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Toshihiro Soma

Publications and source records attributed to Toshihiro Soma.

16 recordsLinked to original sources
PubMed2006

Unblinded pilot study of autologous transplantation of bone marrow mononuclear cells in patients with thromboangiitis obliterans.

BACKGROUND: The short-term clinical benefits of bone marrow mononuclear cell transplantation have been shown in patients with critical limb ischemia. The purpose of this study was to assess the long-term safety and efficacy of bone marrow mononuclear cell transplantation in patients with thromboangiitis obliterans. METHODS AND RESULTS: Eleven limbs (3 with rest pain and 8 with an ischemic ulcer) of 8 patients were treated by bone marrow mononuclear cell transplantation. The patients were followed up for clinical events for a mean of 684+/-549 days (range 103 to 1466 days). At 4 weeks, improvement in pain was observed in all 11 limbs, with complete relief in 4 (36%). Pain scale (visual analog scale) score decreased from 5.1+/-0.7 to 1.5+/-1.3. An improvement in skin ulcers was observed in all 8 limbs with an ischemic ulcer, with complete healing in 7 (88%). During the follow-up, however, clinical events occurred in 4 of the 8 patients. The first patient suffered sudden death at 20 months after transplantation at 30 years of age. The second patient with an incomplete healing of a skin ulcer showed worsening of the lesion at 4 months. The third patient showed worsening of rest pain at 8 months. The last patient developed an arteriovenous shunt in the foot at 7 months, which spontaneously regressed by 1 year. CONCLUSIONS: In the present unblinded and uncontrolled pilot study, long-term adverse events, including death and unfavorable angiogenesis, were observed in half of the patients receiving bone marrow mononuclear cell transplantation. Given the current incomplete knowledge of the safety and efficacy of this strategy, careful long-term monitoring is required for future patients receiving this treatment.

Adult↗
PubMed2006

A new protocol for quantifying CD34(+) cells in peripheral blood of patients with cardiovascular disease.

Increasing evidence points to a role for circulating CD34-positive (CD34(+)) cells in vascular maintenance and neovascularization. Although there are established methods for evaluating absolute numbers of CD34(+) cells in bone marrow or mobilized peripheral blood, there is no convenient and highly reproducible method for quantifying low numbers of CD34(+) cells in blood samples, such as those from the peripheral blood of patients with cardiovascular disease. With current commonly used methods, the mean percentage of CD34(+) cells in leukocyte fractions from such patients was only 0.02%, and the cumulative intra-assay coefficient of variation was approximately 30%. With use of the protocol described herein, actual counts of CD34(+) cells increased approximately 5-fold and cumulative intra-assay coefficients of variation were reduced to approximately 7%. The new method is useful to precisely measure low numbers of CD34(+) cells in samples, and it has potential as a screening tool to evaluate cardiovascular risk in large patient populations.

Aged↗
PubMed2005

Prognostic significance of BACH2 expression in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group.

PURPOSE: BACH2, a B-cell-specific transcription repressor, is abundantly expressed in lymphocytes of B-cell lineage as well as B-cell lymphoma cell lines. BACH2 possesses an inhibitory effect on proliferation of Raji cell lines derived from Burkitt's lymphoma. In this study, the prognostic significance of BACH2 expression was examined in diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: BACH2 expression was immunohistochemically examined on the paraffin-embedded sections obtained by biopsy from 108 patients (62 males and 46 females; age range, 23 to 85 years) with DLBCL. Staining intensity in the cytoplasm of the tumor cells was categorized as equal to or stronger (level 1) or weaker (level 2) than that in the endothelial cells in the same specimens. RESULTS: Level 1 and 2 expression of BACH2 was found in 32.4% and 67.6% of patients, respectively. Patients with level 1 expression showed significantly better disease-free and overall survival rate than those with level 2 expression (both P < .05). Multivariate analysis revealed BACH2 expression level together with performance status, elevated serum level of lactate dehydrogenase, and treatment response to be independent factors for prognosis of the patients. CONCLUSION: BACH2 expression level is a useful marker to predict disease-free and overall survival of patients with DLBCL.

Adult↗
PubMed2005

[Clinical course of the disease and the level of WT1 mRNA in 191 patients with acute myeloid leukemia (AML): joint research by 23 institutions in Japan].

