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Tomomitsu Hotta

Publications and source records attributed to Tomomitsu Hotta.

At least 55 records · Page 3Linked to original sources
PubMed2004

A randomized controlled trial investigating the survival benefit of dose-intensified multidrug combination chemotherapy (LSG9) for intermediate- or high-grade non-Hodgkin's lymphoma: Japan Clinical Oncology Group Study 9002.

The effect of enhancing the dose intensity (DI) of the key drugs in multidrug combination chemotherapy for malignant lymphoma is uncertain. We investigated the survival benefit of dose-intensified multidrug combination chemotherapy for intermediate- or high-grade non-Hodgkin's lymphoma (NHL). Patients without any prior chemotherapy were randomly assigned either to dose-intensified multidrug combination chemotherapy, LSG9 (VEPA-B/FEPP-AB/M-FEPA, treated 3 times every 10 weeks for 28 weeks total), or to control-arm combination chemotherapy, mLSG4 (VEPA-B/FEPP-B/M-FEPA, treated 4 times every 14 weeks for 54 weeks total). The planned DI of doxorubicin and cyclophosphamide were 1.96 and 1.47 times higher, respectively, in LSG9 than in mLSG4. Overall survival, complete response (CR) rate, and toxicities were evaluated. The 447 patients (230 for LSG9 and 217 for mLSG4) were enrolled between February 1991 and March 1995. The 5-year overall survival rates were 56.8% for LSG9 patients and 55.1% for mLSG4 patients (log-rank P = .42). The rates for CR plus uncertain CR were 70.0% for LSG9 and 64.5% for mLSG4. The toxicities of both regimens were similar and tolerable. The median actual DI of doxorubicin and cyclophosphamide were 1.56 and 1.17 times higher, respectively, in LSG9 than in mLSG4. Compared with the control regimen mLSG4, the dose-intensified regimen LSG9 did not show significant survival benefit. An increase in the DI of doxorubicin in multidrug combination chemotherapy did not improve the survival of patients with intermediate- or high-grade NHL.

Adolescent↗
PubMed2004

[Cord blood transplantation supported with ex vivo expanded fraction for a patient with myelodysplastic syndrome and metastatic breast cancer].

Despite the promising outcomes of unrelated cord blood transplantations (UCBT) in pediatric recipients, the major limitation in the widespread use of cord blood (CB) as a source of hematopoietic stem cells (HSC), particularly in adults, is the physiological small number of cells. To overcome this limitation, we developed an ex vivo expansion system for HSC, in which CB CD34+ cells are cultured on feeder cells (HESS-5 cells) in the presence of cytokines (TPO, SCF and Flt3 ligand). A phase I/II clinical trial, approved by our institutional review board, has been started to assess the safety and effectiveness of this system. A 52-year-old woman with metastatic breast cancer and myelodysplastic syndrome (MDS) received a non-myeloablative preparative regimen followed by UCBT. On day 0, 75% of the whole CB and a fraction of CD34 negative cells were transplanted. The remaining 25% of the CB was CD34-selected and expanded on HESS-5 in a non-serum media in the presence of TPO, SCF, and Flt3-L. On day 5, the ex vivo-expanded, CD34+ cells were transplanted. The patient received 1.83 x 10(7)/kg of total nucleated cells and 7.7 X 10(4)/kg of CD34+ cells (expanded and unexpanded). No acute adverse effects were observed after the infusion of the cultured cells. She suffered from pneumonia on day 37, a cerebral hemorrhage on day 48, and died on day 50. Further studies are required to assess the effectiveness of this protocol.

Antigens, CD34↗
PubMed2004

[Measurement of rituximab concentration in the cerebrospinal fluid in CNS lymphoma].

We measured rituximab concentrations in the cerebrospinal fluid (CSF) in 2 patients with diffuse large B-cell lymphoma in whom central nervous system (CNS) invasion had developed. They received rituximab intravenously following irradiation therapy (patient no.1) or along with chemotherapy (patient no.2). The rituximab concentrations in the CSF were considered to be very low (0.2-0.6 microg/ml), and could not be increased significantly by serial intravenous administrations of rituximab. The lymphoma relapsed in patient no.1, and the combined therapy was not effective in patient no.2. An alternative approach such as intrathecal administration of rituximab could be anticipated as a new therapeutic strategy for CNS lymphoma.

