Biomedical subjects

T Hotta

Publications and source records attributed to T Hotta.

At least 19 recordsLinked to original sources

PubMed1998

Involvement of Fas-mediated apoptosis in the hematopoietic progenitor cells of graft-versus-host reaction-associated myelosuppression.

The influence of graft-versus-host (GVH) reaction on the host hematopoietic cells clinically manifests itself both as adverse reactions in transfusion-associated GVH disease (GVHD) and as a therapeutic graft-versus-leukemia (GVL) effect in either donor lymphocytes transfusion (DLT) or allogeneic bone marrow (BM) transplantation. We examined the effect of GVH reaction on the host hematopoiesis in the murine parent-into-F1 (P1 --> F1) model of GVHD. The systemic transfer of 5 x 10(7) of C57BL/6 (B6) splenocytes into (B6xDBA/2)F1 mice (BDF1), which results in acute GVHD, reduced the peripheral blood cell counts, the number of BM cells, and colony-forming unit-granulocyte macrophage (CFU-GM), whereas the injection of 10(8) of DBA/2 cells into BDF1, which results in chronic GVHD, did not affect hematopoiesis 2 weeks after the transfer. To clarify the mechanism of such myelosuppression, we examined the Fas expression in both hematopoietic progenitor cells as well as whole BM cells. The Fas expressions in each fraction significantly increased in BDF1 mice 2 weeks after the induction of acute GVHD, whereas no such effects were observed in the BDF1 mice with chronic GVHD. Furthermore, when such BM cells were incubated with anti-Fas antibody (Jo2), which induces apoptosis through Fas, the fraction of apoptotic cells increased and the number of CFU-GM decreased significantly. The in vivo administration of neutralizing anti-FasL antibody into BDF1 mice receiving with B6 spleen cells thus protected the host mice from BM failure. These results indicate that the functional expression of Fas on hematopoietic cells plays an essential role in the myelosuppressive effect of GVHD.

Animals↗

PubMed1998

Isolation of novel human cDNA (hGMF-gamma) homologous to Glia Maturation Factor-beta gene.

A novel full-length human cDNA homologous to Glia Maturation Factor-beta (GMF-beta) gene was isolated. Sequence analysis of the entire cDNA revealed an open reading frame of 426 nucleotides with a deduced protein sequence of 142 amino acid residues. The deduced amino acid sequences of its putative product is highly homologous to human GMF-beta (82% identity) and named for GMF-gamma. Northern blot analysis indicated that a message of 0.9 kb long, but not 4.1 kb of GMF-beta, is predominantly expressed in human lung, heart, and placenta.

Amino Acid Sequence↗

PubMed1998

Unusual relapse of adult T-cell leukemia/lymphoma after spontaneous remission.

A 42-year-old man was diagnosed with acute adult T-cell leukemia/lymphoma (ATL/L). Abnormal peripheral blood cells (45% of white blood cells) (Fig. 1a), hypercalcemia, and systemic lymphadenopathy were observed. Flow cytometric analysis (FCM) using peripheral mononuclear cells (PMNC) revealed that the immunophenotype of tumor cells was CD4+ CD8- CD25+ CD45RA- CD45RO+. Nevertheless, he developed a spontaneous remission 6 months later. At remission, the number of CD4-, CD25-, and CD45RO-positive cells decreased, while CD8- and CD45RA-positive cells increased to normal levels as previously reported by Suzuki et al. [1]. He was then referred to the outpatient clinic where he was periodically evaluated and received no therapy. Because of a serious sense of fullness he was re-admitted 30 months after diagnosis. Physical examination revealed ascites and small lymphadenopathy in the right axilla. Atypical lymphoid cells were not observed on microscopic examination of the blood smear. FCM using PMNC revealed that CD4+ CD25+ cells (3%) were within the normal range. Serum calcium was also within the normal range. Abdominal ultrasound examination showed massive ascites. Paracentesis demonstrated that the ascitic fluid had a high white blood cell count (3.15 x 10(9)/l) with a marked increase in abnormal large cells (Fig. 1b). FCM using mononuclear cells in the fluid revealed that 87.3% of the cells were double-positive for CD4 and CD25. Southern blot analysis of the cells confirmed monoclonal integration of human T-lymphotropic virus type 1 (HTLV-1) proviral DNA. The integrated genome was considered to be identical with that detected at initial presentation (Fig. 2). A diagnosis of relapsed ATL/L, with the same clone as was detected at initial diagnosis, was made. Although he was treated with cytotoxic drugs, he did not respond and he died of renal failure 1 month after relapse. Autopsy revealed nodular invasive lesions at the rectovesical pouch, omentum, diaphragm, and pericardium with peritoneal dissemination.

