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Biomedical subjects

M Tomonaga

Publications and source records attributed to M Tomonaga.

At least 181 records · Page 10Linked to original sources
PubMed1996

Autoantibodies and immunoglobulins in atomic bomb survivors with human T-lymphotropic virus type I.

The association of human T-lymphotropic virus type I (HTLV-I) with autoimmune disorders was investigated on the basis of prevalence of antinuclear antibody (ANA), rheumatoid factor and anti-thyroglobulin antibody as well as immunoglobulin (Ig) serum level (IgG, IgA, and IgM). The subjects, all atomic bomb survivors, were 59 HTLV-I-seropositive people without HTLV-I-associated myelopathy or adult T-cell leukemia and 149 HTLV-I-seronegative persons. The mean serum level of IgM was higher in HTLV-I-seropositive subjects than in HTLV-I-seronegative subjects, and a significant association with HTLV-I and sex was indicated in the IgM serum level. No association with HTLV-I was indicated in the prevalence of the autoantibodies except for ANA. These results suggest some clear humoral immunity differences between HTLV-I-infected and noninfected subjects, but whether HTLV-I infection can lead to autoimmune disorders remains uncertain.

Adult↗
PubMed1996

CD5-expressing B-cell lymphomas/leukemias: relatively high frequency of CD5+ B-cell lymphomas with an overall poor prognosis in Nagasaki Japan.

To characterize CD5+ B-cell neoplasms in Japan, where chronic lymphocytic leukemia (CLL) is rare and of different subtypes in comparison with Western countries, we collected 58 cases of CD5+ B-cell lymphomas/leukemias and analyzed their clinicopathologic features. According to the French-American-British (FAB) and standard histologic classification, the cases corresponded to small lymphocytic lymphoma (SLL, group I; n = 22, consisting of CLL, n = 10, CLL/PL, n = 3, and CLLmixed, n = 7); intermediate differentiated lymphoma/mantle cell lymphoma (IDL/MCL, group II, n = 18); and others with CD5-positive lymphomas (group III, n = 18). The CD5+ B-cell lymphomas showed morphologic and prognostic variability among the three groups. The clinical and immunophenotypic features were remarkably consistent in leukemic disease being seen in 73% of all cases, splenomegaly in 63%, and intense CD19, CD20, surface membrane immunogobulin M (SmIgM) or SmIgM and SmIgD, light-chain expression, and no CD10 expression. The median survival time of groups I, II, and III was 7.8, 3.3, and 0.8 years, respectively. These findings suggest that CD5 antigens may serve as valid markers for the prognosis and clinical features of B-cell lymphomas and that CD5+ B-cell lymphomas with an overall poor prognosis occurs at a relatively high frequency in Japan. This also suggests that a combination of immunophenotypic and morphologic features is of value for characterizing CD5+ B-cell neoplasms.

Adult↗
PubMed1996

Plasma M-CSF as an indicator of response to chemotherapy in adult T cell leukemia patients.

The plasma concentration of macrophage colony-stimulating factor (M-CSF) was measured in 10 patients with acute type adult T cell leukemia (ATL) during the clinical course before and after chemotherapy. M-CSF concentration decreased significantly when the patients achieved complete remission (CR) or partial remission (PR) (t-test: p = 0.0001). Five of the patients showed disease progression after several months of PR, and plasma M-CSF increased at that time (t-test: p = 0.0456). Thus, plasma M-CSF concentration appeared to accurately reflect the disease activity in ATL. In support of these results, all three ATL cell lines established from these patients secreted M-CSF in vitro after stimulation with phorbol myristate acetate (PMA) or concanavalin A (Con A). Plasma M-CSF concentration, however, increased transiently when the patients were febrile (t-test: p = 0.0001), even though their ATL condition was unchanged. Taken together, these results indicate that there are two sources of increased plasma M-CSF concentration in ATL; ATL cells themselves and normal parenchymal cells that cause this increase as the result of elevated body temperature due to inflammation.

Adult↗
PubMed1996

Features of the cytokines secreted by adult T cell leukemia (ATL) cells.

