Biomedical subjects

Y Takaue

Publications and source records attributed to Y Takaue.

At least 109 records · Page 6Linked to original sources

PubMed1994

Diminished erythropoietin-induced erythroid growth in patients with renal anemia is restored by recombinant human erythroid differentiation factor.

An examination of the in vitro sensitivity of marrow burst-forming units for erythroid (BFU-E) to various concentrations of human recombinant erythropoietin (rEpo) and interleukin-3 (IL-3, 20 ng/mL) in serum-deprived methylcellulose cultures revealed that cells obtained from patients with chronic renal failure showed a defective response to rEpo, particularly at lower concentrations. This poor response was not corrected by the addition of neutralizing antibodies to antitumor necrosis factor-alpha or antiinterleukin-1 alpha/beta. When purified CD34+ cells from these patients were tested for dose-dependent growth to rEpo, the curve resembled that of normal donors, indicating that there was an intrinsic defect in the patients' progenitor/accessory cell interactions. Using unseparated cells from the patients, we then tested whether the interaction between erythroid differentiation factor (EDF) and rEpo affected BFU-E growth. Although EDF, either alone or in combination with IL-3, did not affect the growth of BFU-E in the absence of rEpo, the reduced sensitivity to rEpo in the patients was brought closer to normal limits by the addition of 10 ng/mL EDF to the cultures. The present results may suggest the possibility that, in patients with renal anemia, concomitant administration of EDF may increase the therapeutic ratio of rEpo therapy by enhancing the sensitivity of progenitor cells to rEpo, thereby decreasing the therapeutic dose of costly rEpo.

Activins↗

PubMed1994

High-dose chemotherapy and blood stem cell autografts for children with first relapsed acute lymphoblastic leukemia: a pilot study of the Children's Cancer and Leukemia Study Group of Japan (CCLSG).

This study was performed to determine the value of high-dose chemotherapy and peripheral blood stem cell autografts (PBSCT) in the treatment of children with first relapsed acute lymphoblastic leukemia (ALL). Eighteen children underwent PBSCT during the second complete remission (CR) and had a minimum 10 month follow-up. The median age of the patients was 11 yr (range, 2-17 yr). Fifteen patients received the "MCVAC" regimen, one received high-dose MCNU+busulfan therapy, one received high-dose melphalan+VP-16, and one received melphalan+carboplatin+cytosine arabinoside+MCNU. None of these regimens included total body irradiation. Eight patients developed recurrence of the disease at 1 to 19 mo (median, 3 mo) after PBSCT. Patients in whom the first relapse occurred sooner, that is, within 16 mo of initial therapy, tended to have a better survival rate than those who developed relapse after 30 mo (six of seven survived versus four of 11; not significant). Although the preliminary data provided little conclusive information, it did suggest that incorporation of PBSCT in the salvage protocol of relapsed childhood ALL can be justified.

Adolescent↗

PubMed1994

Synergy among erythropoietin, interleukin 3, stem cell factor (c-kit ligand) and interferon-gamma on early human hematopoiesis.

The stimulatory effect of interferon-gamma (IFN-gamma) on human early hematopoiesis was investigated using CD34+ cells that were purified from peripheral blood as a target. In the presence of human interleukin 3 (IL-3) and stem cell factor (SCF), the growth of colony forming units for granulocyte/macrophage (CFU-GM) in serum-free methylcellulose culture was enhanced up to 5.5-fold over baseline colony formation (n = 10, mean +/- SE, 3.18 +/- 1.00) by coculture with 2.5 x 10(3) U/ml IFN-gamma, whereas burst forming units-erythroid (BFU-E) growth induced by additional erythropoietin (Epo) was reduced dose-dependently. Liquid-suspension culture of the target cells for 24 h with IFN-gamma before secondary plating in serum-free methylcellulose resulted in a marked increase in the colony numbers; 3.62 +/- 1.04-fold for CFU-GM and 5.72 +/- 2.32-fold for BFU-E (n = 5). The effect was most striking in the growth of erythroid lineage supported by Epo alone in serum-free culture. Delayed addition of IFN-gamma between days 4 and 7 of methylcellulose culture suppressed CFU-GM growth, but not that of BFU-E. These results suggest that IFN-gamma is an essential cytokine that affects human hematopoiesis and exerts a bimodal effect on stem cell maturation; potentiating or replacing the effect of early-acting cytokines such as SCF or IL-3, and suppressing the growth of matured progenitor cells.

