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S Hashino

Publications and source records attributed to S Hashino.

At least 73 records · Page 4Linked to original sources

Effects of 15-deoxyspergualin in vitro and in vivo on cytokine gene expression.

Reverse transcriptase-polymerase chain reaction showed that interleukin 3, IL-4, IL-5, IL-6, interferon-gamma and stem cell factor mRNA expression were higher in 15-deoxyspergualin-treated spleen cells than in control spleen cells. Increased IL-2 and IFN-gamma mRNA expression were observed in 15-deoxyspergualin-treated bone marrow cells. On the other hand, increased platelet counts in BALB/c-->C3H/He bone marrow chimeras were observed from days 20 to 33 in our previous work, when they were treated with 15-deoxyspergualin from days 14 to 25. In contrast, marked leukocytopenia and anemia were simultaneously observed, although a marked leukocytosis and a rapid recovery of anemia were observed on day 33 and thereafter. To analyze effects of 15-deoxyspergualin on hematopoiesis and the immune system, we examined mRNA expression in bone marrow and spleen cells from BALB/c-->C3H/He bone marrow chimeras treated with 15-deoxyspergualin from days 14 to 25. Reverse transcriptase-polymerase chain reaction showed that IL-3, IL-4, IL-6, stem cell factor, granulocyte colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor mRNA expression were higher in 15-deoxyspergualin-treated chimeras than in control chimeras, indicating that these cytokines are responsible for an enhancement of hematopoiesis. It was conceivable that IL-6 supported thrombopoiesis in concert with other cytokines. On the contrary, increased IFN-gamma, IL-2, IL-3, IL-4, and IL-10 mRNA expression may play an immunosuppressive role in vivo.

Actins↗

In vivo effects of the immunosuppressant 15-deoxyspergualin on hematopoiesis in murine allogeneic bone marrow chimeras. Its thrombopoietic activity and reversal of adverse effects with granulocyte colony-stimulating factor and/or erythropoietin.

When 15-deoxyspergualin (DSG), a potent immunosuppressant, was administered into [BALB/c-->C3H/He] bone marrow chimeras from day 14 to day 25, increased thrombopoiesis was induced on day 20 to day 33, accompanied by marked leukocytopenia and anemia. The mean platelet counts in DSG-treated and control [BALB/c-->C3H/He] bone marrow chimeras on day 25 were (114.1 +/- 0.5) x 10(4)/microliter versus (58.6 +/- 2.6) x 10(4)/microliter (1.9-fold increase). Colony-forming units-megakaryocyte (CFU-Meg) were not significantly increased in DSG-treated bone marrow chimeras. Colony-forming units-granulocyte/macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E) were decreased during DSG-treatment whereas CFU-Mix colony formations were rather increased, and more primitive hematopoietic progenitor cells (highly proliferative potential colony-forming units [CFU-HPP]) were not decreased in the same time period. Since CFU-GM and BFU-E colony formations were increased immediately after the cessation of DSG treatment, followed by the rebound of leukocyte counts and the recovery of hemoglobin (Hb) levels, the leukocytopenia and anemia appeared to be induced by a cytostatic effect of DSG. The adverse effect of DSG was partly reversed by the simultaneous administration of granulocyte colony-stimulating factor (G-CSF) and/or erythropoietin (EPO), suggesting the need for the administration of these cytokines in the case of bone marrow transplants treated with DSG. Furthermore, it was of note that DSG modulated hematopoiesis and stimulated the production of thrombopoietin (TPO)-like cytokine(s) as well as interleukin-3 (IL-3).

Anemia↗

Evaluation of mixed chimerism by two-step polymerase chain reaction amplification of hypervariable region MCT118 after allogeneic bone marrow transplantation.

We assessed the origin of peripheral blood cells and bone marrow cells of 92 samples obtained from 19 patients after allo BMT by two-step polymerase chain reaction (PCR) amplification of MCT118, one of the variable number of tandem repeat regions (VNTR) which has a different length in 19 of 32 sibling pairs examined, that can detect the DNA pattern of a minor cell population of only 1% without using radioisotopes. Mixed chimerism (MC) was detected in the hematopoietic cells of four patients. Two patients who showed progressive MC developed relapse of leukemia 3 months and 4 months after the detection of MC, and two patients died with bone marrow hypoplasia 61 days and 7 months after BMT. These data suggest the clinical importance of analyzing the correlation of MC and clinical complications after BMT by this method, which can be used to monitor MC in about two thirds of allo BMT patients with an adequate sensitivity.

