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Hiroyasu Ogawa

Publications and source records attributed to Hiroyasu Ogawa.

At least 37 records · Page 2Linked to original sources
PubMed2004

Unmanipulated reduced-intensity stem cell transplantation from a haploidentical donor mismatched at 3 HLA antigens to a patient with leukemic transformation of myelodysplastic syndrome: successful second transplantation after graft rejection.

We present the case of a patient with myelodysplastic syndrome who experienced leukemia transformation and subsequently underwent transplantation of unmanipulated peripheral blood stem cells from a haploidentical sibling mismatched at 3 HLA antigens, along with a reduced-intensity regimen (fludarabine, busulfan, and anti-T-lymphocyte globulin) and tacrolimus-containing graft-versus-host disease (GVHD) prophylaxis. The patient experienced graft rejection but successfully underwent a second transplantation from the same donor with a slightly intensified conditioning regimen. Although the patient developed life-threatening cytomegalovirus (CMV) pneumonia following the second transplantation, he recovered completely from the pneumonia with intensive supportive therapy. He is still in complete remission past day 1000 in the absence of GVHD. As far as we know, this report is the first to describe a successful second transplantation that was performed for graft rejection following HLA-haploidentical nonmyeloablative stem cell transplantation. Furthermore, we emphasize that patients should be carefully monitored for CMV infection when reduced-intensity conditioning is given repeatedly over a short period.

Adult↗
PubMed2004

Allogeneic bone marrow transplantation with non-T-cell-depleted marrow from two HLA-antigen-mismatched related donors.

Allogeneic BMT from 2 antigen-mismatched donors has been difficult to perform without T-cell depletion. Seven patients with advanced-stage hematologic malignancies underwent BMT with intensified graft-versus-host disease prophylaxis consisting of tacrolimus, methotrexate, and methylprednisolone. No rejection or acute GVHD >or= grade III was observed. This preliminary result is very promising.

Adult↗
PubMed2003

Unrelated bone marrow transplantation for non-Hodgkin lymphoma: a study from the Japan Marrow Donor Program.

There is little information available regarding the outcome of unrelated bone marrow transplantation (BMT) for non-Hodgkin lymphoma (NHL). Therefore, we retrospectively analyzed the data of 124 patients who underwent unrelated BMT through the Japan Marrow Donor Program (JMDP) between July 1992 and August 2001. The overall survival (OS), progression-free survival (PFS), cumulative incidences of disease progression, and nonprogression mortality at 3 years after BMT were 49.7%, 42.6%, 24.5%, and 32.9%, respectively, with a median follow-up duration of 565 days among survivors. The incidence of grades II-IV acute graft-versus-host disease (GVHD) was 40.9%. Recipient age, previous history of autologous transplantation, and chemosensitivity at transplantation were independent prognostic factors for OS and PFS. The development of grades II-IV acute GVHD was associated with lower incidence of disease progression after transplantation, which suggested the existence of a graft versus lymphoma effect. Unrelated BMT should be considered as a treatment option for patients with high-risk NHL without an HLA-matched related donor.

Adolescent↗
PubMed2003

Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis.

The Wilms tumor gene, WT1, is overexpressed not only in leukemias and myelodysplastic syndrome (MDS) but also in various types of solid tumors, including lung and breast cancer, and the WT1 protein is a tumor antigen for these malignancies. In clinical trials of WT1 peptide-based cancer immunotherapy, patients with overt leukemia from MDS or MDS with myelofibrosis were injected intradermally with 0.3 mg of an HLA-A*2402-restricted, 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant. Only a single dose of WT1 vaccination resulted in an increase in WT1-specific cytotoxic T-lymphocytes, which was followed by a rapid reduction in leukemic blast cells. Severe leukopenia and local erythema at the injection sites of WT1 peptide were observed as adverse effects. These results have provided us with the first clinical evidence suggesting that WT1 peptide-based immunotherapy is an attractive treatment for patients with leukemias or MDS.

Aged↗
PubMed2003

Monitoring minimal residual disease in leukemia using real-time quantitative polymerase chain reaction for Wilms tumor gene (WT1).