Antigens, CD↗

PubMed1994

[Peripheral blood stem cell transplantation: present status and future prospects].

This is a comprehensive review of autologous peripheral blood stem cell transplantation (PBSCT). Collection of peripheral blood stem cells (PBSC) does not require anesthesia and is less invasive compared to harvesting marrow cells. As the hematopoietic recovery speed after autologous PBSCT is fast, the procedure is associated with less complication compared to marrow transplantation. Thus, high-dose therapy can safely be administered, without the use of aseptic measures, in a larger number of hospitals. Preliminary therapeutic results for the treatment of relapsed childhood acute lymphoblastic leukemia appears to be equivalent to that obtained by application of allogeneic bone marrow transplantation. Alternate use of PBSC includes routine application after consolidation therapy as one of growth factors. Use of PBSC in allogeneic setting has been under intense investigation. Collection, processing and storage of PBSC will shortly become a part of routine procedure in major blood centers and banks.

Blood Component Removal↗

PubMed1994

Cell processing protocol for allogeneic peripheral blood stem cells mobilized by granulocyte colony-stimulating factor.

Although there is a growing body of information available regarding restoration of hematopoiesis with peripheral blood stem cell (PBSC) autografts, few studies have explored this procedure using allografts. In this study with healthy donors, we investigated the feasibility of a protocol for mobilizing PBSC using recombinant human granulocyte colony-stimulating factor (G-CSF) and subsequent bulk depletion of T cells from apheresis-harvested cells. Nine informed healthy donors were given G-CSF subcutaneously at two different dosing schedules (5 micrograms/kg/d in five donors and 2 micrograms/kg/d in four) for 5 consecutive days, and serial changes in blood components, including hematopoietic progenitor cells, were monitored. After 5 days of stimulation with G-CSF, PBSCs were collected by apheresis, and yields were compared. The number of white blood cells (WBC) reached a plateau level on either day 2 (5 micrograms) or 3 (2 micrograms), but the numbers of red blood cells and platelets were not affected. Circulating colony-forming unit-granulocyte/macrophage (CFU-GM) levels started to increase 1 or 2 days after the increase in the WBC count. By performing a 3L apheresis, the number of CFU-GM harvested was 4.6 +/- 3.3 x 10(6) (mean +/- standard error of the mean [SEM]) in the 5-micrograms group and 1.8 +/- 0.7 x 10(6) in the 2-micrograms group. Different procedures for depleting T cells, including the use of L-phenylalanine methyl ester (PME) and flasks coated with anti-CD5/CD8 monoclonal antibodies or neuraminidase-treated sheep red blood cells (SRBC), were also tested on the harvested cells. We found that cell lysis with PME before selective removal of T cells was very effective in reducing the number of cells that required further processing and was suitable for routine use. However, our current procedure resulted in unsatisfactory depletion of T cells (99.5% removal) while retaining hematopoietic progenitor cells (7.5% recovery). Further research is required in this area.

Adult↗

PubMed1994

Effects of rhG-CSF (filgrastim) on the recovery of hematopoiesis after high-dose chemotherapy and autologous peripheral blood stem cell transplantation in children: a report from the Children's Cancer and Leukemia Study Group of Japan.

In a nonrandomized study, hematopoietic recovery kinetics were evaluated in 98 consecutive patients who underwent high-dose chemotherapy without total body irradiation (TBI) and autologous peripheral blood stem cell transplantation (PBSCT). Fifty-three patients received recombinant human granulocyte colony-stimulating factor (rhG-CSF) (filgrastim) therapy after PBSCT, and the data were compared by actuarial analysis to those of 45 historic controls. The number of days required to achieve a white blood cell count (WBC) of 1 x 10(9)/L, an absolute granulocyte count (AGC) of 5 x 10(8)/L, and a platelet count (PLT) of 5 x 10(10)/L were, respectively, 12.8 +/- 6.4 (mean +/- standard deviation [SD]), 13.4 +/- 6.4, and 49.2 +/- 78.2 in treated patients vs. 12.8 +/- 4.6, 14.4 +/- 10.3, and 31.4 +/- 38.8 days in historic controls, with no significant differences. There was no significant difference between the average number of days with fever in the treated group (6.0 +/- 6.6) and that in the control group (4.0 +/- 2.8). All febrile episodes responded promptly and successfully to parenteral antibiotic therapy. Thus, the data may suggest the possibility that therapy with filgrastim has only a limited ability to enhance hematopoietic recovery after PBSCT. To confirm this notion, we initiated a prospective randomized trial by recruiting a larger number of patients.