Aged↗
PubMed2003

The effects of alphaGalCer-induced TCRValpha24 Vbeta11(+) natural killer T cells on NK cell cytotoxicity in umbilical cord blood.

PURPOSE: The first objective of this study was to investigate in vitro effects of alpha-galactosylceramide (alphaGalCer) on the proliferation of umbilical cord blood (UCB) natural killer T (NKT) cells and enhancement of their cytotoxicity. The second one is to examine whether purified NKT cells could affect the cytotoxicity of UCB-NK cells either in the presence or absence of dendritic cells (DCs). METHODS: Mononuclear cells (MNCs) from UCB were cultured for 2 weeks in the presence of IL-2 (100 U/ml), with or without alphaGalCer. The effect of neutralizing monoclonal antibodies (MoAb) against TCRValpha24 and CD1d was also examined. TCRValpha24 Vbeta11 double positive NKT cells were purified by FACS sorter and then cocultured with syngeneic isolated UCB(-)CD56(+)NK cells in either the presence or absence of DCs. The cytotoxicity against various malignant cell targets and cytokine production was determined. RESULTS: The addition of alphaGalCer induced human NKT cells to proliferate in UCB-MNCs to a greater extent than in adult PB-MNCs. However, it suppressed the cytotoxic activity against malignant cell targets. Anti-TCRValpha24 and CD1d MoAb recovered the cytotoxicity by inhibiting the proliferation of UCB-NKT cells. NKT cells cocultured with auto-DCs significantly increased NK cell cytotoxicity against K562, and Raji cells and produced IFN-gamma at much higher levels than UCB-NKT cells alone. CONCLUSION: In UCB samples, alphaGalCer-pulsed DCs and NKT cells acted together to enhance NK cytotoxicity in vitro.

Adult↗
PubMed2003

Deoxycoformycin-containing combination chemotherapy for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study (JCOG9109).

Aggressive adult T-cell leukemia-lymphoma (ATL) generally has a very poor prognosis. Deoxycoformycin (DCF, pentostatin), an inhibitor of adenosine deaminase, has shown promising therapeutic efficacy for ATL. To develop a new effective therapy against aggressive ATL, we carried out a multicenter phase II study of DCF-containing combination chemotherapy. Sixty-two previously untreated patients with ATL (34, 21, and 7 patients with diseases of the acute, lymphoma, and unfavorable chronic types, respectively) were enrolled, but 2 were ineligible because they were judged to be favorable chronic types. A regimen of 1 mg/m2 vincristine intravenously on days 1 and 8, 40 mg/m2 doxorubicin intravenously on day 1, 100 mg/m2 etoposide intravenously on days 1 through 3, 40 mg/m2 prednisolone orally on days 1 and 2, and 5 mg/m2 DCF intravenously on days 8, 15, and 22 was administered every 28 days for 10 cycles unless disease progression or toxic complications occurred. Fifty-two percent of 60 eligible patients responded (95% confidence interval [CI], 38%-65%), with 17 patients (28%) achieving a complete response (CR) (95% CI, 17%-41%) and 14 achieving a partial response. The CR rate was inferior to those of both the previous Japan Clinical Oncology Group (JCOG) study (JCOG8701, 43%), a 9-drug combination chemotherapy of the second generation, and the subsequent JCOG9303 study (35%), a granulocyte colony-stimulating factor-supported, dose-intensified, 9-drug regimen. The median survival time of the 60 eligible patients in JCOG9109 was 7.4 months, and the estimated 2-year survival rate was 15.5%; these results were identical with those of JCOG8701 but inferior to those of JCOG9303. Grade 4 neutropenia and infection of grade 3 or greater were frequent (67% and 22%, respectively), and treatment-related death was observed in 4 patients (7%), septicemia in 2, and cytomegalovirus pneumonia in 2. We conclude that DCF-containing combination chemotherapy is not a promising regimen against aggressive ATL.

Adult↗
PubMed2003

Clinical effects of infusing anti-Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes into patients with severe chronic active EBV infection.