Adult↗

PubMed1998

Clinical significance of granulocyte colony-stimulating factor (G-CSF) receptor expression in acute myeloid leukemia.

We examined granulocyte colony-stimulating factor (G-CSF) receptor (GR) expression on leukemic cells from 44 adults with newly-diagnosed acute myeloid leukemia (AML). GR expression was higher in female patients. G-CSF was administered to AML patients after initial induction therapy without significant acceleration of leukemia, irrespective of GR expression level. G-CSF administration after initial chemotherapy did not adversely influence clinical outcome of GR-positive patients. However, at first relapse, leukemia regrowth was accelerated in 3 of 15 GR-positive patients who received G-CSF after re-induction. It remains to be determined whether leukemia acceleration due to G-CSF contributes to re-induction failure and if G-CSF therapy is a significant risk in relapsed, GR-positive AML patients.

Acute Disease↗

PubMed1998

CDKN2 (MTS1/p16INK4A) gene alterations in adult T-cell leukemia/lymphoma.

p16INK4A is a cyclin-dependent kinase inhibitor (CDKI), and regulates the cell cycle negatively. Recently, p16INK4A protein was shown to be encoded by the CDKN2 gene, which is identical to multiple tumor suppressor gene 1 (MTS1) on chromosome 9p21, where genetic alterations occur frequently in many malignant tumors. As the loss of p16INK4A function by genetic alterations leads to inappropriate progression of the cell cycle, the CDKN2 gene has been investigated intensively as a new candidate tumor suppressor gene in many malignant tumors. Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy associated with human T-cell lymphotrophic virus type 1 (HTLV-1). As the development to ATL is believed to require not only HTLV-1 infection but also accumulation of genetic alterations, we investigated the relationship between alterations in the CDKN2 gene and ATL. Alterations in the CDKN2 gene were detected in approximately 15 to 20% of ATL patients. Interestingly, most of the patients with CDKN2 gene alterations had the aggressive form of ATL. The CDKN2 gene appears to be the major tumor suppressor gene on chromosome 9p21, and alteration in this gene may play an important role during late stages in the transformation process induced by HTLV-1.

Cyclin-Dependent Kinase Inhibitor p16↗

PubMed1998

Production and effects of interleukin-6 and other cytokines in patients with non-Hodgkin's lymphoma.

Cytokines are regulatory molecules that are produced by a variety of cell types and are characterized by numerous biologic functions involved in the regulation of the immune system and hematopoiesis. This review summarizes the functions and regulation of cytokines in lymphomas and discusses the effect of a specific cytokine, interleukin-6 (IL-6), in B-cell lymphomas. IL-6 is a multipotent cytokine that can mediate the differentiation of B-cells into immunoglobulin-secreting cells, stimulate the autocrine or paracrine growth of myeloma cells, induce acute-phase proteins in liver cells, and may influence the pathogenesis of several diseases by autocrine or paracrine mechanisms. Patients with non-Hodgkin's lymphoma (NHL) have increased serum concentrations of IL-6; increased IL-6 levels can be associated with the presence of B-symptoms. Data presented in this review indicate that neoplastic cells from patients with NHL contained high concentrations of IL-6. Thus, elevated serum levels of IL-6 appear to originate from the lymphoma cells in patients with B-cell NHL, suggesting that the neoplastic cells may modulate the general status of patients with B-cell NHL. The inhibition or modification of the production of IL-6 in lymphoma cells may lead to a more effective control of the general status of patients with B-cell NHL.

Acute-Phase Reaction↗

PubMed1997

Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma.