Adult T cell leukemia (ATL) cells show a mature helper-inducer T cell phenotype and are thought to secrete many kinds of cytokines in vivo, complicating the clinical features in these patients. In an attempt to specify the cytokines produced by ATL cells, we measured the cytokine concentration in the culture supernatants of three ATL cell lines, all of which were confirmed to be true peripheral blood ATL cell in origin. All these cell lines showed the same cytokine production profile, secreting IL1-alpha, IL1-beta, LD78(MIP-l alpha), TNF-alpha, IFN-gamma, and GM-CSF, but not secreting IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1 Ra), IL-4, IFN-alpha, and G-CSF irrespective of the stimulatory agents used. Such limited cytokine production may indicate the specific origin of ATL cells within the helper-inducer T cell subtypes. Moreover, these results explain some of the unusual clinical features of ATL patients.

Adult↗
PubMed1996

The significance of artificial cerebrospinal fluid as perfusate and endoneurosurgery.

To compare the benefits of physiological saline solution and artificial cerebrospinal fluid (CSF) as perfusates, we investigated 12 patients with presumed symptomatic aqueductal stenosis by clinical course and CSF analysis. In all patients, endoneurosurgical third ventriculostomy and cine magnetic resonance imaging confirmed the patency of ventriculostomy. After endoneurosurgery, patients who received the saline solution experienced high fever, headaches, and elevated cell count in lumbar CSF. Saline solution provoked a striking inflammatory reaction in the CSF. In contrast, the artificial CSF reduced these conditions to a minimum. Artificial CSF used as a physiological perfusate during endoneurosurgery can suppress host reactions within the CSF pathway and is also available for routine neurosurgical procedures.

Adult↗
PubMed1996

Increased levels of interleukin-6 (IL-6) in serum and spontaneous in vitro production of IL-6 by lymph node mononuclear cells of patients with angio-immunoblastic lymphadenopathy with dysproteinemia (AILD), and clinical effectiveness of cyclosporin A.

Serum levels of cytokines and in vitro cytokine production by lymph node mononuclear cells (LNMC) were studied in four patients with angio-immunoblastic lymphadenopathy with dysproteinemia (AILD) or AILD-type T cell lymphoma. An increased level of serum interleukin-6 (IL-6) was detected on initial diagnosis in both of two patients examined. Spontaneous production of IL-6 by LNMC was detected in all four patients studied. Immunosuppressive therapy with cyclosporin A (CsA) was attempted in a 68-year-old man, who was refractory to intensive combination chemotherapy. The increased level of IL-6 in this patient decreased to normal within 3 weeks of CsA administration and the patient became symptom-free. One and a half months later, the IL-6 level gradually increased along with clinical exacerbation. We also measured serum levels of IL-1 alpha, IL-2, IL-4, IFN-alpha, gamma and TNF-alpha in parallel with IL-6, but these factors were only sporadically detected. IL-6 production by LNMC was stimulated by IL-2 but inhibited by CsA. These observations suggest that IL-6 is one of the important cytokines to be involved in the pathophysiology of AILD and CsA is a useful reagent for relieving symptoms.

Aged↗
PubMed1996

Alterations of the cyclin-dependent kinase inhibitor p19 (INK4D) is rare in hematopoietic malignancies.

Cyclin-dependent kinase inhibitors (CDKIs) can be classified into two groups based on the structure of the proteins. One group includes the p21 (CIP1, WAF1, CAP20), p27 (Kip1), and p57 (Kip2) CDKIs, which contain a homologous amino-terminal cyclin-dependent kinase (cdk) inhibitory domain. The p16 (INK4A), p15 (INK4B), and p18 (INK4C) CDKIs, which have an ankyrin repeat motifs, belong to the other group. The p16 and p15 CDKI genes are very frequently altered in a variety of cancers including hematopoietic malignancies. The p19 (INK4D) gene is a newly cloned CDKI which belongs to the latter group. To determine if p19 genetic alterations play a role in hematopoietic malignancies, we examined DNA from 45 childhood newly diagnosed acute lymphocytic leukemias (ALLs), 30 acute myeloblastic leukemias (AMLs), 10 chronic myelocytic leukemias (CMLs), 45 adult T cell leukemias (ATLs), 70 non-Hodgkin's lymphomas (NHLs), and 20 multiple myelomas (MM) as well as 14 ALL, 20 AML, two ATL, and five lymphoma cell lines. Using Southern blot analysis, one homozygous deletion of the p19 gene was detected in a human immunodeficiency virus (HIV)-related Burkitt-like lymphoma sample. No point mutations in any of the samples were found by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Our investigation suggests that alterations of p19 do not play an important role in the development of most hematopoietic malignancies.

Base Sequence↗
PubMed1995

Alterations of the p27KIP1 gene in non-Hodgkin's lymphomas and adult T-cell leukemia/lymphoma.