We previously showed that Wilms tumor gene (WT1) expression level, measured by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), was useful as an indicator of minimal residual disease (MRD) in leukemia and myelodysplastic syndrome. However, in conventional quantitative RT-PCR (CQ-PCR), RT-PCR must be performed for various numbers of cycles depending on WT1 expression level. In the present study, we developed a new real-time quantitative RT-PCR (RQ-PCR) method for quantitating WT1 transcripts. Results of intraassay and interassay variability tests demonstrated that the real-time WT1 assay had high reproducibility. WT1 expression levels measured by the RQ- and the CQ-PCR methods were strongly correlated (r = 0.998). Furthermore, a strong correlation was observed among WT1 transcript values normalized with 3 different control genes (beta-actin, ABL, and glyceraldehyde-3-phosphate dehydrogenase) and between relative WT1 transcript values with WT1 expression in K562 cells as the reference and absolute WT1 transcript copy numbers per microgram RNA. When WT1 expression and minor bcr-abl expression were concurrently monitored in 2 patients with bcr-abl-positive acute lymphoblastic leukemia, both MRDs changed mostly in parallel, indicating the reliability and validity of our RQ-PCR method. In conclusion, this RQ-PCR method is convenient and reliable for monitoring MRD and enables routine clinical use of a WT1 assay.

Gene Dosage↗
PubMed2003

The lck promoter-driven expression of the Wilms tumor gene WT1 blocks intrathymic differentiation of T-lineage cells.

In the thymi of WT1-transgenic (Tg) mice with the 17AA+/KTS- spliced form of the Wilms tumor gene WT1 driven by the lck promoter, the frequencies of CD4-CD8- double-negative (DN) thymocytes were significantly increased relative to those in normal littermates. Of the 4 subsets of CD4-CD8- DN thymocytes, the DN1 (CD44+CD25-) subset increased in both frequency and absolute cell number, whereas the DN2 (CD44+CD25+) and DN3 (CD44-CD25+) subsets decreased, indicating the blocking of thymocyte differentiation from the DN1 to the DN2 subsets. Furthermore, CD4-CD8+ T-cell receptor (TCR) -gammadelta T-cells increased in both frequency and absolute cell number in the spleen and peripheral blood of the WT1-Tg mice relative to those of normal littermates. The CD8 molecules of these CD4-CD8+ TCRgammadelta T-cells were CD8alphabeta, suggesting that they originated from the thymus. These results are the first direct evidence demonstrating that the WT1 gene is involved in the development and differentiation of T-lineage cells.

Animals↗
PubMed2003

Overexpression of the Wilms' tumor gene WT1 in head and neck squamous cell carcinoma.

The expression levels of the Wilms' tumor gene WT1 were examined in 56 cases of head and neck squamous cell carcinoma (HNSCC) using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). They included 4 cases of floor of mouth, 9 of gingiva, 25 of tongue, 10 of oropharynx, 3 of hypopharynx, and 5 larynx squamous cell carcinoma (SCC). All (100%) of 4 cases of floor of mouth, 5 (56%) of 9 gingiva, 17 (68%) of 25 tongue, 8 (80%) of 10 oropharynx, all (100%) of 3 hypopharynx, and all (100%) of 5 larynx SCC overexpressed the WT1 gene in the range of 3.07 x 10(-4)-8.60 x 10(-1) levels (the WT1 expression level in K562 leukemic cells was defined as 1.0). Thus, 42 (75%) out of 56 cases of HNSCC overexpressed the WT1 gene. The high expression level of the WT1 gene significantly correlated with poor histological tumor differentiation and high tumor stage of HNSCC. Immunohistochemical analysis confirmed the expression of WT1 protein in 6 cases (one floor of mouth, 2 tongue, 2 oropharynx, and one larynx SCC) with overexpression of the WT1 gene. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of 10 exons of the WT1 gene in 5 different HNSCC. These findings suggest an important role of the wild-type WT1 gene in the tumorigenesis of HNSCC.

Adult↗
PubMed2003

Overexpression of the Wilms' tumor gene WT1 in primary thyroid cancer.

The expression levels of the Wilms' tumor gene WT1 were examined in 34 primary thyroid cancers (24 papillary, 5 follicular, 1 anaplastic, and 4 medullary carcinomas), 17 thyroid follicular adenomas, and 6 normal-appearing thyroid tissues using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). In 33 of 34 thyroid cancers, the WT1 mRNA was expressed at levels ranging from 5.0 x 10 (-5) to 8.3 x 10 (-2) levels (WT1 expression level in K562 leukemic cells was defined as 1.0). The WT1 mRNA expression levels were significantly higher than those in either thyroid follicular adenomas (P < 0.001) or normal-appearing thyroid tissues (P < 0.01). Immunohistochemical analysis confirmed the expression of WT1 protein in 20 of 21 thyroid cancers with WT1 mRNA expression. WT1 protein was also detected in 6 of 7 follicular adenomas with WT1 mRNA expression. However, the intensity of staining of WT1 protein in adenoma cells was weaker than that in cancer cells and its expression was restricted to approximately 30-80% of adenoma cells in the tumors examined. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of the 10 exons of the WT1 gene in all of the 9 different thyroid cancers. These findings indicate an important role of the wild-type WT1 gene in the tumorigenesis of primary thyroid cancer.