Immune cell therapy with autologous Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes (CTLs) or lymphokine-activated killer (LAK) cells was performed in 2 adults with severe chronic active EBV infection (SCAEBV). The patient in case 1, who had complications of pancytopenia, high fever, and massive splenomegaly, was treated with 13 doses of LAK cell infusion followed by 4 doses of autologous CTL infusion. The patient in case 2, who had liver dysfunction due to natural killer cell-type infection, was treated with 4 doses of autologous CTL infusion. In case 1, the LAK cell infusions were effective in lowering the viral load and improving several biochemical parameters (lactate dehydrogenase, soluble interleukin 2 receptor) and resulted in complete amelioration of the high fever. Subsequent infusions of autologous CTLs reduced the viral load only temporarily and were accompanied by an increase in frequency of EBV-specific T-cells in the blood. However, the patient's main problem of pancytopenia was not resolved. In case 2, infusion of autologous CTLs did not improve the patient's hepatic dysfunction or viral load but caused a significant increase in autoantibody levels. Thus the effect of auto-CTL treatment was limited or deteriorative in SCAEBV patients.

Adoptive Transfer↗
PubMed2003

In vivo and in vitro differentiation of myocytes from human bone marrow-derived multipotent progenitor cells.

OBJECTIVE: Recent studies have shown that bone marrow (BM) contains cells capable of differentiating into myocytes in vivo. However, addition of demethylation drugs has been necessary to induce myocyte differentiation from BM cells in vitro, and precise mechanisms of BM cells' conversion to myocytes and the origin of those cells have not been established. We investigated the expression of myogenic markers during differentiation and maturation of myocytes from BM-derived multipotent adult progenitor cells (MAPC) under physiological culture condition. MATERIALS AND METHODS: Frozen BM samples from 21 healthy donors were used as a source of MAPC. To induce myocyte differentiation MAPC was cultured in the presence of 5% FCS, VEGF, bFGF, and IGF-1, and the expressions of myocyte markers were examined at various time points. We also investigated engraftment and differentiation of MAPC-derived myocytes in vivo. RESULTS: Frozen BM-derived MAPC, cultured under the physiological myogenic condition, demonstrated spatial expression patterns of several myocyte markers similar to that of authentic myocyte differentiation. When injected into murine muscles, MAPC treated with the myogenic condition engrafted and differentiated into myocyte marker-positive cells and myotubes in vivo. CONCLUSION: For the first time, we were able to induce myocyte formation from BM cells under the physiological condition in vitro and demonstrated that treating cells with this condition prior to intramuscular injection increased efficiency of engraftment and differentiation in vivo.

Adolescent↗
PubMed2003

Frequencies of dendritic cells (myeloid DC and plasmacytoid DC) and their ratio reduced in pregnant women: comparison with umbilical cord blood and normal healthy adults.

CD11c(+) peripheral blood myeloid dendritic cells (MDC), and CD123(bright) plasmacytoid cells (PDC), are two human dendritic cell (DC) populations. In the present study, the percentages of MDC [lin(-)/HLA-DR(+)/CD123(-)/CD11c(+)] and PDC [lin(-)/HLA-DR(+)/CD123(bright)] in a peripheral blood (PB) sample obtained from women at the time of delivery and in their umbilical cord blood (UCB) were compared with those in the PB of healthy volunteers. The percentages of MDC and PDC were determined by four-color flow cytometry. The percentages of MDC and PDC were significantly lower in the PB obtained at delivery (MDC, 0.11% +/- 0.08%; PDC, 0.06% +/- 0.06%) and in the UCB (MDC, 0.15% +/- 0.03%; PDC, 0.05% +/- 0.05%) than in the PB of the controls (males, 0.28% +/- 0.12%, 0.11% +/- 0.06%; females, 0.32% +/- 0.13%, 0.11% +/- 0.07%). Among the pregnant women at delivery, there were significant correlations between the percentage of MDC or percentage of PDC in the PB at delivery and the respective parameter in the UCB. The PB of other pregnant women, at 20-35 weeks of gestational age, also indicated significantly low percentages of MDC and PDC (0.1% +/- 0.1%, 0.06% +/- 0.07%). The ratio of MDC/PDC was not reduced in the UCB (4.25 +/- 2.74), but was reduced in the PB obtained at delivery and the PB obtained during pregnancy (0.79 +/- 0.91) in comparison with that in age-matched, nonpregnant females (3.96 +/- 2.95). It was assumed that reduction of MDC during pregnancy plays an important role in maintaining immune tolerance against the embryo.

