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Biomedical subjects

K Kawa

Publications and source records attributed to K Kawa.

At least 19 recordsLinked to original sources
PubMed2003

Unrelated bone marrow transplantation for Epstein-Barr virus-associated T/NK-cell lymphoproliferative disease.

Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disease (LPD) has been linked to several different disorders, including chronic active EBV infection, EBV-associated hemophagocytic syndrome, hypersensitivity to mosquito bites, hydroa vacciniforme, aggressive NK-cell leukemia, and nasal/nasal-type NK-cell lymphoma. In most instances, these disorders are refractory to conventional treatments and have a poor prognosis. Here, we report a new treatment strategy for EBV-associated T/NK-cell LPD, consisting of immunochemotherapy, intensive combination chemotherapy, and stem cell transplantation. The five patients studied, two with T-cell and three with NK-cell LPD, lacked a human leukocyte antigen-matched, related donor, and therefore received bone marrow grafts from HLA-matched, unrelated donors. The preconditioning regimen consisted of total-body irradiation (12 Gy), etoposide (900 mg/m(2)), and cyclophosphamide (120 mg/kg) or melphalan (210 mg/m(2)). All patients had residual LPD by a quantitative PCR technique prior to transplantation. After unrelated bone marrow transplantation (UBMT), four of the five patients remain in continuous complete remission at a median of 19 months, without detectable EBV-DNA in peripheral blood. Thus, UBMT appears to be a reasonable option for the treatment of patients with EBV-associated T/NK-cell LPD. Detection of EBV-DNA by PCR offers an important tool for assessing minimal residual disease in patients with EBV-associated T/NK-cell LPD.

Adolescent↗
PubMed2003

Lack of clinical utility of minimal residual disease detection in allogeneic stem cell recipients with childhood acute lymphoblastic leukemia: multi-institutional collaborative study in Japan.

The clinical utility of minimal residual disease (MRD) measurements following allogeneic stem cell transplantation (SCT) in childhood ALL is controversial. We therefore performed a multi-institutional study of MRD in bone marrow samples taken before SCT and at 1, 3, 6 and 12 months after SCT. Case-specific clonal rearrangements of IgH and TCR genes and expression levels of Wilms' tumor 1 (WT1) mRNA were determined by PCR or RT-PCR methods. In total, 95 cases met all criteria for analysis of informative IgH/TCR markers and quantitative WT1 mRNA expression levels. During the 2-year (median 414 days) study period, 20 patients relapsed. Although the proportion of patients with a positive IgH/TCR result before SCT was significantly reduced at 1 month after treatment (P<0.001), attesting the efficacy of SCT, serial measurements of IgH/TCR rearrangements did not correlate with leukemic relapse. Clonal switch was demonstrated in 11 of the 14 patients with bone marrow relapse, indicating that the poor predictive power of the MRD assay most likely reflected the loss of PCR targets. WT1 expression was not related to either MRD detection by IgH/TCR assays or to clinical leukemic relapse. The clinical value of serial MRD monitoring would be limited in ALL patients undergoing SCT.

Adolescent↗
PubMed2003

Graft-versus-tumor effect in a patient with advanced neuroblastoma who received HLA haplo-identical bone marrow transplantation.

A 5-year-old boy received CD34-positive HLA haplo-identical bone marrow transplantation from his father as treatment for refractory advanced neuroblastoma. He had residual disease in the para-aortic lymph nodes and multiple bones after the transplant. However, all of his residual disease had disappeared completely 3 years later. He developed grade I acute graft-versus-host disease (GVHD) but had no symptoms of chronic GVHD or any other complications. This case demonstrates the possibility of a graft-versus-tumor effect against neuroblastoma by HLA-mismatched allogeneic hematopoietic stem cell transplantation.

Bone Marrow Transplantation↗
PubMed2002

Experience with International Neuroblastoma Staging System and Pathology Classification.