Adenocarcinoma, Follicular↗
PubMed2003

Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma.

Expression of the Wilms' tumor gene WT1 was examined in 59 cases of colorectal adenocarcinoma to examine the involvement of WT1 in tumorigenesis. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) showed that WT1 mRNA was expressed in the range from 7.2 x 10(-5) to 4.9 x 10(-1) levels (WT1 expression level in K562 leukemic cells was defined as 1.0) in all (100%) of the 28 cases of colorectal adenocarcinoma examined, and that the WT1 mRNA expression levels were higher in 20 (71%) of the 28 cases compared to those of normal-appearing mucosal tissues examined. Immunohistochemical analysis using an anti-WT1 antibody was performed on 46 cases of colorectal adenocarcinoma (15 of the 28 cases with WT1 mRNA expression and 31 newly collected cases), and the expression of WT1 protein was detected in 41 (89%) of the 46 cases. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of the 10 exons of the WT1 gene in any of 5 different colorectal adenocarcinomas. These results may indicate an important role of the wild-type WT1 gene in tumorigenesis of colorectal adenocarcinoma.

Adenocarcinoma↗
PubMed2003

[Current status of reduced-intensity stem cell transplantation; survey in the Kinki area].

The status of reduced-intensity stem cell transplantation (RIST) in the Kinki area was investigated by questionnaires. We sent out questionnaires to 72 institutions and received 51 replies (72.2%). RIST was performed in 16 institutions (31.4%). A total of 91 cases were included of whom approximately 70% were non-remission or advanced hematological malignancies. Various conditioning regimens were used for RIST, most often consisting of fludarabine, busulfan and antithymocte globulin. Acute GVHD developed in 57% of all patients. Relapse or disease progression developed in 42.7% of evaluable patients. The overall survival rate was 54.6%, and 80% of low risk patients were alive at the time of analysis.

Adolescent↗
PubMed2003

[Mini-transplantation from HLA-mismatched donors].

Bone marrow transplantation(BMT) from genotypically human leukocyte antigen (HLA)-matched siblings improves long-term survival in patients with hematologic malignancies. However, more than 70% of patients who could benefit from allogeneic BMT do not have a matched sibling donor. Furthermore, allogeneic BMT has been limited to young patients because of the increased risk for regimen-related toxicity and graft-versus-host disease(GVHD) that occurs with increasing age. HLA-haploidentical minitransplantation may solve these problems. In minitransplants using a preconditioning regimen consisting of fludarabine, busulfan and anti-T-lymphocyte globulin and a GVHD prophylaxis of tacrolimus and methylprednisolone, we showed that minitransplantation from HLA-haploidentical related donors was possible.

Animals↗
PubMed2003

Huge post-operative ulcer following hydroxyurea therapy in a patient with polycythemia vera.

A 75-year old woman was referred to our hospital due to a worsening post-operative cutaneous ulcer. She had a history of polycythemia vera and had been treated with a daily dose of 500mg hydroxyurea (HU) for six years. She underwent a right hernioplasty in another hospital in September 2002. Two days after the hernioplasty, the skin around the wound became erythematous and necrosis was observed. Even with the administration of antibiotics and debridment was performed three times, her condition deteriorated and she was referred to our hospital. On admission, a 22x15cm ulcer was observed on the lower abdomen. With termination of HU, the cutaneous ulcer became smaller and with the withdrawal of other medication, the ulcer size continued to decrease. Although post-operative cutaneous ulcer complicated by HU administration has rarely been reported, our case clearly indicates that early termination of HU should be considered when patients develop symptoms preceding cutaneous ulcer.

Aged↗
PubMed2002

The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia.