Adolescent↗

PubMed1994

Comparative analysis of engraftment after cryopreservation of peripheral blood stem cell autografts by controlled- versus uncontrolled-rate methods.

Peripheral blood stem/progenitor cells (PBSC) were cryopreserved by different methods and their clonogenic viabilities were compared. The traditional cryopreservation method involves controlled-rate freezing with 10% dimethyl sulfoxide (DMSO) and a programmed freezer (PF). The alternative method incorporates 6% hydroxyethyl starch and 5% DMSO without PF. In this non-randomized study, we analyzed the data of 24 patients (aged 1-17 years) who were in their first complete remission and who had undergone PBSC autograft (PBSCT) for high-risk acute lymphoblastic leukemia, to determine the effects of these two different methods of cryopreservation on time to engraftment and transfusion requirements after PBSCT. In all patients, PBSC were collected within 5 months of diagnosis and all had been conditioned with the high-dose MCVAC regimen (MCNU, cytosine arabinoside, etoposide and cyclophosphamide) without total body irradiation. Twelve patients received PBSC that had been cryopreserved by the uncontrolled method without PF and the data were compared by actuarial analysis to those of 12 historical controls whose cells had been frozen by PF. No difference was observed in the time to engraftment of granulocytes and platelets or the transfusion requirements between the two groups. Our results indicate that, in terms of preserving engraftment potential, the simplified uncontrolled-rate cryopreservation method is at least as effective as the traditional controlled-rate freezing procedure with PF.

Adolescent↗

PubMed1994

Assessment of testicular biopsy after cessation of maintenance chemotherapy in childhood acute lymphoblastic leukemia: a report from the Children's Cancer and Leukemia Study Group.

Among 484 male patients with acute lymphoblastic leukemia (ALL) registered into the protocols CCLSG 811, 841 and 874, from 1981 through 1990, 246 patients completed their protocols and were in continuous complete remission (CCR) for more than 3 years. One hundred and seven patients received bilateral testicular biopsies at the time of cessation of maintenance chemotherapy. Eight patients (7.5%) were found to have occult testicular leukemia (TL). Three of them did not receive any additional therapy and all suffered subsequent relapses; one bone marrow relapse and two testicular relapses. The other 3 patients received testicular radiation combined with an additional 2 years of chemotherapy, resulting in CCR for more than 6 years 10 months, 7 years 6 months, and 8 years 6 months. One with chemotherapy alone and another with radiation alone showed subsequent relapse. Overt TL after negative initial biopsy was developed in 3 (3.0%) of the 99 patients. All of them received testicular radiation with chemotherapy, resulting again in CCR for more than 1 year 0 months and 5 years 3 months; one patient showed relapse in testes and bone marrow after 3 years 8 months of CCR. These studies suggested that occult TL has an adverse prognostic significance unless retrieval chemotherapy is given and that performance of testicular biopsy at completion of maintenance chemotherapy is not contributory to prolongation of disease-free survival for males with ALL because the treatment employing testicular radiation plus retrieval chemotherapy for both occult TL and isolated overt TL after off-therapy is similarly very effective.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Regeneration of immunity and varicella-zoster virus infection after high-dose chemotherapy and peripheral blood stem cell autografts in children.