Adult↗
PubMed2003

Transplantation of mesenchymal stem cells embedded in Atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration.

Intervertebral disc degeneration is considered to be one of the major causes of low back pain. Despite this irreversible phenomenon, attempts to decelerate disc degeneration using various techniques have been reported. However, to date there has been no proven technique effective for broad clinical application. Based on previous studies, we hypothesize that maintenance of proteoglycan content in the disc is achieved by avoiding the depletion of nucleus pulposus and preserving the structure of the annulus is a primary factor in decelerating disc degeneration. One novel approach to solve the dilemma of intervertebral disc degeneration is found at the stem cell level. Mesenchymal stem cells (MSCs) are known to possess the ability to differentiate into various kinds of cells from mesenchymal origin. Although the majority of cells that contribute to disc formation are known to obtain chondrocyte-like phenotypes, no reported study has emphasized the correlation with mesenchymal stem cells. To evaluate the possible potential of MSCs in disc cell research and treatment of degenerative disc disease, autologous MSCs embedded in Atelocollagen gel were transplanted into the discs of rabbits which had undergone a procedure proven to induce degeneration. The results suggest that MSC transplantation is effective in decelerating disc degeneration in experimental models and provided new hopes for treatment of degenerative disc disease in humans. Atelocollagen gel served as an important carrier of MSCs in transplantation, permitting proliferation, matrix synthesis and differentiation of MSCs. This study strengthens the viable efficacy of practical application of MSCs in treatment of intervertebral disc disease.

Animals↗
PubMed2003

The in vitro generation of Ph1+ ALL-specific HLA-A24-restricted cytotoxic T lymphocytes using a synthetic 16 mer minor bcr-abl peptide.

Sixteen mer peptide, which spans the junctional region of the acute lymphoid leukemia (ALL)-specific minor bcr-abl fusion protein and contains a motif that can bind to human leukocyte antigen (HLA)-A24, was constructed. We tried to generate Philadelphia chromosome 1 (Ph1) positive ALL-specific cytotoxic T lymphocytes (CTLs) from eight normal HLA-A24+ individuals with peptide-pulsed autologous dendritic cells (DCs). CTLs could be generated from the mononuclear cells (MNCs) of a single donor, which could kill peptide-pulsed autologous DCs and two A24+ ALL lines, while an HLA-A24+ CML line was only weakly killed and unpulsed DCs or the control lines Daudi or K562 were not recognized. Those CTLs consisted predominantly of CD8+ T cells whose cytotoxicity could be neutralized by monoclonal antibodies to HLA-class I or HLA-A24, and also produced interferon (IFN)-gamma after being stimulated with peptide-pulsed DCs.

Antigen Presentation↗
PubMed2003

Umbilical cord blood dendritic cells are a rich source of soluble HLA-DR: synergistic effect of exosomes and dendritic cells on autologous or allogeneic T-Cell proliferation.

In this study, we compared soluble HLA-DR (sHLA-DR) production in the culture supernatants of various cell sources [T and B cells, monocytes and dendritic cells (DCs) either from adult peripheral blood (PB) or umbilical cord blood (UCB)]. DCs produced the highest amount of sHLA-DR molecules as compared to other cell sources, with UCB DCs producing the highest amount. Different kinetics of sHLA-DR production were found between immature and mature UCB DCs (mDC, iDC) (derived either from CD34(+) or CD14(+) cells). Maximum production of sHLA-DR was observed in 72-hour culture supernatants of both CD34- and CD14-derived mDCs, whereas it peaked in the 24-hour culture supernatants from iDC. sHLA-DR molecules were pelleted after sequential centrifugation from UCB CD34(+) DCs and were found to contain both 36 kD alpha-chain and 29 kD beta-chain of HLA-DR, CD86, and Fas molecules. These sHLA-DR containing vesicles/exosomes alone evoked weak proliferative responses from autologous and allogeneic T cells, but the immune response was significantly increased when vesicles/exosomes were presented with DCs.

Adult↗
PubMed2003

Multicenter prospective study of clonal complications in adult aplastic anemia patients following recombinant human granulocyte colony-stimulating factor (lenograstim) administration.