The International Neuroblastoma Staging System and Pathology Classification were proposed in 1988 and in 1999, respectively, but their clinical value has not yet been fully studied in new patients. Six hundred and forty-four patients with neuroblastoma treated between January 1995 and December 1999 were analysed by these classifications. The 4-year overall survival rate of patients <12 months of age with INSS stages 1, 2A, 2B, 3 and 4S disease was 98.5%, which was significantly higher than the 73.1% rate in stage 4 patients <12 months (P<0.0001). When patients were > or = 12 months, the 4-year overall survival rate of patients with neuroblastoma at 1, 2A, 2B and 3 stages was 100% and that of patients at stage 4 was 48.5% (P<0.0001). As to the International Neuroblastoma Pathology Classification histology, the 4-year overall survival rate was 98.8% in patients with favourable histology and 60.7% in those with unfavourable histology in the <12 months group (P<0.0001). In the > or = 12 months group, the 4-year oral survival of patients with favourable histology was 95.3% and that of patients with unfavourable histology was 50.6% (P<0.0001). Among biological factors, MYCN amplification, DNA diploidy and 1p deletions were significantly associated with poor prognosis in patients <12 months, as were MYCN amplification and DNA diploidy in patients > or = 12 months of age. Multivariate analysis showed that the INSS stage (stage 4 vs other stages) and International Neuroblastoma Pathology Classification histology (unfavourable vs favourable) were significantly and independently associated with the survival of patients undergoing treatment, stratified by age, stage and MYCN amplification (P=0.0002 and P=0.0051, respectively).

Age Factors↗
PubMed2002

Impaired activity of plasma von Willebrand factor-cleaving protease may predict the occurrence of hepatic veno-occlusive disease after stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a life-threatening complication after stem cell transplantation (SCT), characterized by thrombus formation in hepatic venules leading to a symptom triad of hyperbilirubinemia, hepatomegaly, and ascites. Multifactorial defects in the hemostatic system may contribute to its pathogenesis, but its remains to be investigated. Unusually large VWF multimers (UL-VWFMs), produced in and released from vascular endothelial cells, are most biologically active in the interaction with platelets under a high shear stress. UL-VWFMs are cleaved and degraded into smaller VWFMs by a specific liver producing plasma protease, termed VWF-cleaving protease (VWF-CPase), which has recently been identified as a metalloprotease solely produced in liver, termed ADAMTS13. Herein, we studied the correlation between plasma VWF-CPase activity and UL-VWFMs in 21 patients who received SCT, seven patients with VOD and 14 patients without VOD. In non-VOD patients, activities (mean +/- 1s.d.) of VWF-CPase were 78 +/- 17% of the control before the conditioning regimen, 76 +/- 18% on day 0, 64 +/- 19% on day 7, 57 +/- 23% on day 14, 68 +/- 13% on day 21 and 79 +/- 19% on day 28 after SCT. The respective values in VOD patients were 32 +/- 19%, 27 +/- 15%, 18 +/- 11%, 22 +/- 18%, 26 +/- 22% and 12 +/- 4%. Thus, VWF-CPase activity was significantly reduced in VOD patients, even before the conditioning regimen, and such a difference was not found in other laboratory tests. However, despite such a clear difference, UL-VWFMs were present in plasmas of both patient groups, together with the increase of VWF antigen and ristocetin cofactor activity. These results indicate that the measurement of this enzyme activity is extremely useful in predicting the occurrence of VOD prior to a demonstration of its direct involvement in its pathogenesis.

ADAM Proteins↗
PubMed2002

Polymorphisms of transforming growth factor-beta1 and transforming growth factor-beta1 type II receptor genes are associated with acute graft-versus-host disease in children with HLA-matched sibling bone marrow transplantation.

The aim of this study was to determine whether the gene polymorphisms of Th1/Th2 and immunoregulatory cytokines were associated with aGVHD in Japanese children receiving allogeneic bone marrow transplantation (allo BMT). We investigated polymorphisms of genes encoding interleukin (IL)-4, IL-4 receptor (IL-4 R), IL-10, transforming growth factor (TGF)-beta1, TGF-beta1 type II receptor (TGF-beta1 RII), interferon (IFN)-gamma, IFN-gamma type 2 receptor (IFN-gamma R2), and IFN regulatory factor (IRF)-1. Sixty-seven patients were treated with allo BMT from HLA-identical siblings, and aGVHD was observed in 38. TGF-beta1 codon 10 leucine (Leu) /proline (Pro) polymorphism in donors was associated with the development of aGVHD. Patients having donors with the Pro allele had aGVHD more frequently than those without Pro allele (30/45 vs 8/20, odds ratio = 3.00; P = 0.04). TGF-beta1 RII 1167 C/T polymorphism in recipients was also associated with the development of aGVHD. The incidence was significantly higher in recipients with T allele than in those without T allele (21/27 vs 16/35, odds ratio = 4.16; P = 0.01). In conclusion, genetic backgrounds of TGF-beta1 and TGF-beta1 RII may be involved in the development of aGVHD in HLA-matched sibling BMT in Japanese children.

