Fulminant septicemia caused by Bacillus cereus following reduced-intensity umbilical cord blood transplantation.
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Adult↗
Biomedical subjects
Yoichi Takaue
Publications and source records attributed to Yoichi Takaue.
Feasibility of early tapering of cyclosporine following reduced-intensity stem cell transplantation for advanced hematologic or solid malignancies.
Although some researchers have reported that early tapering of cyclosporine is feasible and beneficial to augment graft-versus-leukemia effects after conventional stem-cell transplantation, there is little information on the feasibility of this strategy following reduced-intensity stem cell transplantation (RIST). We summarized outcomes of 17 patients who underwent early tapering of cyclosporine following RIST from HLA-identical siblings.
Adult↗
Reduced-intensity allogeneic hematopoietic stem-cell transplantation as an immunotherapy for metastatic colorectal cancer.
BACKGROUND: Allogeneic stem-cell transplantation (allo-SCT) can induce curative graft-versus-leukemia reactions for hematologic malignancies through allogeneic immunity. Because the gastrointestinal tract is a target of graft-versus-host disease (GvHD), colorectal cancer might be a candidate for allo-SCT. METHODS: Four patients with metastatic colorectal cancer underwent reduced-intensity stem-cell transplantation (RIST) in the National Cancer Center Hospital between July 2002 and February 2003. Three patients received transplants from an human leukocyte antigen (HLA)-identical related donor, and the remaining patient received selected CD34-positive cells from a two-loci HLA-mismatched donor. The basis of preparative regimen was busulfan 4 mg/kg for 2 days and fludarabine 25 mg/kg for 6 days. RESULTS: All the patients tolerated the preparative regimen and achieved engraftment without significant toxicities. All developed acute or chronic GvHD. Although serum levels of CA19-9 and carcinoembryonic antigen were transiently elevated after RIST in all the patients, the levels subsequently decreased below the levels from before RIST in all but one patient. Three had measurable lesions before RIST, one achieved partial response, and the others stable disease, which was durable for 120 and 60 days. Three patients died; the causes of death were progressive disease, GvHD, and accident. Postmortem examination was obtained for two patients; in one patient, the peritoneal metastatic lesions macroscopically disappeared, and in the other patient, the supraclavicular lymph node disappeared while the other measurable lesions remained stable. CONCLUSIONS: All the patients showed some evidence suggesting the presence of a graft-versus-tumor effect for colorectal cancer, which should be confirmed in a future prospective trial.
Adult↗
Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases.
PURPOSE: The purpose of this research was to evaluate the feasibility of reduced-intensity unrelated cord-blood transplantation (RI-UCBT) in adult patients with advanced hematological diseases. EXPERIMENTAL DESIGN: Thirty patients (median age, 58.5 years; range, 20-70 years) with advanced hematological diseases underwent RI-UCBT at Toranomon Hospital between September 2002 and August 2003. Preparative regimen composed of fludarabine 25 mg/m(2) on days -7 to -3, melphalan 80 mg/m(2) on day -2, and 4 Gy total body irradiation on day -1. Graft-versus-host disease prophylaxis was composed of cyclosporin alone. RESULTS: Twenty-six patients achieved primary neutrophil engraftment after a median of 17.5 days. Median infused total cell dose was 3.1 x 10(7)/kg (range, 2.0-4.3 x 10(7)/kg). Two transplant-related mortalities occurred within 28 days of transplant, and another 2 patients displayed primary graft failure. Cumulative incidence of complete donor chimerism at day 60 was 93%. Grade II-IV acute graft-versus-host disease occurred in 27% of patients, with median onset 36 days. Primary disease recurred in 3 patients, and transplant-related mortality within 100 days was 27%. Estimated 1-year overall survival was 32.7%. Excluding 7 patients with documented infection, 19 patients displayed noninfectious fever before engraftment (median onset, day 9). Manifestations included high-grade fever, eruption, and diarrhea. The symptoms responded well to corticosteroid treatments in 7 of 13 treated patients. CONCLUSION: This study demonstrated the feasibility of RI-UCBT in adults.