Base Sequence↗

Recipient-mediated effect of a traditional Chinese herbal medicine, ren-shen-yang-rong-tang (Japanese name: ninjin-youei-to), on hematopoietic recovery following lethal irradiation and syngeneic bone marrow transplantation.

Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NYT), a traditional Chinese herbal medicine, was evaluated for recipient-mediated effect on hematopoietic recovery in a murine model of syngeneic bone marrow transplantation (BMT). BALB/c recipient mice were preconditioned with a lethal total body irradiation (TBI) at a dose of 6.5 Gy and transplanted with syngeneic bone marrow (BM) cells. NYT treatments, given intraperitoneally (i.p.) once per day for 3 consecutive days in a dose of 0.625 mg, were performed either before or after TBI and BMT to assess any recipient-mediated effect of this compound. NYT pretreatment was as effective as NYT posttreatment in enhancing the total number of colony-forming unit erythroid (CFU-E) and colony-forming unit granulocyte-macrophage (CFU-GM) per marrow and spleen after TBI and BMT. NYT pretreatment caused a significant increase in marrow and splenic CFU-E and CFU-GM numbers over a prolonged period following TBI and BMT, and affected late-stage erythropoiesis (CFU-E) more profoundly than early-stage erythropoiesis (burst-forming unit erythroid, BFU-E). NYT pretreatment significantly accelerate recovery of not only erythrocyte and leukocyte counts but also platelet counts after transplantation with a limited number (1 x 10(5)) of BM cells. The same treatment, however, was significantly less effective in hematopoietic recovery after transplantation with a minimal number (1 x 10(4)) of BM cells, indicating that NYT accelerates recovery of donor-derived rather than recipient-derived cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effects of interleukin-6 on hematopoiesis in allogeneic and syngeneic bone marrow chimeras.

Effects of interleukin-6 (IL-6) on hematopoietic progenitor cells were analyzed in murine bone marrow chimeras. When IL-6 was injected into syngeneic [C3H/He-->C3H/He] bone marrow chimeras from day 1 to day 12, the numbers of highly proliferative potential colony-forming units (CFU-HPP) or colony-forming units mix (CFU-Mix) in spleen cells and bone marrow cells increased on day 14 although there was a marked increase in spleen cells but not in bone marrow cells on day 21. The numbers of CFU-HPP increased in spleen cells from allogeneic [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 on days 14 and 21. In syngeneic bone marrow chimeras, the numbers of colony-forming units granulocyte/macrophage (CFU-GM) and burst colony-forming units (BFU-E) increased similarly to those of CFU-HPP and CFU-Mix on day 14. On day 21, these were mainly increased in spleen cells. In allogeneic bone marrow chimeras, IL-6 decreased the numbers of CFU-GM and BFU-Mix dose-dependently on day 14. Only 10 micrograms of IL-6 increased the numbers of CFU-GM and BFU-E on day 21. In our previous work, we showed that platelet counts increased on day 14 in syngeneic bone marrow chimeras injected with IL-6, whereas platelet and leukocyte counts increased on days 14 and 24 in allogeneic bone marrow chimeras injected with IL-6, correlating inversely with the numbers of hematopoietic progenitor cells. Overall, primitive hematopoietic progenitors (i.e., CFU-HPP and CFU-Mix) existed primarily in spleen cells of allogeneic bone marrow chimeras on day 14, whereas those in spleen cells of syngeneic bone marrow chimeras were found on day 21. These findings indicate that the effect of IL-6 on hematopoiesis in allogeneic bone marrow chimeras is completely different from that in syngeneic bone marrow chimeras, probably via graft-versus-host reaction (GVHR) but not GVH disease (GVHD).

Animals↗

Effects of 15-deoxyspergualin on proliferative responses and cytokine gene expression in vitro.

