by methylcellulose culture with various combinations of cytokines (stem cell factor [SCF], interleukin [IL]-3, IL-6, granulocyte-colony stimulating factor [G-CSF], erythropoietin [EPO]) and compared with bone marrow (BM)-MNC. Moreover, distribution of the subpopulations divided by CD34, CD38, HLA-DR and CD33 was compared by flow-cytometry. Colonies derived from CB-MNC were so large that they could be observed with the naked eye and consisted of a variety of types of hematopoietic cells. Mixed-cell colonies were formed to a much greater extent in CB-MNC than in BM-MNC. Addition of EPO, IL-3, and SCF had rapid effects on the growth of mixed-cell colonies. The subpopulations of immature hematopoietic progenitor cells (CD34+, CD38-, HLA-DR-), which are supposed to be able to differentiate into hematopoietic precursors and stromal cells, were significantly higher in CB-MNC (8.7 +/- 6.6%) than in BM-MNC (0.0 +/- 0.1%; P < 0.001). These results suggest that CB is a rich source of immature hematopoietic progenitor cells compared to BM.

Antibodies, Monoclonal↗
PubMed1994

Peripheral blood progenitor cell transplantation estimated by three-colour (CD34, HLA-DR, CD33) flow cytometry.

The relationships between transfused cell number of CD34+ cell subpopulations divided by HLA-DR and CD33 antibodies and hematopoietic recovery patterns after peripheral blood progenitor cell transplantation (PBPCT) subsequent to myeloablative chemoradiotherapy were investigated in 14 children with cancer. Both logarithm of transfused CD34+ cell number/10(6)/kg and logarithm of transfused cell number/10(6)/kg of the CD34+HLA-DR+CD33+ subpopulation, which is supposed to be myeloid-committed cells, were correlated with myeloid recovery after PBSCT, though they were not correlated with erythroid or platelets recovery. On the other hand, logarithm of transfused cell number/10(6)/kg of CD34 + HLA-DR-CD33-subpopulation, which is supposed to be immature progenitor cells, was not correlated with myeloid recovery but correlated with erythroid recovery and platelet recovery. These results suggested that rapid myelopoiesis after PBPCT occurs following transfusion of sufficient numbers of myeloid-committed cells and complete hematopoietic reconstitution occurs after transfusion of sufficient numbers of immature hematopoietic progenitor cells.

Adolescent↗
PubMed1994

[Effective combination therapy by recombinant erythropoietin and cepharanthin in a girl with refractory anemia].

A 3-year-old girl was admitted with a one-month history of a tendency to bleed to Jikei Kashiwa hospital in May, 1992. She developed pancytopenia as follows; hemoglobin: 8.6 g/dl, red blood cell: 316 x 10(4)/microliters, reticulocyte: 9,480/microliters, white blood cell: 2,500/microliters (neutrophil: 400/microliters) and platelet count: 2.7 x 10(4)/microliters. Her bone marrow was hypoplastic, but was so dysplastic in 3 cell-lines as to be diagnosed as hypoplastic refractory anemia. After two courses of methylprednisolone pulse therapy followed by oral prednisolone therapy which were not effective and were supplemented by blood transfusions, the treatment of 20mg/day oral Cepharanthin, a biscoclaurine alkaloid, and intravenous recombinant human erythropoietin (rhEPO) twice a week at dose of 6,000 U/week was initiated in January, 1993. About 3 months later she showed a steady rise in hemoglobin concentration (from 4.1 to 11.9 g/dl) and platelet count (from 4,000 to 39,000/microliters). Although the rhEPO was tapered and ceased in September, 1993, her hemoglobin concentration has ranged from 11.0 to 11.9 g/dl and her platelet count from 30,000 to 40,000/microliters by giving her Cepharanthin and low dose prednisolone.

Alkaloids↗
PubMed1993

Neurofibromatosis type 1 and childhood cancer.

BACKGROUND: Patients with neurofibromatosis type 1 (NF1) are prone to develop malignancy, particularly malignant schwannoma and glioma in adults. METHODS: To assess the risk for childhood malignancy in NF1, 26,084 patients with cancer younger than 15 years of age registered from 1969 to 1989 in the Japan Children's Cancer Registry were reviewed. The incidence of NF1 in each type of cancer was compared with that in the Japanese population. RESULTS: Fifty-six children with cancer had NF1 in the national registry. The incidence of NF1 (0.21%) was 6.45 times that of the expected estimated rate of 1 per 3000 in the Japanese population. These tumors tended to be type and site specific. The NF1 incidence was extremely high in optical nerve glioma (12.5%), other central nervous system gliomas (0.9%), and malignant schwannoma (31.4%). For nonneural tumors, NF1 incidence was increased in rhabdomyosarcoma (1.36%), particularly those in urogenital organs, and in myelogenous leukemia (0.27%). Epithelial carcinomas were not observed in the group of patients with NF1. CONCLUSION: The risk for glioma and malignant schwannoma increases in children and adults with NF1. Moreover, the risk for two childhood malignancies, myelogenous leukemia and rhabdomyosarcoma, increases in children with NF1. The NF1 gene seems to increase the risk not only for neural tumors but also for some non-neural tumors in an age-specific, organ-dependent pattern of carcinogenesis.

Adolescent↗