Adult↗
The mouse natural killer T cell-associated antigen recognized by U5A2-13 monoclonal antibody is intercellular adhesion molecule-1.
Natural Killer T (NKT) cells in mice are generally defined as NK1.1(+) T cells, although NK1.1 antigen is expressed only in C57BL/6 and related strains. This has precluded investigations of other strains. To find a novel NKT cell surface marker, we generated a monoclonal antibody (mAb), U5A2-13, which recognizes phenotypically and functionally similar populations to NKT cells in naïve mice irrespective of strain. Here, by using a COS-7 expressional cloning system, we molecularly cloned a cDNA encoding a protein reactive with the U5A2-13 mAb and then identified it as intercellular adhesion molecule-1 (ICAM-1). Importantly, the U5A2-13 mAb did not stain hepatic mononuclear cells from ICAM-1 gene disrupted mice. Furthermore, Pepscan method disclosed that the discontinuous epitope for U5A2-13 mAb is composed of three loops located in extracellular domain two of ICAM-1. Overall, U5A2-13, a mAb originally established for mouse NKT cells, recognizes a novel conformational epitope of ICAM-1.
Animals↗
Graft-versus-Tax response in adult T-cell leukemia patients after hematopoietic stem cell transplantation.
Adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) is characterized by poor prognosis after chemotherapy. Recent clinical trials have indicated, however, that allogeneic but not autologous hematopoietic stem cell transplantation (HSCT) for ATL can yield better clinical outcomes. In the present study, we investigated cellular immune responses of ATL patients who obtained complete remission after nonmyeloablative allogeneic peripheral blood HSCT from HLA-identical sibling donors. In the culture of peripheral blood mononuclear cells (PBMCs) from a post-HSCT but not pre-HSCT ATL patient, CD8(+) CTLs proliferated vigorously in response to stimulation with autologous HTLV-I-infected T cells that had been established before HSCT in vitro. These CTLs contained a large number of monospecific CTL population directed to a HLA-A2-restricted HTLV-I Tax 11-19 epitope. The frequency of Tax 11-19-specific CD8+ CTLs in this patient markedly increased also in vivo after HSCT, as determined by staining with HLA-A2/Tax 11-19 tetramers. Similar clonal expansion of HTLV-I Tax-specific CTLs exclusively directed to a HLA-A24-restricted Tax 301-309 epitope was observed in the PBMCs from another ATL patient after HSCT from a HTLV-I-negative donor. Among four post-HSCT ATL patients tested, HTLV-I-specific CTLs were induced in the PBMC culture from three patients but not from the remaining one who had later recurrence of ATL. These observations suggested that reconstituted immunity against antigen presentation in ATL patients after HSCT resulted in strong and selective graft-versus-HTLV-I response, which might contribute to graft-versus-leukemia effects.
Aged↗
Development of early neutropenic fever, with or without bacterial infection, is still a significant complication after reduced-intensity stem cell transplantation.
Little information is available on the clinical characteristics of infectious complications that occur in the early period after reduced-intensity stem cell transplantation (RIST). We retrospectively investigated the clinical features of neutropenic fever and infectious episodes within 30 days after RIST in 76 patients who had received fluoroquinolones as part of their antibacterial prophylaxis. Preparative regimens included cladribine 0.66 mg/kg or fludarabine 180 mg/m2 plus busulfan 8 mg/kg. All but 1 patient survived 30 days after transplantation, and 75 patients (99%) became neutropenic within a median duration of 9 days. Neutropenic fever was observed in 29 patients (38%), and bacterial infection was confirmed in 15 (20%) of these, including bacteremia (n = 13), bacteremia plus pneumonia (n = 1), and urinary tract infection (n = 1). The causative organisms were gram-positive (n = 9) and gram-negative organisms (n = 7), with a mortality rate of 6%. Neither viral nor fungal infection was documented. Multivariate analysis showed that the presence of neutropenia at the initiation of preparative regimens was an independent risk factor for subsequent documented bacterial infections (P =.026; 95% confidence interval, 1.25-35.1). We conclude that neutropenic fever and bacteremia remain common complications in RIST.