15-deoxyspergualin (DSG)-treated BALB/c spleen cells showed increased spontaneous proliferation and increased alloreactive mixed lymphocyte reactions (MLRs) when a 3-h treatment was carried out. However, when spleen cells were treated with DSG for 5 days without washing out DSG, decreased spontaneous proliferation was observed, although alloreactive MLRs against C3H/He and C57BL/6 alloantigens were increased. In contrast, cyclosporin A (CsA) induced markedly decreased alloreactive MLRs. Decreased concanavalin A (Con A)- and pokeweed mitogen (PWM)-induced responses were observed in spleen cells treated with DSG for 3 h; whereas increased phytohemagglutinin (PHA)-induced responses were observed. On the other hand, increased Con A- and PHA-induced responses were observed in spleen cells treated with DSG for 2 days, whereas PWM-induced responses were decreased. CsA-treatment induced markedly decreased mitogen-induced responses. These results suggest that the immunosuppressive mechanism of DSG differs from that of CsA. Reverse transcriptase-polymerase chain reaction (RT-PCR) method showed that interleukin 1 beta (IL-1 beta), IL-2, IL-3, IL-4, IL-5, and leukemia inhibitory factor (LIF) mRNA expression in DSG-treated spleen cells were increased by Con A stimulation, thus indicating that DSG modulates cytokine gene expression and inducing immunosuppressive mechanisms different from CsA.

Animals↗

In vivo administration of interleukin-6 in murine allogeneic bone marrow chimeras: early and delayed enhancement of hematopoiesis accompanied with split tolerance but not with graft-versus-host disease.

Interleukin-6 (IL-6) induced increased, leukocyte and platelet counts on around day 20 when it was administered into [BALB/c-->C3H/He] bone marrow chimeras from day 1 to day 12. Increased leukocyte counts and hemoglobin (Hb) levels were also observed at around day 60 and from day 41 to 80, respectively. On the other hand, hematopoietic recovery in [C3H/He-->C3H/He] bone marrow chimeras injected with IL-6 was different from that in [BALB/c-->C3H/He] bone marrow chimeras, showing no delayed and long-lasting increase in Hb levels but showing an early and transient increase in Hb levels and platelet counts. Sera from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 showed predominant productions of IL-3 and/or IL-4. Reverse transcriptase polymerase chain reaction (RT-PCR) showed that stem cell factor (SCF) mRNA expression was increased in bone marrow or spleen cells from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 on day 36. Furthermore, we analyzed influence of IL-6 on graft-versus-host disease (GVHD) in [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6. Decreased survival days and body weights were not observed when compared with the control. Histopathological changes of the liver due to GVHD were also not obvious. However, alloreactive mixed lymphocyte reactions (MLRs) were readily detected although cytotoxic T cells were not generated. Since H-2 typing showed that donor-type chimerism was predominantly observed, it was suggested that split tolerance might be induced by IL-6 administration. Increased IL-2 levels were not detected in sera from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 whereas IL-4 was detected in the same sera, indicating that type 2 helper T (TH2) cells appeared to be predominantly generated. These results suggest that IL-3/IL-4 and SCF appeared to synergistically support delayed effects on hematopoiesis in [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 although early effects appeared to be mediated mainly by IL-6 directly or indirectly. Furthermore, IL-6 could induce split tolerance in [BALB/c-->C3H/He] bone marrow chimeras via a preferable activation of TH2 type cells without inducing severe GVHD.

Animals↗

Cytokine gene expression in the mixed lymphocyte culture in allogenic bone marrow transplants as a predictive method for transplantation-related complications.

We have investigated cytokine gene expression in the two-way mixed lymphocyte cultures (MLC) enhanced by concanavalin A to assess whether this is a useful predictive method for severe graft-versus-host disease (GVHD) and graft failure in nine allogeneic bone marrow transplantation (allo-BMT) patients. Our present study revealed that increased IL-2, IL-5 and IFN-gamma mRNA expression and IL-2 and IFN-gamma production in the MLC in two cases with severe lethal transplantation-related complications (graft failure and grade III acute GVHD). These findings suggest that increased cytokine mRNA expression and cytokine products in this assay may be predictive of the development of transplantation-related complications.