We assessed recovery of the immune system in 41 children who underwent high-dose chemotherapy (without total body irradiation) and autologous peripheral blood stem cell transplantation (PBSCT) for acute leukemias or non-Hodgkin's lymphoma. The analysis was in two parts. Firstly, we performed serial monitoring of regenerating subsets and blastogenesis of lymphocytes. We then reviewed the incidence of varicella-zoster virus (VZV) infection, based on the belief that this served as a clinical indication of immunological recovery. The CD4/CD8 ratio markedly decreased in all patients, with a nadir at 3 months, due to both abnormally low levels of CD4+ cells and sustained higher levels of CD8+ cells. These abnormalities were sustained for > 12 months post-graft. Within 6 months after PBSCT, all patients showed a decreased in vitro response to mitogens including PHA, Con A and PWM but these responses gradually recovered during the subsequent 6 months. All patients had a previous history of chicken pox. The actuarial incidence of VZV was 45% at 6 months and 67% at 12 months. All patients were treated with intravenous acyclovir with relief of pain and cutaneous healing within 10 days. No patient developed visceral dissemination. These findings suggest that at least in children, no major difference is apparent between immunological reconstitution in bone marrow transplantation and PBSCT. The development of minor and reversible VZV is a common event in this group of patients.

Adolescent↗

PubMed1994

Engraftment potential of peripheral and cord blood stem cells evaluated by a long-term culture system.

The experiment was performed in an attempt to seek a suitable indicator of allogeneic transplantation using cord blood cells. The number of colony-forming cells (CFC) recovered after 5 weeks of culture represents that of primitive progenitors present in the initiating cell population. In this study of nine children who underwent autologous peripheral blood stem cell transplantation (PBSCT), we measured the amount of colony-forming units-granulocyte/macrophage (CFU-GM) and total CFC output after 5 weeks in long-term culture (LTC-CFC) contained in the infused grafts and compared them to the speed of hematopoietic recovery after marrow ablation. In this patient population, we found a significant negative correlation between the number of infused CFU-GM/kg body weight and the time to achieve an absolute granulocyte count (AGC) of 0.5 x 10(9)/L (r = -0.867, p < 0.01), but not with the time to achieve a platelet count of 50 x 10(9)/L (r = -0.700, p = 0.05). Although the number of infused LTC-CFC/kg did not correlate with the early phase of granulocyte recovery, a significant correlation was observed with platelet recovery speed (r = -0.930, p < 0.01) and with the time to regain an absolute granulocyte count of 2 x 10(9)/L after the nadir of the transient decrease in the number of AGC, which occurred 3 to 7 weeks following PBSCT (r = 0.967, p < 0.01). On the other hand, CFU-GM/kg showed no significant correlation with this late engraftment speed. Thus, LTC assay may reflect the kinetics of immature progenitor cells which are capable of reconstituting stable hematopoiesis after marrow ablative therapy. The data were then used in a comparative analysis of the transplantation potential of peripheral vs. cord blood stem cells. The numbers of LTC-CFC and CFU-GM per mononuclear cell (MNC) from cord blood were 2.5-fold and two-fold greater than those from peripheral blood cells, respectively. These results suggest the advantage of cord blood as an additional stem cell source in transplantation.

Adolescent↗

PubMed1993

Effects of immunosuppressants, FK506, deoxyspergualin, and cyclosporine A on immature human hematopoiesis.

Effects of the immunosuppressants, FK506, deoxyspergualin (DSG), and cyclosporine A (CsA) on the growth of human hematopoietic progenitor cells were tested in the presence of interleukin-3 (IL-3) with purified bone marrow and blood cells as targets in methylcellulose culture. FK506 had a significant stimulatory effect on the growth of colony-forming units/granulocyte-macrophage (CFU-GM) and burst-forming units/erythroid (BFU-E) from peripheral blood and cord blood cells but not from bone marrow cells. Neither DSG nor CsA had an effect on any type of target cell. Liquid-suspension-limiting dilution assay with IL-3 showed that FK506 directly stimulated the growth of blood progenitors in a dose-dependent manner with single-hit kinetics. Liquid-suspension preincubation of blood cells with FK506 before culture in methylcellulose induced a significant increase in the amount of IL-3-supported growth of CFU-GM and BFU-E, whereas initial preincubation with IL-3 and subsequent culture with FK506 plus IL-3 exerted its stimulatory effect only on BFU-E. These data suggest that the stimulation of hematopoietic progenitor cells by FK506 occurs at a very early stage of maturation and diminishes with further myeloid development.