BACKGROUND: Mutations of the p53 gene are associated with a poor prognosis in several types of cancer. We investigated the prognostic importance of p53 mutations in patients with aggressive B-cell lymphoma. METHODS: We examined the relation between the presence or absence of a detectable p53 mutation in lymphoma cells and the response to chemotherapy and overall survival in 102 previously untreated patients with aggressive B-cell lymphoma. Mutations of the p53 gene were identified by polymerase-chain-reaction-mediated analysis of single-strand conformation polymorphisms and by direct sequencing. RESULTS: Of 102 cases of aggressive B-cell lymphoma, 22 (22 percent) involved p53 mutations. The rate of complete remission was significantly lower in patients with a tumor carrying a p53 mutation (6 of 22 patients, 27 percent) than in those with the wild-type p53 gene (61 of 80 patients, 76 percent) (P<0.001). Overall survival was significantly lower among patients with p53 mutations than among those with the wild-type p53 gene; the Kaplan-Meier estimates of survival at five years were 16 percent and 64 percent, respectively (P<0.001). Multivariate analysis incorporating prognostic factors from the international prognostic index demonstrated that p53 mutations had independent effects on the rates of complete remission and survival. When we categorized patients according to the international prognostic index, we found no effect of p53 mutations in patients in the groups at high-intermediate and high risk. However, these mutations were significantly associated (P< 0.001) with low rates of complete remission (33 percent vs. 91 percent) and survival (27 percent vs. 81 percent at five years) in the groups at low and low-intermediate risk. CONCLUSIONS: Mutations of the p53 gene are associated with a poor prognosis in patients with aggressive B-cell lymphoma.

Aged↗

PubMed1997

Hypermethylation of the p15INK4B gene in myelodysplastic syndromes.

Previous studies have shown that the cyclin-dependent kinase inhibitor (CDKI) genes p15INK4B and p16INK4A are frequently inactivated by genetic alterations in many malignant tumors and that they are candidate tumor-suppressor genes. Although genetic alterations in these genes may be limited to lymphoid malignancies, it has been reported that their inactivation by aberrant methylation of 5' CpG islands may be involved in various hematologic malignancies. In this study, we investigated the p15INK4B and p16INK4A genes to clarify their roles in the pathogenesis of myelodysplastic syndrome (MDS). Southern blotting analysis showed no gross genetic alterations in either of these genes. However, hypermethylation of the 5' CpG island of the p15INK4B gene occurred frequently in patients with MDS (16/32 [50%]). Interestingly, the p15INK4B gene was frequently methylated in patients with high-risk MDS (refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-t], and overt leukemia evolved from MDS; 14/18 [78%]) compared with patients with low-risk MDS (refractory anemia [RA] and refractory anemia with ring sideroblast [RARS]; 1/12 [8%]). Furthermore, methylation status of the p15INK4B gene was progressed with the development of MDS in most patients examined. In contrast, none of the MDS patients showed apparent hypermethylation of the p16INK4A gene. These results suggest that hypermethylation of the p15INK4B gene is involved in the pathogenesis of MDS and is one of the important late events during the development of MDS.

Carrier Proteins↗

PubMed1997

Analysis of intramedullary cell density by MRI using the multiple spin-echo technique.

Analysis of the intramedullary cell distribution by magnetic resonance imaging (MRI) using conventional techniques involves subjectively interpreting images and estimating the cell distribution on the basis of signal intensity characteristics. In recent years, attempts have been made to achieve more precise analysis by new techniques, including chemical shift imaging. The multiple spin-echo (MSE) technique offers some advantages over conventional MRI. Since it allows measurement of the transverse magnetization decay curve at 32 or more points, it is capable of separating several tissue components with different relaxation times. In addition, this technique can be used with MRI instruments having a static magnetic field as low as 1.0 Tesla. In the present study, the intramedullary cell density was assessed by MRI using the MSE technique in 4 patients with aplastic anemia (AA), 4 patients with myelodysplastic syndrome (MDS), and 5 normal subjects. The water component of the marrow (with a short relaxation time) and the fat component (with a long relaxation time) were separated from each other by analyzing MR images obtained using the MSE technique, and the signal intensity ratio of the 2 components was calculated. The ratio was significantly higher in the AA group than in the other groups (AA vs. MDS, P = 0.0209, AA vs. normal controls, P = 0.0143). The present technique appears promising for quantitative assessment of the intramedullary cell density.