We evaluated the clinical course of acute myeloid leukemia (AML) and the levels of WT1 mRNA in 191 AML patients. Of 114 previously untreated patients with AML, 107 cases were positive for WT1 mRNA (93.9% : 107/114). WT1 mRNA expression-levels declined to below 50 copies/microg RNA ("negative") after remission was achieved in all 66 patients who achieved remission and 84.8% (47/54) cases were "negative" at the end of the follow-up periods. On the other hand, WT1 mRNA was expressed in 87.0% of non-remission cases (47/54), maintaining 50 copies/microg of RNA or higher ("positive"). In all 29 cases who relapsed during the follow-up observation period after achieving remission, WT1 mRNA levels declined transiently approximately around the time of achieving remission and then rose again when the disease relapsed. Moreover, we determined the time of elevation of WT1 mRNA in 29 relapsed cases. In 79.3% of relapsed cases (23/29), WT1 mRNA levels rose above 200 copies/microg RNA, 43 days (median) before the diagnosis of "relapse". Given the percent of the correct diagnosis, WT1 mRNA at 200 copies/microg RNA appeared to be a reasonable cut-off level for early detection of AML-relapse. The WT1 mRNA level reflected the clinical condition. Taken together, these findings indicate that WT1 mRNA levels allow us to detect the presence of so-called "minimal residual disease" (leukemic cells) that cannot be detected by morphological examination. Besides these promising data, this kit is suitable for routine monitoring of AML because this kit utilizes peripheral blood as a test specimen, reducing the patient's burden at the time of collection of clinical samples as compared with bone marrow aspirate.

Adult↗
PubMed2004

Circulating CD34-positive cells provide an index of cerebrovascular function.

BACKGROUND: Increasing evidence points to a role for circulating endothelial progenitor cells, including populations of CD34- and CD133-positive cells present in peripheral blood, in maintenance of the vasculature and neovascularization. Immature populations, including CD34-positive cells, have been shown to contribute to vascular homeostasis, not only as a pool of endothelial progenitor cells but also as a source of growth/angiogenesis factors at ischemic loci. We hypothesized that diminished numbers of circulating immature cells might impair such physiological and reparative processes, potentially contributing to cerebrovascular dysfunction. METHODS AND RESULTS: The level of circulating immature cells, CD34-, CD133-, CD117-, and CD135-positive cells, in patients with a history of atherothrombotic cerebral ischemic events was analyzed to assess possible correlations with the degree of carotid atherosclerosis and number of cerebral infarctions. There was a strong inverse correlation between numbers of circulating CD34- and CD133-positive cells and cerebral infarction. In contrast, there was no correlation between the degree of atherosclerosis and populations of circulating immature cells. Analysis of patients with cerebral artery occlusion revealed a significant positive correlation between circulating CD34- and CD133-positive cells and regional blood flow in areas of chronic hypoperfusion. CONCLUSIONS: These results suggest a possible contribution of circulating CD34- and CD133-positive cells in maintenance of the cerebral circulation in settings of ischemic stress. Our data demonstrate the utility of a simple and precise method to quantify circulating CD34-positive cells, the latter providing a marker of cerebrovascular function.

AC133 Antigen↗
PubMed2004

Effect of heparin addition on expansion of cord blood hematopoietic progenitor cells in three-dimensional coculture with stromal cells in nonwoven fabrics.

Primary human cord blood mononuclear cells (CB MNCs) were inoculated into layers of primary human bone marrow stromal cells prepared in a nonwoven fabric porous carrier [three dimensional (3-D)] or on a dish [two dimensional (2-D)] using a cytokine-free medium and were cultured for 7 days with or without the addition of heparin. The number of progenitor cells increased threefold during the 3-D coculture, whereas it decreased in the 2-D culture. Heparin addition to the 3-D coculture further increased the number of progenitors twofold, whereas the addition of desulfated heparin had no effect. The heparin effect was also observed in a 3-D culture of CB MNCs without stromal cells when conditioned medium was employed. The coating of the carrier with N-(O-beta-(6-O-sulfogalactopyranosyl)-6-oxyhexyl)-3,5-bis (dodecyloxy)-benzamide instead of heparin addition also increased the number of progenitor cells in the 3-D culture of CB MNCs without stromal cells when the conditioned medium was employed. The 3-D coculture constructed with nonwoven fabrics and stromal cells was clearly superior to the 2-D culture because of the expansion of CB hematopoietic progenitor cells without cytokine addition. Heparin addition to the 3-D coculture further increased the number of progenitor cells, which may result from a synergistic effect of soluble cytokines produced by stromal cells with the sulfur group of heparin.

Animals↗
PubMed2004

Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model.