Acute Disease↗
PubMed2001

Clinical and virologic characteristics of chronic active Epstein-Barr virus infection.

Thirty patients with chronic active Epstein-Barr virus (CAEBV) infection were analyzed. The study group included 18 male and 12 female patients, ranging in age from 5 to 31 years with a mean age of 14.2 years. Not all patients had high titers of EBV-specific antibodies, but all patients had high viral loads in their peripheral blood (more than 10(2.5) copies/microg DNA). Fifty percent of the patients displayed chromosomal aberrations, and 79% had monoclonality of EBV. Patients were divided into 2 clinically distinct groups, based on whether the predominantly infected cells in their peripheral blood were T cells or natural killer (NK) cells. Over a 68-month period of observation, 10 patients died from hepatic failure, malignant lymphoma, or other causes. Patients with T-cell CAEBV had a shorter survival time than those with NK-cell type of disease.

Adolescent↗
PubMed2001

Observation of untreated patients with neuroblastoma detected by mass screening: a "wait and see" pilot study.

BACKGROUND: Recent studies have indicated that mass screening for neuroblastoma detects tumors that otherwise would have regressed spontaneously without recognition. Therefore, we started an observation program for these patients to determine how frequently spontaneous regression occurs. PROCEDURE: Eighteen patients were detected by mass screening between June 1994 and December 1996. Eight of these cases matched the following criteria and entered the observation program: Stage I or II, less than 5 cm in diameter; no involvement of large vessels or organs; not difficult to resect; informed consent. If there were an increase in tumor size, an elevation of tumor markers, or evidence of metastasis, the tumor would be immediately resected. RESULTS: Five of the eight cases showed spontaneous regression. Although the remaining three tumors were resected 6-10 months after diagnosis, all patients survived without evidence of recurrence. CONCLUSIONS: At least 60% of neuroblastoma cases who entered our observation program regressed spontaneously.

Adrenal Gland Neoplasms↗
PubMed2001

t(10;11)-acute leukemias with MLL-AF10 and MLL-ABI1 chimeric transcripts: specific expression patterns of ABI1 gene in leukemia and solid tumor cell lines.

The recurrent translocation t(10;11) is associated with acute myeloid leukemia (AML). The AF10 gene on chromosome 10 at band p12 and MLL at 11q23 fuse in the t(10;11)(p12;q23). Recently, we have identified ABI1 as a new partner gene for MLL in an AML patient with a t(10;11)(p11.2;q23). The ABI1 is a human homologue of the mouse Abl-interactor 1 (Abi1), encoding an Abl-binding protein. The ABI1 protein exhibits sequence similarity to homeotic genes, and contains several polyproline stretches and a src homology 3 (SH3) domain. To clarify the clinical features of t(10;11)-leukemias, we investigated 6 samples from acute leukemia patients with t(10;11) and MLL rearrangement and detected MLL-AF10 chimeric transcripts in 5 samples and MLL-ABI1 in one. The patient with MLL-ABI1 chimeric transcript is the second case described, thus confirming that the fusion of the MLL and ABI1 genes is a recurring abnormality. Both of the patients with MLL-ABI1 chimeric transcript are surviving, suggesting that these patients have a better prognosis than the patients with MLL-AF10. To investigate the roles of AF10 and ABI1 further, we examined the expression of these genes in various cell lines and fresh tumor samples using the reverse transcriptase-polymerase chain reaction method. Although AF10 was expressed in almost all cell lines similarly, the expression patterns of ABI1 were different between leukemia and solid tumor cell lines, suggesting the distinctive role of each isoform of ABI1 in these cell lines. We also determined the complete mouse Abi1 sequence and found that the sequence matched with human ABI1 better than the originally reported Abi1 sequence. Further functional analysis of the MLL-AF10 and MLL-ABI1 fusion proteins will provide new insights into the leukemogenesis of t(10;11)-AML.