Adolescent↗

Cytokines involved in graft-versus-host disease.

Graft-versus-host disease (GVHD) is one of the major complications which should be resolved to improve the survival rates in allogeneic bone marrow transplantation (BMT). Recently, several cytokines have been identified, suggesting that they form a cytokine network and play an important role in immune system and hematopoiesis. Among several cytokines, it has been reported that tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) are mainly involved in GVHD. In the present report, we analyzed the role of cytokines in GVHD. When we measured serum cytokine levels, IL-6, interferon gamma (IFN gamma), and TNF alpha levels were increased prior to the onset of acute GVHD. For chronic GVHD, a similar pattern of cytokine increment was observed. Interestingly, these cytokines appeared to interact synergistically to induce clinical GVHD, suggesting that none of those cytokines does not function solely. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that increased IL-1 beta mRNA expression was also observed in acute GVHD in addition to increased IL-6 and TNF alpha mRNA expressions. Unexpectedly, no increased IL-2 levels were observed in both assays. In hyperacute GVHD, only IL-6 level was increased. However, in vivo administration of IL-6 into allogeneic bone marrow chimeras did not induce severe GVHD. Therefore, some other factors also appeared to be involved in inducing hyperacute GVHD. Furthermore, it is important to consider the role of inhibitory cytokines such as transforming growth factor beta (TGF beta) or IL-10.

Animals↗

Allogeneic bone marrow transplantation as a therapeutic modality for hematological disorders: a report based on 39 cases.

The outcomes of 39 patients with hematological disorders who had undergone allogeneic bone marrow transplantation (BMT) from September 1986 to March 1992 were reported. The length of follow-up was six to 50 months. Twenty patients with acute leukemia, eight patients with aplastic anemia, seven patients with chronic myelogenous leukemia, two patients with non-Hodgkin's lymphoma, and two patients with myelodysplastic syndrome were included. Major complications were acute graft-versus-host disease (GVHD) (17 cases out of 36 evaluable cases; 47 percent), chronic GVHD (13/25; 52 percent), sepsis (20/41; 49 percent), interstitial pneumonitis (IP) (10/30; 33 percent), and veno-occlusive disease (VOD) of the liver (5/41; 12 percent). Acute and chronic GVHD were well managed with cyclosporin, methotrexate, and steroids. VOD of the liver seemed to be associated with the pretransplant regimen including busulfan and cyclophosphamide. The overall probability of disease free survival of 39 patients who had undergone allogeneic BMT was 0.56. This includes nine high risk cases such as HLA antigen mismatch between the donor and the recipient, and as in the second or subsequent remission or in relapsed cases. The probability of disease free survival in patients with acute leukemia, chronic myelogenous leukemia, and aplastic anemia including high risk cases was 0.55 (n = 20), 0.71 (n = 7), and 0.50 (n = 8) respectively. These results indicate that allogeneic BMT is the major therapeutic strategy for patients whose survival could not be expected by conventional chemotherapy and that drug intensification for conditioning regimen is also important.

Adolescent↗

Cytokine gene expression by concanavalin A-stimulated peripheral mononuclear cells after bone marrow transplantation: an indicator of immunological abnormality due to chronic graft-versus-host disease.

The response of IFN-gamma, IL-2 and IL-5 mRNA expression to the stimulation of concanavalin A (Con A) in peripheral blood mononuclear cells (PBMC) after bone marrow transplantation (BMT) was analyzed using reverse-transcriptase polymerase chain reaction (RT-PCR) to assess the recovery of T cell function. The subjects were 23 patients undergoing allogeneic BMT, 1 syngeneic BMT, 1 autologous BMT and 2 normal individuals. IFN-gamma mRNA expression increased after Con A stimulation in 6 patients who had limited chronic graft versus host disease (GVHD), 14 patients who did not have chronic GVHD, each one patient receiving syngeneic and autologous BMT and 2 normal individuals. On the other hand, IFN-gamma mRNA expression was not increased by Con A stimulation in 4 patients who had extensive chronic GVHD. Also, the concentration of IFN-gamma in cultured medium in a patient with extensive chronic GVHD was not detectable. A similar low response of IL-2 and IL-5 mRNA expression to Con A was observed in these patients with extensive chronic GVHD. These findings indicate that the cytokine productive capacity of T cell (IFN-gamma and IL-2 could be produced by type 1 T helper (Th1) cells and IL-5 could be produced by type 2 T helper (Th2) cells) was suppressed in patients who had extensive chronic GVHD, while that capacity was almost normal in patients without chronic GVHD and with limited chronic GVHD. Therefore, the analysis of cytokine gene response to Con A stimulation may provide useful information regarding immune reconstitution after BMT.