Adolescent↗

PubMed1997

Enhancement of tumor cell susceptibility to tumor-infiltrating lymphocytes by cisplatin.

Some means of enhancing the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TIL) are required in adoptive immunotherapy. This study was designed to investigate whether or not tumor cell lysis by TIL was enhanced by treatment of the tumor cells with cisplatin, and also to clarify the mechanism of cisplatin's action on tumor cells. Autologous tumor cells and established cancer cell lines, including KATO-III and MKN-28, were used. Cytotoxic activities of TIL, the surface antigens of tumor cells, conjugation of TIL and tumor cells, and the production of TNF alpha from TIL were analyzed. Tumor cells treated with 2 micrograms/ml cisplatin for 12 h in vitro were more susceptible to bulk-cultured TIL and TIL clones. The surface antigens of tumor cells were not altered by the treatment with cisplatin. Cisplatin-treated tumor cells showed a higher binding ratio to TIL than did non-treated tumor cells. The anti-(tumor necrosis factor) (anti-TNF) or anti-TNF receptor antibody blocked the enhancement of cytotoxic activity by cisplatin. Thus, it was clarified that cisplatin enhanced the susceptibility of tumor cells to bulk-cultured TIL and TIL clones. Furthermore, the enhancement of cytotoxic activity by TIL in cisplatin-treated tumor cells was caused by a higher binding ratio to TIL and higher susceptibility to the TNF produced by TIL.

Antigens, Neoplasm↗

PubMed1997

Periosteal chondrosarcoma invading the medullary cavity.

We present a case of periosteal chondrosarcoma of the femur, in which a tumor invaded the medullary cavity and the lesion was clearly demonstrated only on MRI. To the best of our knowledge, there have been no previous reports of an intramedullary lesion caused by periosteal chondrosarcoma demonstrated on MRI.

Adult↗

PubMed1997

A randomized study comparing VMCP and MMPP in the treatment of multiple myeloma.

PURPOSE: To compare VMCP, a multidrug combination chemotherapy comprising vincristine (VCR), melphalan (MPH), cyclophosphamide (CPM) and prednisolone (PSL), with MMPP comprising MPH, ranimustine (MCNU), procarbazine, and PSL as induction, to elucidate the value of alternating combination chemotherapy, and to search for an appropriate maintenance therapy in multiple myeloma. METHODS: At 16 institutions in the Nagoya City area, we carried out a randomized trial of VMCP versus MMPP as the initial treatment. Patients who were refractory or resistant to the initial therapy were crossed over into the other arm (crossover trial). For patients who achieved a partial response (PR) or a minor response (MR) and in whom the paraprotein level ceased to decrease, the maintenance therapy was randomized either to an MPH/PSL combination (MP) or to alternating combination therapy (AT) with VMCP and MMPP. RESULTS: In the 94 evaluable patients of the 111 enrolled, the response rate (PR rate) was 27.7% (13/47) in the VMCP arm and 44.7% (21/47) in the MMPP arm (P = 0.0859). The crossover trial resulted in a PR rate of 15.8% (3/19) for the VMCP-->MMPP crossover and 14.3% (2/14) for the MMPP-->VMCP crossover. The median survival time was 23.4 months for those initially begun in the VMCP arm and 24.9 months for those in the MMPP arm, showing a tendency for better survival during a follow-up of 2-6 years with MMPP treatment, but without statistical significance. The survival time of patients with progressive disease was significantly shorter than that of patients with PR, MR or no change (NC). However, there was no significant difference in the survival rate among those who achieved PR, MR, or NC. As to the maintenance therapy, there was no significant difference in survival between MP therapy and AT. Patients who reached a plateau phase survived significantly longer than those who did not. Except for six cases of grade 3 or 4 neurotoxicity in the VMCP arm, there was no significant difference in the hematologic or gastrointestinal toxicity between the two arms. CONCLUSIONS: We conclude that VMCP is less effective for myeloma than MMPP as the induction treatment, that alternating noncrossresistant chemotherapeutic combinations do not offer an advantage in multiple myeloma, and that patients who reach a plateau phase have a significantly longer survival time.

Adult↗

PubMed1997

IgD monoclonal gammopathy of undetermined significance.