Acute Disease↗
PubMed2001

Successful allogeneic stem cell transplantation from an unrelated donor for aggressive Epstein-Barr virus-associated clonal T-cell proliferation with hemophagocytosis.

We present here a case of aggressive Epstein-Barr virus (EBV)-associated clonal T-cell proliferation with hemophagocytosis that was successfully treated by allogeneic stem cell transplantation using an unrelated donor. A 17-year-old woman was admitted into the hospital with a high fever and liver dysfunction. Laboratory data including bone marrow aspiration revealed hemophagocytic syndrome with proliferation of immature T-lymphoid cells. The clonal proliferation of EBV-infected T cells was confirmed by Southern blot analysis using a terminal-repeat probe from the EBV genome and also by demonstrating T cell-receptor beta gene rearrangement. Intensive immunochemotherapy consisting of cyclosporin A, vincristine, etoposide, and high-dose methylprednisolone did not control the disease and relapse occurred repeatedly. Therefore, during remission after chemotherapy according to the CHOP-E regimen, the patient underwent allogeneic bone marrow transplantation (BMT) from an HLA-matched, unrelated donor. Donor selection was performed with help from the Japanese Association for Marrow Donor Program (JMDP). The patient has remained in good condition without recurrence of disease for 18 months after BMT. Allogeneic BMT is the treatment of choice for aggressive EBV-associated hemophagocytic lymphohistiocytosis even in the case where an HLA-matched sibling donor is not available, especially when the patient is refractory to intensive chemotherapy and/or there is a ready recurrence of disease after conventional therapy.

Adolescent↗
PubMed2001

Pneumococcal arthritis affects performance status in patients with chronic GVHD of the skin following allogeneic bone marrow transplantation.

We encountered 2 patients with pneumococcal arthritis following bone marrow transplantation (BMT). Both patients received grafts from unrelated human lymphocyte antigen (HLA)-matched donors and had suffered from chronic graft-versus-host disease (GVHD). One, a 10-year-old boy, suffered from Epstein-Barr virus-related lymphoproliferative disease (EB-LPD) and received oral 6-mercaptopurine and methotrexate to manage lymphadenopathy. Twenty-four months after BMT and 7 months after the onset of EB-LPD, pneumococcal arthritis occurred in both knee joints. The other patient, a 10-year-old girl, received multiagent immunosuppressive therapy for her chronic GVHD. At 51 months following BMT, pneumococcal arthritis occurred in her left knee joint. Chronic GVHD of the skin delayed the recovery from the arthritis in both patients. This complication is quite rare but can be very serious, in regard to the patient's performance status following BMT. Although vaccination against pneumococcus or preventive antibiotics should be administered to high-risk patients, early diagnosis and treatment may be the best strategy for pneumococcal arthritis.

Anti-Bacterial Agents↗
PubMed2001

Kinetics of plasma cytokines after hematopoietic stem cell transplantation from unrelated donors: the ratio of plasma IL-10/sTNFR level as a potential prognostic marker in severe acute graft-versus-host disease.

The plasma levels of a panel of cytokines and cytokine-associated molecules (IL-1alpha, IL-2, IL-4, IL-6, IL-10, IL-12, IL-15, macrophage colony-stimulating factor (M-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), soluble tumor necrosis factor receptor I or II (sTNFRI or II)) were assessed in 56 plasma samples of 13 pediatric patients undergoing hematopoietic stem cell transplantation (HSCT, bone marrow in 12 and cord blood in one) from unrelated donors. Eight patients developed severe (grade III-IV) acute GVHD (aGVHD). The plasma IL-6, IL-10, M-CSF, sTNFRI and II levels were significantly high in the severe aGVHD group compared to the mild aGVHD group (grade 0-II). The plasma IL-15 level increased transiently in the early period following HSCT and remained high in the severe aGVHD group even after 4 weeks following HSCT. Based on analysis of the correlations between the kinetics of the plasma cytokine levels after HSCT and the clinical manifestations of aGVHD, IL-15 and/or M-CSF were involved in the development of aGVHD, following elevation of the plasma IL-10 and sTNFRI or II levels. These kinetics suggest that IL-10 and sTNFRs worked as suppressor cytokines and seemed to suppress clinical manifestations of aGVHD. Furthermore, it seemed that the plasma ratio of IL-10/sTNFRII from 5 to 12 weeks following HSCT was linked to the poor outcome in the patients with severe aGVHD, suggesting that IL-10 plays an important role in protecting hosts from transplantation-related complications, including GVHD.