Adolescent↗

Hyperacute graft-versus-host disease accompanied by increased serum interleukin-6 levels.

Hyperacute graft-versus-host disease (GVHD), which progresses severely and rapidly, was observed in three patients with acute leukemia transplanted with bone marrow cells from human leukocyte antigens (HLA)-identical and mixed leukocyte reactions (MLR)-negative siblings. Hyperacute GVHD developed in these patients within 7 days after bone marrow transplantation (BMT) and was rapidly aggravated inspite of cyclosporin A (CyA) and short-term methotrexate (MTX) prophylaxis and treatment with bolus methylprednisolone (mPSL). These patients showed markedly increased serum interleukin-6 (IL-6) levels after BMT, whereas other cytokines such as interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), and IL-2 were not increased compared with pretreatment levels. These findings suggest that markedly increased IL-6 levels may be related to hyperacute GVHD.

Acute Disease↗

Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease.

In patients with acute graft-versus-host disease (GVHD), IL-6 gradually increased > 14 days before clinical onset of acute GVHD and decreased when acute GVHD disappeared. Interferon-gamma (IFN gamma) levels increased < 14 days before clinical acute GVHD and decreased at the disappearance of acute GVHD. Tumor necrosis factor-alpha (TNF alpha) levels increased almost simultaneously with the onset of acute GVHD and also decreased when it disappeared. However, these results do not necessarily mean that the increased levels of IL-6, IFN gamma and TNF alpha induced acute GVHD; they merely show that acute GVHD is observed more frequently in patients with increased IL-6, IFN gamma and TNF alpha levels than in those with normal levels. Although increased IL-6 levels were also observed in patients without acute GVHD, concomitant increase of IFN gamma and TNF alpha was not detected in such cases, showing that IL-6 can be increased by even graft-versus-host reaction (GVHR) which may not develop into clinical acute GVHD. Taken together, acute GVHD appeared to be induced by synergistic interaction of IL-6, IFN gamma and TNF alpha, consistent with a cytokine cascade. A similar interaction of IL-6 and TNF alpha was also observed in chronic GVHD. Although IFN gamma levels were slightly increased in chronic GVHD and sometimes aggravated the disease status, IL-6 and TNF alpha appeared to be more closely involved in the induction of chronic GVHD. In autologous BMT, increased cytokine levels were not observed unless IL-2 was administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

Antileukemic effect of interleukin-2 on spontaneous development of leukemia after H-2-compatible allogenic bone marrow transplantation in AKR/J mice.

AKR/J mice, highly susceptible to spontaneous T cell leukemogenesis, were protected from developing the disease by H-2-compatible allogenic bone marrow transplantation (BMT) and intermittent treatment with interleukin-2(IL-2). Allogeneic BMT from C3H/HeJ mice and treatment with PBS yielded T cell leukemia in chimeras after the same latent period as that observed in normal AKR/J mice. In contrast, IL-2-treated chimeras caused an incidence of only 40% T cell leukemia. The preventing effect of IL-2 on leukemia development was not observed in one-year-treated chimeras, probably due to a lack of continuous antileukemic effects over the long term. Both LAK and NK activities in spleen cells were significantly increased in IL-2-treated chimeras. The cytotoxicity against T cell lymphoma cell line derived from AKR/J also increased in the IL-2-treated chimeras. Similarly, LPS-, PWM-, and IL-2-induced responses were increased in the IL-2-treated chimeras. TNF-alpha secretion from spleen cells also rose after IL-2-administration. IL-1 beta, IFN-gamma, and TNF-alpha mRNA became detectable in spleen cells using the PCR technique. The characteristics of leukemia cells in chimeras with overt leukemia were not directly affected by IL-2 administration. It is suggested that partial inhibition of spontaneous T cell leukemia development in AKR/J mice by allogeneic BMT and IL-2 may be due to the enhancement of graft-versus-leukemia effects. Further study may provide insights into the mechanisms involved in preventing leukemia development after allogenic BMT and IL-2 in AKR/J mice.