Antigens, CD↗

PubMed1993

Granulocyte colony-stimulating factor (CSF), macrophage-CSF, granulocyte-macrophage CSF, interleukin-3, and interleukin-6 levels in sera from children undergoing blood stem cell autografts.

Endogenous production of granulocyte colony-stimulating factor (G-CSF), macrophage CSF (M-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), and interleukin-6 (IL-6) was investigated in 10 children who underwent a total of 12 courses of autologous peripheral blood stem cell transplant (PBSCT) by measuring their serum levels using immunoassay kits. The serum G-CSF level increased immediately following infusion of PBSC graft, peaked between days 3 and 7 posttransplant and then declined by the time the granulocyte count rose. No definitive association was found between the continuous high levels of G-CSF and infective episodes, the number of infused nucleated cells, monocytes, CFU-GM, or the number of days required to achieve greater than 0.5 x 10(9)/L granulocyte, greater than 1.0 x 10(9)/L leukocyte, or greater than 50 x 10(9)/L platelet counts. After PBSCT, IL-6 levels tended to be elevated. No detectable serum level of GM-CSF or IL-3 (< 50 pg/mL) was observed before PBSCT and 4 patients showed a transient increase in the GM-CSF level after PBSCT. No significant change was observed in the post-transplant serum levels of IL-3 or M-CSF. The role of endogenously secreted cytokines in early hematopoietic recovery after PBSCT needs further clarification, but, at present, routine use of exogenous G-CSF therapy is not recommended.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Effect of alternating combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, cisplatin, and etoposide for small cell lung cancer on hematopoietic progenitors in the peripheral blood.

The effects of a combination chemotherapy (CAV-PVP) consisting of cyclophosphamide, doxorubicin, hydrochloride (dox) and vincristine (CAV) alternating with cisplatin and etoposide (PVP) on peripheral blood hematopoietic progenitor cells (PBHPs) were studied in five patients with small cell lung cancer (SCLC). The kinetics of the CFU-GM levels were different during the CAV and PVP phases. None of the five patients displayed a rebound increase in the level of peripheral blood CFU-GM during the CAV phase. In contrast, all five patients displayed a rebound increase in peripheral blood CFU-GM levels during the PVP phase of the alternative combination chemotherapy (3-5 weeks after the initiation of PVP regimen). These findings indicate the optimal timing for leukapheresis to obtain PBHPs in SCLC patients which have been treated with an alternating combination chemotherapy consisting of CAV-PVP.

Adult↗

PubMed1993

Toxicities associated with cryopreserved and thawed peripheral blood stem cell autografts in children with active cancer.

To evaluate the safety of cryopreserved and thawed peripheral blood stem cell (PBSC) autografts in children with active cancer, a toxicity assessment was made of 54 PBSC transfusions to 52 children (aged 1-16 years; median, 9 years). Patients were conditioned with high-dose chemotherapy without total body irradiation. The volume of PBSCs transfused varied from 46 to 500 mL (219.6 +/- 118.4 mL, mean +/- SD), with a mean of 0.91 g per kg of dimethyl sulfoxide. Insignificant and transient toxicities included hemoglobinuria in 40 patients (74%), headache in 38 (70%), nausea in 37 (69%), and vomiting in 25 patients (46%). Significant shock developed in 8 patients (15%), but they recovered quickly, whether they had supportive therapy or not. Vomiting and hyperbilirubinemia were the only toxicities that showed a correlation with the amount of PBSCs transfused. The data suggest that transient toxicity associated with PBSC autografts is rather common in children, and close observation of patients for possible serious morbidity is required.

Adolescent↗

PubMed1993

Peripheral blood stem cell autografts for the treatment of childhood cancer: a review of the Japanese experience. Japanese Cooperative Study Group of PBSCT (JCSG/PBSCT).