We describe here a case of monoclonal gammopathy of undetermined significance (MGUS) of IgD type. A trace of serum M-protein was noticed on electrophoresis when a Japanese man visited his primary care physician for medical examination. However, he was asymptomatic. Serum immunoelectrophoresis showed IgD lambda M-protein. Bone marrow examination revealed normocellular marrow with 1.5% plasma cells. Renal function, serum calcium level and complete blood cell count were all within normal limits and a systemic bone survey disclosed no lytic lesions. He was followed for 26 months without chemotherapy, and no disease progression to overt myeloma nor development of systemic amyloidosis resulted. This is, to our knowledge, the third case of IgD MGUS and the first one reported from Japan.

Connectin↗

PubMed1997

Clonality in hematopoietic disorders.

Clonality analysis using the polymorphism of X-linked genes, such as the phosphoglycerate kinase (PGK), hypoxanthine phosphoribosyl transferase (HPRT) genes and CAG repeat of the human androgen receptor (HU-MARA) gene and the hypervariable DXS255 gene have been widely used in the assessment of many hematologic diseases. Monoclonal hematopoiesis was clearly demonstrated in myelodysplastic syndromes (MDS), myeloproliferative disorders (MPD) and leukemia by the X-inactivation analysis. Previous studies also found a higher incidence of monoclonality in aplastic anemia and 'clonal remission' in acute leukemia. However, recent studies have shown that clonal hematopoiesis in aplastic anemia or remission of leukemia is rarer than previously thought when skewed X-inactivation was extensively ruled out by comparison with T-lymphocytes as an internal control. However, a polyclonal pattern obtained by X-inactivation cannot exclude the possibility of a small clonal cell population presenting in aplastic anemia. However, recent studies have demonstrated that residual polyclonal (possibly normal) hematopoietic progenitor cells can be detected in the bone marrow of MDS and MPD patients whose peripheral blood granulocytes showed a monoclonal pattern. This may suggest a novel approach to treatment of these diseases.

Cloning, Molecular↗

PubMed1997

Complementarity determining region-III is a useful molecular marker for the evaluation of minimal residual disease in mantle cell lymphoma.

Bone marrow (BM) and peripheral blood (PB) involvement in 10 patients with mantle cell lymphoma (MCL) was analysed by a polymerase chain reaction (PCR)-mediated RNase protection assay. The complementarity determining regions (CDR)-III of all 10 MCLs examined was amplified efficiently with consensus V(H) and J(H) primers by PCR. and BM and/or PB involvement was evaluated by RNase protection assay in all 10 patients examined. Our assay showed BM and/or PB of the entire group to have neoplastic cells at presentation, despite the fact that eight patients were found to have BM and/or PB involvement on the basis of morphological examination and/or surface marker analysis. We also examined minimal residual disease (MRD) after conventional chemotherapy, and detected MRD in a patient in complete remission (CR). Although previous studies have shown that t(11;14) breakpoint amplification by PCR was only applicable to about 30-40% of cases, the present study indicates that CDR-III is a useful molecular marker and the PCR-mediated RNase protection assay is a good tool for the evaluation of MRD in MCL. It is suggested that BM and PB of MCL patients are quite frequently involved at presentation and even after conventional chemotherapy at the molecular level.

Aged↗

PubMed1997

The production of tissue inhibitors of metalloproteinases (TIMPs) in megakaryopoiesis: possible role of platelet- and megakaryocyte-derived TIMPs in bone marrow fibrosis.