Acute Disease↗
PubMed2001

[CD34+ progenitor cell transplantation from HLA-mismatched donors to two patients with chronic active Epstein-Barr virus infection].

We report two boys with chronic active Epstein-Barr virus infection (CAEBV) refractory to conventional chemotherapy, who received HLA-mismatched allografts of CD34-positive progenitor cells from their fathers. One patient developed veno-occlusive disease (VOD) of the liver on day 18 after transplantation and died on day 26. The other patient received the allograft during partial remission. Although he suffered recurrent infections due to Streptococcus viridans, he is now doing well 23 months after transplantation. CAEBV refractory to chemotherapy is considered to be a fatal EBV-infected T/NK-cell lymphoproliferative disease, and our experiences suggest that CD34-positive progenitor cell transplantation for patients with CAEBV lacking HLA-matched donors may be a feasible and useful treatment. However, the timing of transplantation is considered to be critical, and should be performed when the patient is in good clinical condition.

Antigens, CD34↗
PubMed2000

Allogeneic hematopoietic transplantation of CD34+ selected cells from an HLA haplo-identical related donor. A long-term follow-up of 135 patients and a comparison of stem cell source between the bone marrow and the peripheral blood.

We studied the outcome of allogeneic transplants in 135 patients who received selected BM and/or PBSC CD34+ cells from HLA haplo-identical related donors. Donor engraftment was achieved in 108 of 128 evaluable transplants. Engraftment failure occurred more often in non-malignant than in malignant diseases (10 of 25 vs 17 of 103, P = 0.010). The CD34+ cell dose was associated with the speed of neutrophil and platelet recovery, but the cell source was not. Acute GVHD (> or = grade II) developed in 21.0 +/- 3.7%. Chronic GVHD occurred more frequently in malignancies than in non-malignancies (44.1 +/- 7.6% vs 0.0%, P = 0.0075), and more in PBSC recipients than in BM recipients (53.6 +/- 9.4% vs 17.4 +/- 9.3%, P = 0.0054). Relapse rate was higher in high risk patients than in standard risk patients (78.7 +/- 7.1% vs 22.1 +/- 10.0%, P = 0.0001). Probabilities of disease-free survival (DFS) were 14.2 +/- 3.5% in malignancies and 25.7 +/- 9.2% in non-malignancies. Probabilities of DFS in standard and high risk patients were 39.4 +/- 9.2% and 5.7 +/- 2.8% (P = 0.0001). A high incidence of graft failure, infection and relapse was observed and resulted in high mortality.

Actuarial Analysis↗
PubMed2000

Epstein-Barr virus--associated diseases in humans.

It has been known for 30 years that Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, is the etiologic agent of acute infectious mononucleosis and is closely associated with the genesis of Burkitt's lymphoma and undifferentiated nasopharyngeal carcinoma. Recent studies have demonstrated that EBV is also implicated in a variety of other diseases, such as EBV-associated hemophagocytic syndrome, chronic active EBV infection, T-cell lymphoma, natural killer cell leukemia/lymphoma, lymphoproliferative diseases in immunocompromised hosts, Hodgkin's disease, pyothorax-associated B-cell lymphoma, smooth-muscle tumors, and gastric carcinoma. Thus, the virus continues to attract worldwide attention, and it is now appropriate for a reappraisal of the relation between EBV and human diseases. This review summarizes the recent progress in research on EBV and the clinical findings of EBV-associated diseases and provides a basis for the development of new therapeutic strategies.

Epstein-Barr Virus Infections↗