Adolescent↗
Early central nervous system complications after reduced-intensity stem cell transplantation.
To investigate clinical characteristics of early central nervous system (CNS) complications after reduced-intensity stem cell transplantation (RIST), we reviewed the medical records of 232 patients who had undergone RIST for hematologic diseases at our institutions between September 1999 and June 2003. All patients had received purine analog-based preparative regimens. Stem cell sources comprised granulocyte colony-stimulating factor-mobilized blood from HLA-identical or 1 locus-mismatched related donors (n = 151), unrelated bone marrow (n = 44), or unrelated cord blood (n = 37). Graft-versus-host disease prophylaxis incorporated cyclosporine with or without methotrexate. Diagnosis of CNS complications was based on clinical, radiologic, and microbiological findings. CNS complications occurred in 18 patients (7.8%), with a median onset of 22 days, and were infectious (n = 1), metabolic (n = 15), or cerebrovascular (n = 2). Symptoms included seizures (n = 7), visual disturbance (n = 2), headache (n = 8), nausea (n = 8), vomiting (n = 6), impaired consciousness (n = 16), and hemiparesis (n = 3). Complications improved promptly in 10 patients, and 8 patients died without improvement within 30 days. Multivariate analysis with logistic regression identified umbilical cord blood transplantation as a significant risk factor for early CNS complications (odds ratio, 14.5; 95% confidence interval, 3.7-56.9; P <.0001). CNS complications are a significant problem after RIST, particularly with umbilical cord blood. Limbic encephalopathy is an unrecognized subtype of neurotoxicity after umbilical cord blood transplantation.
Adult↗
Incidence of invasive aspergillosis after allogeneic hematopoietic stem cell transplantation with a reduced-intensity regimen compared with transplantation with a conventional regimen.
To evaluate the clinical characteristics of invasive aspergillosis (IA) after reduced-intensity stem cell transplantation (RIST) compared with those after conventional stem cell transplantation (CST), we examined the medical records of 486 CST and 178 RIST recipients. The overall incidence of IA after allogeneic transplantation was 35 (5.3%) of 664, which gave a 3-year cumulative incidence of 5.6%. The estimated 3-year incidence of IA in CST and RIST was 4.5% and 8.2% (P = .045), respectively, but the mortality rates were similar (76% and 86%). The median onset of IA after RIST (day 127) occurred significantly later than that after CST (day 97). A multivariate analysis revealed that IA was associated with age older than 50 years (relative risk, 2.12; 95% confidence interval, 1.08-4.17; P = .03) and the presence of acute and/or chronic GVHD (relative risk, 6.2; 95% confidence interval, 2.4-16.4; P = .0002). IA remains an important complication after allogeneic transplantation, regardless of the type of conditioning regimen.
Adolescent↗
Allogeneic hematopoietic stem cell transplantation with a reduced-intensity conditioning regimen for treatment of metastatic renal cell carcinoma: single institution experience with a minimum 1-year follow-up.
OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of allogeneic hematopoietic stem cell transplantation with a reduced-intensity conditioning regimen (RIST) for interferon-alpha-refractory metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Of 26 patients referred to the National Cancer Center Hospital for possible RIST between June 2000 and April 2002, an HLA-identical relative was identified for 12 patients. Nine patients underwent RIST. The conditioning regimen consisted of fludarabine 180 mg/m2 or cladribine 0.66 mg/kg, plus busulfan 8 mg/kg and rabbit antithymocyte globulin 5 mg/kg. Graft-vs-host disease (GVHD) prophylaxis was cyclosporine alone. RESULTS: All patients achieved engraftment without grade III to IV nonhematologic regimen-related toxicity. All patients achieved complete donor-type chimerism without donor lymphocyte infusion by day 60. Four patients developed acute GVHD, and four developed chronic GVHD. One patient (11%) achieved partial response. As of July 2003, six patients were alive at median follow-up of 681 days. The actuarial overall survival rate was 89% at 1 year and 74% at 2 years. The overall survival rate tended to be higher in the 12 patients with a matched donor than in the other 14 patients without a matched donor (p = 0.088). CONCLUSION: Our RIST procedure is feasible without severe toxicity. The efficacy of RIST for RCC should be confirmed in phase II/III clinical trials.
Acute Disease↗
Generation of cytotoxic donor CD8+ T cells against relapsing leukemic cells following allogeneic transplantation by stimulation with leukemic cell- or leukemic lysate pulsed donor cell-derived dendritic cells.
To treat leukemia relapse after allogeneic hematopoietic stem cell transplantation (HSCT), we investigated the possibility of immunotherapy using donor CD8+ T cells that were generated by stimulating leukemic cell-derived dendritic cells (leukemic-DCs) or leukemic cell lysate pulsed donor cell-derived DCs (donor-DCs). Leukemic- and donor-DCs were generated from mononuclear cells of patients and CD14+ cells of HLA-matched donors, respectively. The expression of CD80, CD83, CD86, CD1a, and CD40 on leukemic-DCs was significantly lower than that on donor-DCs. Donor-DCs exhibited a higher capacity to stimulate allogeneic T cells compared with leukemic-DCs. Donor CD8+ T cells stimulated by leukemic- or donor-DCs were more cytotoxic than unprimed CD8+ T cells, and slightly higher cytotoxicity was observed with donor-DCs compared to leukemic-DCs. This study indicates that leukemic- or donor-DCs pulsed with leukemic cell lysates can effectively prime donor cytotoxic T cells in vitro, and that they may be used as a potential alternative tool for treating leukemic patients who relapse after allogeneic HSCT.
CD8-Positive T-Lymphocytes↗
Balance between acute graft-versus-host disease and graft-versus-tumor effect after reduced-intensity transplantation for metastatic renal cell carcinoma.
We describe a patient who had received reduced-intensity stem cell transplantation (RIST) for metastatic renal cell carcinoma (RCC). A 37-year-old man developed rapid progression of RCC during steroid therapy for immune-mediated thrombocytopenia and graft-versus-host disease (GVHD). After discontinuation of corticosteroid, RCC achieved long stable disease with the presence of chronic GVHD, despite low dose of prednisolone. This case suggests the impact of immunosuppression on progression of metastatic RCC after RIST.
Acute Disease↗
Fatal hepatic failure associated with graft rejection following reduced-intensity stem-cell transplantation for chronic idiopathic myelofibrosis (CIMF).
A 54-year-old man with chronic idiopathic myelofibrosis (CIMF) underwent RIST. His clinical course had been uneventful until day 60, when splenomegaly reappeared. Hepatic dysfunction developed on day 75. Recipient-type hematopoiesis increased to 51% on day 90. After rapid tapering of cyclosporin, serum levels of AST and ALP normalized in parallel with recovery of complete chimerism on day 134. Yet, jaundice progressed. He died of liver failure on day 176. Postmortem examination revealed neither GVHD nor VOD. Graft rejection following RIST for CIMF may lead to fatal hepatic damage through extramedullary hematopoiesis in the liver or cytokine-mediated immune dysregulations.
Chronic Disease↗
Reduced-intensity hematopoietic stem cell transplantation (RIST) for solid malignancies.