The protein p27KIP1 belongs to a recently identified family of proteins termed cyclin-dependent kinase inhibitors (CDKIs). These proteins play an important role in regulating cell-cycle progression and loss of their function has been implicated in tumorigenesis. Transforming growth factor beta (TGF-beta) may induce cell growth arrest through p27 activation. TGF-beta often loses its ability to arrest growth of transformed cells; this could potentially occur through a defect in p27. To determine the role of p27 in tumorigenesis, we examined its mutational status in 74 non-Hodgkin's lymphomas (NHLs) (52 of B-cell phenotype, 22 of T-cell phenotype), 5 lymphoma cell lines, and 42 adult T-cell leukemias/lymphomas (ATLs) using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and Southern blot analyses. A nonsense mutation (stop codon) that could result in expression of a truncated nonfunctional p27 protein was detected at codon 76 in one case of acute lymphomatous ATL, but not in matched normal tissues. Previously undescribed polymorphisms were also identified at codon 109 in the lymphomas and at codon 55 in the ATLs. Two homozygous deletions of the p27 gene were detected in one case of B-immunoblastic NHL and in one case of acute ATL by Southern blot hybridization. These results indicate that p27 gene alterations are rare events in NHLs and ATLs, but may play an important role in the pathogenesis of some hematologic malignancies.

Base Sequence↗
PubMed1995

A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase.

A multicenter randomized study was conducted to compare the effect of interferon-alpha (IFN-alpha) with that of busulfan in newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase. From October 1988 to October 1991, 170 patients were randomized to receive either IFN-alpha or busulfan. Of 159 eligible patients, 31 (38.8%) of 80 patients in the IFN-alpha group and 43 (54.4%) of 79 patients in the busulfan group achieved complete hematologic remission, and 38.8% in the IFN-alpha group and 43.0% in the busulfan group achieved partial hematologic remission. A complete cytogenetic response was induced in seven (8.8%) of 80 patients treated with IFN-alpha and two (2.5%) of 79 patients treated with busulfan, and a partial cytogenetic response was 7.5% (6/80) and 2.5% (2/79), respectively. The difference in major (complete and partial) cytogenetic response between the two groups was significant (P = .046). At a median follow-up of 50 months, the predicted 5-year survival rate was 54% in the IFN-alpha group and 32% in the busulfan group (P = .0290), and the predicted 5-year rate of remaining in chronic phase was 41% in the IFN-alpha group and 29% in the busulfan group (P = .1165). As compared with the patients with no cytogenetic response, the patients with any cytogenetic response (complete, partial or minor) after the IFN-alpha or busulfan treatment were significantly superior in the duration of chronic phase (IFN-alpha group; P = .0017, busulfan group; P = .0010) even after correction for the time to response using the landmark analysis. However, there was no significant difference in survival rate in the IFN-alpha group (P = .1065). There was no significant difference in survival rate (P = .3923) and the duration of chronic phase (P = .6258) between the IFN-alpha and the busulfan group in the patients with a cytogenetic response (complete, partial or minor). These results demonstrate that IFN-alpha treatment produces a significantly superior cytogenetic response and survival rate as compared with the busulfan treatment, and unexpectedly, that busulfan can also eliminate Philadelphia chromosome positive clone in a few patients who showed prolonged survival rate and duration of chronic phase.

Adult↗
PubMed1995

Homozygous deletions of the p15 (MTS2) and p16 (CDKN2/MTS1) genes in adult T-cell leukemia.

Adult T-cell leukemia (ATL) is associated with prior infection with human T-cell leukemia virus type I (HTLV-I). Twenty to 40 years often elapse from viral infection to overt ATL, suggesting that other genetic events must occur to produce frank leukemia. The p15 (MTS2) and p16 (CDKN2/MTS1) genes located on chromosome 9p have been implicated as candidate tumor-suppressor genes in several types of tumors. We examined for alterations of these genes in ATL using Southern blot and polymerase chain reaction-single-strand conformation polymorphism analyses. Both p15 and p16 genes were homozygously deleted in 4 of 23 acute/lymphomatous ATL (17%). An additional 3 (13%) and 4 (17%) acute/lymphomatous samples had hemizygous deletions in at least one exon of p15 and p16, respectively. One of 14 chronic ATL samples had a homozygously deleted p16 gene and another had a hemizygous deletion of p16. Neither homozygous nor hemizygous deletions of the p15 gene were found in chronic ATL. In total, 10 of 37 (27%) ATL samples had loss of the p15 and/or p16 genes. No point mutations of the p15 and p16 genes were found. The ATL patient with a homozygously deleted p16 in the chronic phase rapidly progressed to acute ATL and died within 6 months of the initial diagnosis. One instructive patient had no detectable deletion of the p15 and p16 genes during the chronic phase of ATL but had a homozygous deletions of both genes when she progressed to acute ATL. Our results suggest an association of p15/p16 deletions with development of acute ATL.