We quantified tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in serum and plasma in normal control subjects and patients with a low or high platelet count, using one-step sandwich enzyme immunoassays. The serum levels of TIMP-1 and TIMP-2 were 101.1 +/- 13.3 ng/ml, and 82.7 +/- 26.3 ng/ml, respectively, in normal subjects. In patients with an elevated platelet count, such as in essential thrombocytosis, polycythaemia vera, and myelofibrosis, serum levels of TIMP-1 and TIMP-2 were 351.6 +/- 200.9 ng/ml and 148.9 +/- 84.0 ng/ml, respectively. Serum levels of TIMP-1 and TIMP-2 in patients with a low platelet count, such as in aplastic anaemia and idiopathic thrombocytopenic purpura, were 57.2 +/- 25.8 ng/ml and 19.7 +/- 7.68 ng/ml, respectively. The serum level of TIMP-1 was significantly correlated with the platelet count in all subjects. The correlation between the serum level of TIMP-2 and the platelet count was not as strong. The level of TIMP-1 in platelet-depleted plasma was not correlated with the platelet count. Immunohistochemical staining using monoclonal antibodies against TIMP-1 and TIMP-2 showed that megakaryocytes and platelets were positive for both TIMP-1 and TIMP-2, confirming that they are rich sources of TIMPs. TIMP-1 and TIMP-2 stimulated the proliferation of bone marrow fibroblasts, although their effect was less potent than that of TGF-beta and PDGF. Erythroleukaemia and megakaryoblastic cell lines showed the highest secretion of TIMP-1 among the leukaemia cell lines examined. There was no lineage specificity for TIMP-2 secretion. These results suggest that TIMPs released from megakaryocytes or from local platelet coagulation may be important in the development of bone marrow fibrosis.

Blood Platelet Disorders↗

PubMed1997

Phase I study of cladribine (2-chlorodeoxyadenosine) in lymphoid malignancies. Cladribine Study Group.

Cladribine (2-chlorodeoxyadenosine;) is a purine analogue with clinical activity against hairy cell leukemia, chronic lymphocytic leukemia and indolent lymphoma. To clarify the toxicity profiles of cladribine, we conducted a phase I and pharmacological study of cladribine with a schedule of seven-day continuous intravenous infusion every 28 days up to a maximum of three cycles. We enrolled 10 previously-treated patients with various lymphoid malignancies. No dose-limiting toxicity (grade 4 hematologic and/or grade 3 or more non-hematologic) was observed in the three patients who received 0.06 mg/kg/day (Level 1). Of the seven patients who received 0.09 mg/kg/day (Level 2), one patient developed grade 4 hypoxemia and grade 4 thrombocytopenia, and another developed grade 4 neutropenia. Of the seven patients treated at Level 2, one with cutaneous T-cell lymphoma attained complete remission, and one with mantle cell lymphoma, one with chronic lymphocytic leukemia and one with adult T-cell leukemia-lymphoma attained partial remission. A pharmacokinetic analysis of the seven patients without leukemic cells showed that their area under the concentration versus time curves of plasma cladribine increased dose-dependently from 2661.3 +/- 300.4 nM x h at Level 1 (n = 3) to 3411.3 +/- 341.0 nM x h at Level 2 (n = 4) (P = 0.034). We conclude that the recommended phase II dose of cladribine (0.09 mg/kg/day as a seven-day continuous i.v. infusion) in Caucasian patients can be safely administered to Japanese patients. The encouraging results prompted us to plan subsequent phase II studies of cladribine against adult T-cell leukemia-lymphoma, hairy cell leukemia and indolent lymphoma.

Aged↗

PubMed1997

CDKN2 (MTS1/p16INK4A) gene alterations in hematological malignancies.

Cyclin dependent kinases (CDKs) make complexes with cyclins, and regulate cell cycle progression by their serine/threonine kinase activities. CDK inhibitors (CDKIs) arrest the inappropriate progression of the cell cycle by combining with CDKs. Because the functional loss of CDKIs may permit unlimited cell growth, their disruptions are thought to be associated with tumorigenesis. Recently, one CDKI, p16, was found, and its gene, CDKN2 (MTS1/p16INK4A), was identified on chromosome 9p21. Intensive investigations of the CDKN2 gene in various tumors have shown that alterations frequently occur in this gene, thus suggesting that the CDKN2 gene is a tumor suppressor gene. In hematological malignancies, CDKN2 gene alterations may be limited to lymphoid malignancies, especially T-cell type acute lymphocytic leukemias, in which frequent chromosomal abnormalities in the 9p21 region have been reported. The CDKN2 gene is also inactivated in some patients with non-Hodgkin's lymphomas, adult T-cell leukemias, and lymphoid blastic crisis of chronic myelogenous leukemias. The main mechanism of CDKN2 gene inactivation is thought to be homozygous deletion, but point mutations may also inactivate it in some cases. The CDKN2 gene appears to be the major tumor suppressor gene on chromosome 9p21, and it is thought to be involved in the tumorigenesis of various lymphoid malignancies.

Carrier Proteins↗