Harvesting peripheral blood stem cells (PBSC) for autografts (PBSCT) in children with active cancers is a safe and reliable procedure with a low incidence of serious morbidity. A significant correlation between the number of infused CFU-GM and the time to both granulocyte and platelet engraftment was found. Cells induced by G-CSF could speed the recovery of granulocyte or platelet counts after PBSCT. In terms of preserving engraftment potential, cryopreservation of PBSC by a simplified uncontrolled-rate method is at least as effective as the traditional controlled-rate freezing procedure with a programmed freezer. As the serum G-CSF level increases immediately following infusion of PBSC graft, therapy with G-CSF may have only a limited ability to further enhance hematopoietic recovery after PBSCT. Preliminary results of high-dose chemotherapy without TBI and PBSCT for the treatment of children with relapsed ALL are encouraging.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Effects of progenitor cell dose and preleukapheresis use of human recombinant granulocyte colony-stimulating factor on the recovery of hematopoiesis after blood stem cell autografting in children.

The effects of progenitor cell dose on the recovery kinetics of hematopoiesis were assessed in 34 children who underwent marrow-ablative chemotherapy with peripheral blood stem cell (PBSC) autografting. One patient was not engrafted, probably because of a low dose of reinfused cells. In 25 patients whose PBSCs were harvested after intensive chemotherapy without recombinant granulocyte colony-stimulating factor (rG-CSF), we found a significant correlation between the colony-forming unit for granulocyte-macrophage (CFU-GM) infused per kilogram of the patient's body weight and the time to achieve an absolute granulocyte count (AGC) of > 0.5 x 10(9)/L (r = -0.817, p < 0.001) or a platelet count of > 50 x 10(9)/L (r = -0.703, p < 0.001). No association was seen between the number of burst-forming units for erythroid (BFU-E) infused and the speed of hematopoietic recovery. In the other 8 patients with low progenitor yields (< 1 x 10(5) CFU-GM/kg), in vivo induction of PBSC was attempted by administering rG-CSF (250 to 1000 micrograms/m2/day). Seven-day administration of rG-CSF before each leukapheresis increased the committed (CFU-GM: 37.7-fold; BFU-E: 45.6-fold) as well as multipotent (CFU-mix: 6.8-fold) progenitors. These collected cells were cryopreserved and then reinfused. Using a model for simulating hematopoietic recovery kinetics, we suggest that cells induced by rG-CSF could speed the recovery of granulocyte or platelet counts after PBSC autografting.

Adolescent↗

PubMed1993

A newborn case of extrarenal malignant rhabdoid tumor.

Malignant rhabdoid tumor is initially differentiated from renal tumors and characterized by extremely rapid growth. We report a newborn case of extrarenal malignant rhabdoid tumor and review the literature.

Diagnosis, Differential↗

PubMed1993

Measurement of serum levels of macrophage colony-stimulating factor (M-CSF) in patients with uremia.

Serum levels of monokines, including macrophage colony-stimulating factor (M-CSF), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) and IL-1 beta (IL-1 beta), were measured in patients with chronic renal failure in an attempt to clarify the kinetics of these cytokines in the course of renal anemia. M-CSF was the only monokine detectable in the serum from all patients as well as healthy donors, making this cytokine feasible and reliable for serial evaluations. On all occasions, the level of M-CSF in uremic patients was significantly higher than that in healthy donors (29.4 +/- 12.3 vs. 5.5 +/- 1.1 ng/mL). In patients undergoing hemodialysis, the serum level of M-CSF was greater than that in patients undergoing continuous ambulatory peritoneal dialysis or in uremic patients without dialysis therapy. No difference was observed, however, in the levels of IL-1 alpha, IL-1 beta and TNF-alpha levels in these groups. Patients with severe anemia were subsequently treated with 60 to 80 U/kg per week of human recombinant erythropoietin (rhEpo) for 3 months. After this replacement therapy, hemoglobin levels increased with a variable change ranging from 0 to 3.5 g/dL. The pretherapy M-CSF level, however, was found to predict statistically the response to the therapy (p < 0.05). Patients with a lower pretherapy value responded better to rhEpo therapy; those with a higher level showed a minor degree of response. From these results, we postulate that the elevated M-CSF serum level in uremic patients is in part a consequence of the dialysis procedure and that rhEpo therapy is more effective in patients who are under sophisticated dialysis protocol and have a lower M-CSF level.

Erythropoietin↗