Acute Disease↗
PubMed1995

Molecular detection of pre-ATL state among healthy HTLV-1 carriers in an endemic area of Japan.

Adult T-cell leukemia/lymphoma (ATL) usually develops after age 40 in Japan, suggesting a long latency since HTLV-I is considered to be transmitted mainly from mothers to babies via breast milk. Our previous studies had suggested that HTLV-I carriers who have a monoclonal integration of HTLV-I proviral DNA in the peripheral blood cells, designated pre-ATL, account for about 2% of healthy carriers and are at high risk of developing ATL. Their ages ranged from 32 to 80 (median 57). Nevertheless, many cases of pre-ATL showed a long-lasting carrier state (10-year probability around 90%). In the present investigation we conducted a large-scale molecular detection of monoclonal integration in a population (481 cases) of healthy carriers with ages ranging from 16 to 82 (median 49) for the purpose of clarifying the earliest onset of this pre-ATL state. Southern-blot analysis of DNA extracted from peripheral blood mononuclear cells revealed 6 cases (1.2%) with a monoclonal band. All of these 6 were older than 40; no single positive case was found in 220 carriers under age 40. These results indicate that the molecularly detectable pre-ATL state also develops after a long latency. Thus the pre-ATL state seems to be a subtype of ATL showing an extremely indolent course of disease development, but not merely an early phase of all subtypes of ATL. We propose that, in order to reveal a promoter(s) responsible for the development of ATL from the pre-ATL state, intensive epidemiological investigation of life style, eating habits, occupation and exposure to carcinogens must be conducted on this unique group prone to ATL. It is also important to perform such an epidemiological study on the general population of carriers by paying special attention to the first 3-4 decades of each carrier's life in Japan and by comparing the data with those from carriers in different geographical areas of the world.

Adolescent↗
PubMed1995

Morphological comparison of dysplastic changes between de novo acute myeloid leukemia (AML) with trilineage myelodysplasia and AML developed from de novo myelodysplastic syndromes.

To elucidate the clinical and morphological differences between de novo acute myeloid leukemia (AML) with trilineage myelodysplasia (AML/TMDS) and AML developed from de novo myelodysplastic syndrome (MDS), we analyzed 12 and 13 cases, respectively. The median age of AML/TMDS patients was lower, but not significantly so, than the median age of patients with AML from MDS (45 vs 55 years). Platelet counts and the percentage of peripheral blasts were significantly higher in the patients with AML/TMDS than in the patients with AML from MDS (p < 0.05 and p < 0.01, respectively). Four patients with AML from MDS could not be classified into FAB subtypes. Eight patients (67%) with AML/TMDS achieved complete remission (CR). Nine with AML from MDS were treated with less intensive regimens; none of these patients achieved CR. In the comparison of dysplastic changes in both groups, the rate of pseudo-Pelger anomaly was significantly higher in the patients with AML from MDS (p < 0.001), and micromegakaryocytes and multinuclear erythroblasts were also more frequent in the patients with AML from MDS than in those with AML/TMDS (p < 0.05). The overall survival curves showed that the 12 patients with TMDS had a significantly better survival than the 13 patients with AML from MDS (p < 0.01). Our findings suggest that AML/TMDS is a subtype of de novo AML and is different from AML from MDS. Further study is required to determine the biological differences between AML with TMDS and AML transformed from MDS.

Adolescent↗
PubMed1995

Clinical significance of tissue polypeptide antigen in serum of acute nonlymphocytic leukemia.

Tissue polypeptide antigen (TPA) in serum was measured at diagnosis in 27 patients with acute nonlymphocytic leukemia (ANLL) (1 FAB M0, 1 M1, 10 M2, 7 M3, 5 M4, 1 M5, 1 M6 and 1 MU). Statistical analysis disclosed a close correlation of TPA level with age (P < 0.01), hemoglobin level (P < 0.05), therapeutic response (P < 0.01) and the length of survival after the initial diagnosis (P < 0.02). A significant difference in TPA level was present between patients with complete remission and those with poor response. To our knowledge, this is the first report to prove a correlation of TPA level with therapeutic response and the length of survival in ANLL.