To elucidate the relationship between treatment with granulocyte colony-stimulating factor (G-CSF) and the development of chromosomal abnormalities and clonal evolution in adult aplastic anemia (AA) patients, we performed a prospective multicenter study. Of the 104 registered patients, 91 were found by the central review committee to have the diagnosis of AA. Of the 91 patients, 84 were determined to be evaluable in this study and were treated with regimens including G-CSF (lenograstim). A time-course study (at registration and 6 and 12 months after registration) of G-banded chromosomes, fluorescence in situ hybridization (FISH) analysis for monosomy 7, and morphological assessment of bone marrow was performed with these patients during the 1-year follow-up period. G-banding analysis demonstrated the development of cytogenetic abnormalities in 10 (16.1%) of the 62 evaluable patients. The most common aberration was monosomy 7. FISH analysis demonstrated monosomy 7 in 7 (10.4%) of the 67 evaluable patients. Evolution into myelodysplastic syndrome (MDS) was observed in 5 (7.7%) of the 65 patients who underwent morphological assessment of bone marrow. All patients who developed cytogenetic abnormalities or MDS received immunosuppressive agents and/or steroids with G-CSF. This study demonstrated that some adult AA patients exhibit evolution into MDS and development of chromosomal abnormalities such as monosomy 7. Although the incidence seems to be comparable with that found in previous studies, further long-term follow-up will be necessary to confirm the relationship between G-CSF and the development of chromosomal abnormalities and MDS.

Adolescent↗
PubMed2003

Comparison of soluble and membrane bound HLA-class I and DR levels in umbilical cord blood and adult peripheral blood.

HLAs are membrane bound (membrane HLA mHLA) or secreted as soluble forms(soluble HLA = sHLA) in plasma or serum. Umbilical cord blood (UCB) mHLA, from mononuclear cells (MNCs), and sHLA were quantified by flow cytometry and enzyme linked immunosorbant assay (ELISA), respectively, and compared to levels of MNC-mHLA and sHLA in adult peripheral blood (PB). The mean fluorescence intensity (MFI) of mHLA-I was 3-fold lower in UCB-MNCs than in adult PB-MNCs, however, due to higher cell numbers in UCB, total mHLA-I quantities per ml of blood were not different in UCB and adult PB. In addition, sHLA-I in UCB was significantly lower than in adult PB. The MFI of mHLA-DR from UCB-MNCs was significantly higher than the MFI of mHLA-DR in adult PB-MNCs, and the total mDR quantity (per ml of blood) in UCB was 3-fold higher than in adult PB. sHLA-DR concentrations, however, were equivalent in UCB and adult PB. These findings indicate that fetal tissue or cells might excrete smaller quantities of both sHLA-I and sDR antigens than adult tissues or cells. Alternatively, fetal sHLA antigens might be unstable and degradated compared to those of adult.

Adult↗
PubMed2002

A highly sensitive strategy for SCID-repopulating cell assay by direct injection of primitive human hematopoietic cells into NOD/SCID mice bone marrow.

To measure the ability of human hematopoietic stem cells (HSCs), the SCID-repopulating cell (SRC) assay has been widely used. Conventionally, human HSCs are transplanted into a nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse via a tail vein. However, those cells must go through various obstacles until they reach the mouse marrow environment, which could explain the generally low homing efficiency in this system. Thus, the capability of HSCs may not be studied accurately by this intravenous transplantation method. In our attempt to reveal actual SRC potential, ie, self-renewal and multilineage differentiation in recipient bone marrow, we introduced cells into mouse marrow directly (intrabone marrow [iBM]) to minimize the effect of factors that may interfere with the homing of HSCs and compared the results obtained by intravenous and iBM methods. When cord blood CD34(+)CD38(-) cells were transplanted in NOD/SCID mice by iBM, a 15-fold higher frequency of SRC, 1 in 44 CD34(+)CD38(-) cells, was achieved compared with 1 in 660 by the intravenous method. Furthermore, the iBM transplant showed high levels of engraftment in the secondary transplantation. Pretreatment of CD34(+) cells with antibodies that block either very late antigen 4 (VLA-4) or VLA-5 reduced engraftment partially, whereas blockage of both molecules resulted in complete inhibition of engraftment, which suggests that VLA-4 and VLA-5 are involved in different processes in engraftment or have complementary roles. Our results indicate that the iBM injection strategy is a more sensitive and direct way to measure the capability of human SRCs and is useful to investigate the interaction of HSCs and marrow environment in vivo.

Animals↗