Thrombo-occlusive cerebrovascular disease resulting in stroke and permanent neuronal loss is an important cause of morbidity and mortality. Because of the unique properties of cerebral vasculature and the limited reparative capability of neuronal tissue, it has been difficult to devise effective neuroprotective therapies in cerebral ischemia. Our results demonstrate that systemic administration of human cord blood-derived CD34(+) cells to immunocompromised mice subjected to stroke 48 hours earlier induces neovascularization in the ischemic zone and provides a favorable environment for neuronal regeneration. Endogenous neurogenesis, suppressed by an antiangiogenic agent, is accelerated as a result of enhanced migration of neuronal progenitor cells to the damaged area, followed by their maturation and functional recovery. Our data suggest an essential role for CD34(+) cells in promoting directly or indirectly an environment conducive to neovascularization of ischemic brain so that neuronal regeneration can proceed.

Animals↗
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

Analysis of hematopoietic microenvironment containing spatial development of stromal cells in nonwoven fabrics.

We previously reported that a 3D coculture system for hematopoietic cells with spatial development of stromal cells in nonwoven fabrics was superior to a conventional 2D coculture system with respect to progenitor expansion and stem cell maintenance. The hematopoietic environments in 2D and 3D coculture systems were compared and it was found there were no differences in the amounts of soluble factors, e.g., mRNA levels of stem cell factor (SCF) and thrombopoietin (TPO), the secretion of SCF, and hematopoietic stimulating activity of culture supernatant. On the other hand, the total amount of insoluble factors such as extracellular proteins around the stromal cells and the mRNA level of laminin alpha5 were apparently higher in the 3D culture.

Journal Article↗
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

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↗
PubMed2002

Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies.

Wilms tumor gene WT1 is expressed at high levels in hematopoietic malignancies, such as leukemias and myelodysplastic syndromes (MDS), and in various kinds of solid tumors, including lung cancer, and it exerts an oncogenic function in these malignancies. IgM and IgG WT1 antibodies were measured by means of dot blot assay in 73 patients with hematopoietic malignancies (16 acute myeloid leukemia [AML], 11 acute lymphoid leukemia [ALL], 13 chronic myeloid leukemia [CML], and 33 MDS) and 43 healthy volunteers. Immunoglobulin IgM, IgG, and IgM+IgG WT1 antibodies were detected in 40 (54.8%), 40 (54.8%), and 24 (32.8%), respectively, of the 73 patients with hematopoietic malignancies, whereas 7 (16.2%), 2 (4.7%), and none of the 43 healthy volunteers had IgM, IgG, or IgM+IgG WT1 antibodies, respectively. Furthermore, immunoglobulin isotype class switching of WT1 antibodies from IgM to IgG occurred in conjunction with disease progression from refractory anemia (RA) to RA with excess of blasts (RAEB), and further to RAEB in transformation (RAEB-t) in MDS patients. These results showed that humoral immune responses against the WT1 protein could be elicited in patients with WT1-expressing hematopoietic malignancies, and they suggested that the helper T-cell responses needed to induce humoral immune responses and immunoglobulin isotype class switching from IgM to IgG were also generated in these patients. Our findings may provide new insight into the rationale for elicitation of cytotoxic T-cell responses against the WT1 protein in cancer immunotherapy using the WT1 vaccine.

Adolescent↗
PubMed2002

Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells.

The Wilms' tumour gene, WT1, is expressed at high levels in leukaemia cells and plays an important role in leukaemogenesis. WT1 is also expressed in human normal CD34+ bone marrow (BM) cells at about 100 times lower levels than in leukaemia cells. To identify and characterize WT1-expressing cells in CD34+ BM cells, they were sorted into single cells and analysed for WT1 expression using two kinds of single-cell reverse transcriptase polymerase chain reaction (RT-PCR) methods. Using the semiquantitative single-cell polyA-PCR + sequence-specific (SS)-PCR method, WT1 expression was detected in four (1.3%) out of 319 CD34+ BM single cells. To confirm the above results, a single-cell nested sequence-specific (NSS)-RT-PCR method that was less quantitative but more sensitive than the polyA-PCR + SS-PCR method was also performed, and WT1 expression was detected in 15 (1.1%) out of 1315 CD34+ BM single cells. In total, WT1 expression was found in 19 (1.2%) out of 1634 CD34+ BM single cells. No significant differences in the frequencies of WT1-expressing cells were found between CD34+CD38- and CD34+CD38+ BM single cells. Furthermore, WT1-expressing CD34+ BM single cells expressed WT1 at levels similar to those in K562 leukaemia single cells. Analysis of lineage-specific and cell cycle gene expression in WT1-expressing CD34+ BM single cells showed that the WT1 gene could be expressed in both uncommitted, dormant CD34+CD38- and lineage-committed, proliferating CD34+CD38+ BM cells. Our results could indicate that these WT1-expressing CD34+ BM cells were normal counterparts of leukaemia cells.

Antigens, CD34↗