Reduced intensity stem cell transplantation (RIST) is a new approach of stem cell transplantation, which has shown promising features as reported in multiple phase I and II studies. Elderly patients, who are not eligible for conventional myeloablative hematopoietic stem cell transplantation (HSCT), are now treatable with RIST. It has also reduced regimen-related toxicity and provided better prognosis in short-term follow-up than conventional HSCT. Among solid tumors, metastatic renal cell carcinoma was found to respond well to RIST. Clinical studies are currently being conducted to evaluate the efficacy of RIST in other types of solid tumors. However, the mechanism of graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) effects remains unclear. More knowledge on the mechanism is crucial to enhance the antitumor effect and to improve the prognosis further.
Animals↗
Comparative analysis of clinical outcomes after allogeneic bone marrow transplantation versus peripheral blood stem cell transplantation from a related donor in Japanese patients.
A reduced incidence of graft versus host disease (GvHD) has been documented among Japanese allogeneic bone marrow transplantation (BMT) patients, as the Japanese are genetically more homogeneous than western populations. To clarify whether this ethnic difference affects the results of allogeneic peripheral blood stem cell transplantation (PBSCT), we conducted a nationwide survey to compare clinical outcomes of allogeneic PBSCT (n = 214) and BMT (n = 295) from a human leucocyte antigen-identical-related donor in Japanese patients. The cumulative incidence of grades II-IV acute GvHD was 37.4% for PBSCT and 32.0% for BMT. The cumulative incidence of extensive chronic GvHD at 1 year was significantly higher after PBSCT than BMT (42% vs. 27%; P < 0.01). The organ involvement patterns of GvHD were different between the two groups. By multivariate analyses, the incidence of chronic GvHD was significantly increased in PBSCT, whereas the stem cell source did not affect the incidence of acute GvHD, transplant-related mortality, relapse or survival. We concluded that Japanese PBSCT patients have an increased risk of chronic GvHD compared with BMT patients, but the incidence of acute GvHD was still lower than in western populations. Thus, the choice of haematopoietic stem cell source should be considered based on data for individual ethnic populations.
Acute Disease↗
EBV-positive Burkitt lymphoma as a late-onset posttransplantion lymphoproliferative disorder after allogeneic stem cell transplantation.
Posttransplantation lymphoproliferative disorder (PTLD) is one of the well-recognized complications after allogeneic stem cell transplantation (SCT). It generally occurs early after SCT, and only a few reports of late-onset cases are available. We report a 58-year-old male patient who developed lymphoma 4 years after allogeneic SCT for chronic myeloid leukemia. The presence of c-myc translocation and Epstein-Barr virus-encoded RNA in the lymphoma cells, without rearrangement of the 3'-bcr region, confirmed the histopathologic diagnosis of Burkitt lymphoma. DNA chimerism analysis revealed that the lymphoma cells were of donor origin. The patient achieved complete response with intensive chemotherapy. To our knowledge, this is the first report of Burkitt lymphoma as a PTLD occurring after allogeneic SCT.
Burkitt Lymphoma↗
Selective decontamination of digestive tract in intensive care.
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Decontamination↗
Fatal deep vein thrombosis after allogeneic reduced intensity hematopoietic stem cell transplantation for the treatment of metastatic gastric cancer.
A 61-year-old man received reduced intensity stem cell transplantation (RIST) for the treatment of metastatic gastric cancer. The cytoreductive course of RIST was uneventful until day 0, when fever suddenly developed and his performance status deteriorated. Edema developed in the bilateral lower extremities by day 7, which was diagnosed by Doppler ultrasonography as deep vein thrombosis (DVT) involving the femoral veins to the inferior vena cava. While the edema improved with anticoagulation treatment, gastrointestinal graft-versus-host disease (GVHD) followed on day 13. Diarrhea subsided spontaneously, but hypoalbuminemia persisted, with the subsequent development of oliguria and jaundice on day 18. He died of sepsis on day 30, without any evidence of cancer progression. This case demonstrates that DVT is a potentially significant problem following RIST for solid tumors.
Anticoagulants↗