Animals↗

Monoclonal gammopathy (IgA: lambda) after autologous T-cell-depleted bone marrow transplantation in a patient with non-Hodgkin's lymphoma.

We report a case study of a patient suffering from T-lymphoblastic lymphoma, for whom autologous T-cell-depleted bone marrow transplantation was carried out. Low-dose cyclosporin A (CsA) was administered just after autologous bone marrow transplantation (ABMT) for induction of autologous graft-versus-host disease. Three months later, the lymphoma relapsed with marked monoclonal gammopathy of the immunoglobulin A type, which had not been seen before ABMT. It is suggested that the regrowth of the lymphoma cells was related to the maturation of B cells or the secretion of immunoglobulins from plasma cells, associated with some cytokines produced under the condition of an abnormal immunological circumstance after ABMT plus CsA.

Adult↗

In vitro expansion of murine hematopoietic progenitor cells in liquid cultures for bone marrow transplantation: effects of stem cell factor.

In this study, we demonstrated that recombinant stem cell factor (SCF), when used in combination with interleukin-1 (IL-1), IL-3 and IL-1 plus IL-3, promoted the expansion of immature murine hematopoietic progenitor cells in liquid cultures. In cultures with IL-1 plus IL-3 plus SCF, high proliferative potential-colony forming cells (HPP-CFC) increased 7-8-fold compared with the increase in fresh bone marrow cells, while SCF alone had no effect on the expansion of HPP-CFC. SCF also increased the numbers of colony forming unit-spleen (CFU-S) cells in combination with IL-1 plus IL-3. Transplantation of bone marrow cells cultured with IL-1 plus IL-3 plus SCF resulted in reconstitution of hematopoiesis in lethally irradiated mice earlier than transplantation of fresh bone marrow cells. These results raised the possibility that in vitro expansion of hematopoietic progenitor cells, carried out with SCF in combination with IL-1 and IL-3 in liquid cultures, can be utilized in bone marrow transplantation.

Animals↗

Bone marrow transplantation for hematological diseases in Hokkaido--June 1985 to December 1991.

Bone marrow transplantation (BMT) was started in Hokkaido in 1985. In the present report we have reviewed the clinical outcome of patients treated with BMT for hematological diseases in Hokkaido. Fifty-eight allogeneic and 19 autologous transplants were registered by December 1991. The underlying diseases consisted of 47 leukemias, 14 lymphomas, 10 aplastic anemias and six myelodysplastic syndromes. Among the allogeneic BMT cases, 55 were human leucocyte antigen (HLA) identical and three were mismatched. Among the autologous BMT patients, two received their marrow purged with 4-hydroperoxycyclophosphamide and five, with monoclonal antibodies and complements. The conditioning regimens used for malignancies were chiefly cyclophosphamide (CY) plus total body irradiation, or busulfan plus CY. In many cases, cytokines were used for rapid recovery of decreased leukocytes. Engraftment was observed in 50 out of 52 evaluated allogeneic and 18 out of 19 autologous transplants. Ten allogeneic patients suffered from severe acute graft-versus-host diseases (GVHD), and extensive chronic GVHD appeared in 16 patients. Relapses were observed in four cases of allogeneic BMT and six of autologous BMT. The major complications were interstitial pneumonitis (IP) and severe infections. Long-term survival rates were almost 60% in both allogeneic and autologous transplants. Mild acute GVHD and limited chronic GVHD increased the survival rates. The results indicated that substantial problems such as GVHD, IP and relapses must be controlled in the near future for an improved outcome to be made possible.

Adolescent↗