Adolescent↗
PubMed1995

Inversion(10)(q11q24) in a case of adult T-cell leukemia.

We report a case of adult T-cell leukemia (ATL) with complex chromosome abnormalities including an inversion (10)(q11q24) in a 64-year-old man. Although some abnormalities of chromosome 10 have been seen in ATL and other lymphoid neoplasias, inv(10)(q11q24) has previously been reported only in a case of T-cell chronic lymphocytic leukemia. Recent studies have revealed a rearrangement of a novel homeobox-containing gene called TCL-3 or HOX11 on 10q24 in T-cell acute lymphoblastic leukemia with the specific chromosome translocation t(10;14)(q24;q11), and thus the significance of 10q24 aberrations in leukemogenesis is indicated. We suggest that, despite the rarity of this anomaly, inv(10) (q11q24) may be a new chromosome inversion related to T-cell neoplasia and that the 10q24 anomaly may be an important cytogenetic clue for the elucidation of the pathogenesis of some peripheral T-cell neoplasias.

Chromosome Inversion↗
PubMed1995

The radiographic restoration of the ventricular system after third ventriculostomy.

Ten adult patients were treated by third ventriculostomy for idiopathic aqueductal stenosis. Idiopathic aqueductal stenosis was diagnosed according to MR imaging; aqueductal stenosis secondary to tumor, hemorrhage, and/or infection was excluded. Following a third ventriculostomy under a flexible neuroendoscope, all patients were reviewed at 1, 3, 6, 12, and 24 months, and MR images with ventricular measurements were repeated for evaluation of the radiographic restoration of the ventricular system. The ventricular structures arranged in order of restoration were the size of the III ventricle, the upward deviation of the brain stem, and the size of the lateral ventricle in response to third ventriculostomy. The restoration of the whole ventricle steadied within two years. Our results contribute new information regarding restoration of the ventricular system under aqueductal stenosis and produce evidence that third ventriculostomy is a reasonable treatment based upon the patient's physiological condition.

Adult↗
PubMed1995

Clinical significance of serum thymidine kinase in adult T-cell leukaemia and acute myeloid leukaemia.

To clarify the clinical and biological significance of serum thymidine kinase (TK) in adult T-cell leukaemia (ATL) associated with human lymphotropic virus type-I (HTLV-I) and in acute myeloid leukaemia (AML), TK was measured in 52 patients with ATL (acute ATL, 35 patients; lymphoma ATL, two patients; chronic ATL, 12 patients; smouldering ATL, three patients), and in 27 patients with AML (one FAB MO, one M1, 10 M2, seven M3, five M4, one M5, one M6, one MU). In ATL patients, statistical analysis disclosed a close correlation between TK level and the leucocyte count (P < 0.01), and absolute number of abnormal lymphocytes (P < 0.01). However, no correlation was observed between serum lactic dehydrogenase (LDH) level and these items. Concerning the therapeutic response, a statistical difference was present in TK between complete remission and no response (P < 0.05), but not in LDH. We also investigated a significant inverse correlation between TK level as well as LDH level and the length of survival after the initial diagnosis (P < 0.01). In AML patients a close correlation of TK level with the count of leucocytes (P < 0.01), percentage of blasts in the blood (P < 0.05), therapeutic response (P < 0.01) and the length of survival after the initial diagnosis (P < 0.05) was present. Therefore the TK level may indicate the aggressiveness of leukaemic cells and predict the response to the chemotherapy and the length of survival in ATL and AML.

Acute Disease↗
PubMed1995

Successful bone marrow transplantation for idiopathic hypereosinophilic syndrome.

A 21-year-old man who had an increased number of eosinophils with morphological abnormalities, bone marrow fibrosis and multiple organ dysfunction failed to respond to methylprednisolone and hydroxyurea. He was diagnosed with hypereosinophilic syndrome (HES) probably due to myeloproliferative disorder, and underwent allogeneic bone marrow transplantation (allo-BMT) from an HLA-identical sibling. The engraftment was confirmed on day 21 after BMT, but the patient developed acute graft-versus-host disease (GVHD) with grade I veno-occlusive disease, and transient increase of eosinophils of the donor type followed by chronic GVHD of the extensive type. These complications were eventually controlled with cyclosporin A. The patient survived free of disease for more than a year after BMT. Allo-BMT seems to be a possible treatment of HES/MPD.

Adult↗