In acute-type leukemia, no method for the prediction of relapse following allogeneic stem cell transplantation based on minimal residual disease (MRD) levels is established yet. In the present study, MRD in 72 cases of allogeneic transplantation for acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia (accelerated phase or blast crisis) was monitored frequently by quantitating the transcript of WT1 gene, a "panleukemic MRD marker," using reverse transcriptase-polymerase chain reaction. Based on the negativity of expression of chimeric genes, the background level of WT1 transcripts in bone marrow following allogeneic transplantation was significantly decreased compared with the level in healthy volunteers. The probability of relapse occurring within 40 days significantly increased step-by-step according to the increase in WT1 expression level (100% for 1.0 x 10(-2)-5.0 x 10(-2), 44.4% for 4.0 x 10(-3)-1.0 x 10(-2), 10.2% for 4.0 x 10(-4)-4.0 x 10(-3), and 0.8% for < 4.0 x 10(-4)) when WT1 level in K562 was defined as 1.0). WT1 levels in patients having relapse increased exponentially with a constant doubling time. The doubling time of the WT1 level in patients for whom the discontinuation of immunosuppressive agents or donor leukocyte infusion was effective was significantly longer than that for patients in whom it was not (P <.05). No patients with a short doubling time of WT1 transcripts (< 13 days) responded to these immunomodulation therapies. These findings strongly suggest that the WT1 assay is very useful for the prediction and management of relapse following allogeneic stem cell transplantation regardless of the presence of chimeric gene markers.

Acute Disease↗
PubMed2002

Enhanced induction of human WT1-specific cytotoxic T lymphocytes with a 9-mer WT1 peptide modified at HLA-A*2402-binding residues.

The Wilms' tumor gene WT1 is overexpressed in most types of leukemias and various kinds of solid tumors, including lung and breast cancer, and participates in leukemogenesis and tumorigenesis. WT1 protein has been reported to be a promising tumor antigen in mouse and human. In the present study, a single amino-acid substitution, M-->Y, was introduced into the first anchor motif at position 2 of the natural immunogenic HLA-A*2402-restricted 9-mer WT1 peptide (CMTWNQMNL; a.a. 235-243). This substitution increased the binding affinity of the 9-mer WT1 peptide to HLA-A*2402 molecules from 1.82 x 10(-5) to 6.40 x 10(-7) M. As expected from the increased binding affinity, the modified 9-mer WT1 peptide (CYTWNQMNL) elicited WT1-specific cytotoxic T lymphocytes (CTL) more effectively than the natural 9-mer WT1 peptide from peripheral blood mononuclear cells (PBMC) of HLA-A*2402-positive healthy volunteers. CTL induced by the modified 9-mer WT1 peptide killed the natural 9-mer WT1 peptide-pulsed CIR-A*2402 cells, primary leukemia cells with endogenous WT1 expression and lung cancer cell lines in a WT1-specific HLA-A*2402-restricted manner. These results showed that this modified 9-mer WT1 peptide was more immunogenic for the induction of WT1-specific CTL than the natural 9-mer WT1 peptide, and that CTL induced by the modified 9-mer WT1 peptide could effectively recognize and kill tumor cells with endogenous WT1 expression. Therefore, cancer immunotherapy using this modified 9-mer WT1 peptide should provide efficacious treatment for HLA-A*2402-positive patients with leukemias and solid tumors.

HLA-A Antigens↗
PubMed2002

Combination of tacrolimus, methotrexate, and methylprednisolone prevents acute but not chronic graft-versus-host disease in unrelated bone marrow transplantation.

BACKGROUND: Graft-versus-host disease (GVHD) is still a major problem in allogeneic bone marrow transplantation (BMT). Prophylactic regimens used against GVHD in unrelated BMT, including cyclosporine (CsA)-plus-methotrexate (MTX), CsA-plus-MTX-plus-prednisone, and tacrolimus (FK506)-plus-MTX, are still unsatisfactory (34-70% occurrence of grades II-IV GVHD). To address this problem, we examined the efficacy of FK506-plus-MTX-plus-methylprednisolone (mPSL) in 20 patients who underwent BMT from unrelated donors. METHODS: All patients received FK506 beginning the day before transplantation at a dose of 0.03 mg/kg per day by continuous intravenous (IV) infusion. MTX was administered at a dose of 10 mg/m(2) IV on day 1, and 7 mg/m(2) on days 3, 6, and 11. Intravenous administration of mPSL was started at a dose of 2 mg/kg per day on day 1. In the absence of acute GVHD, mPSL was gradually tapered from day 29. RESULTS: Development of acute GVHD was almost completely suppressed (one patient with grade I, none with grades II-IV). However, the incidence and severity of chronic GVHD did not decrease. Eight of 12 patients with extensive chronic GVHD died of thrombotic microangiopathy or infection. A vigorous fluctuation (>100 U/mL per 10 days) of the soluble interleukin 2 receptor level in the serum after engraftment was highly related to the occurrence of chronic GVHD. CONCLUSIONS: An FK506-plus(+)-MTX-plus(+)-mPSL prophylactic regimen could almost completely suppress acute GVHD but not chronic GVHD in unrelated BMT. In this GVHD prophylactic system, the extent of the change of soluble interleukin 2 receptor level may be a good predictor of development of chronic GVHD.

Acute Disease↗