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At least 667 records · Page 37Linked to original sources
PubMed2004

Clinical relevance of survivin as a biomarker in neoplasms, especially in adult T-cell leukemias and acute leukemias.

Survivin has been identified as one of the top 4 transcripts among 3.5 million human transcriptomes uniformly up-regulated in cancer tissues but not in normal tissues. Therefore, we quantitatively determined the messenger RNA (mRNA) expression profile for survivin by a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) technique in 113 patients with leukemias, such as adult T-cell leukemia (ATL), acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia in crisis, and chronic lymphocytic leukemia (CLL), and in 25 cell lines, including 7 ATL cell lines and 15 solid-tumor cell lines. Furthermore, we examined whether the plasma level of survivin protein as measured by enzyme-linked immunosorbent assay (ELISA) substituted for mRNA expression by PCR quantification. Gene expression was quantitatively confirmed to be up-regulated in approximately 90% of ATL and acute leukemia cases and in all of the cell lines tested, whereas it was down-regulated in almost all cases of CLL. Furthermore, with respect to the interpretation of the gene expression findings, attention was paid to standardization with a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in the real-time PCR quantification, because the variability in GAPDH expression among the different cell types was significant. GAPDH expression was relatively low in ATL cells and high in ALL and AML cells. The rates of increase in the levels of survivin protein in the plasma of ATL patients and in the supernatants from in vitro cultures of solid-tumor cell lines were low compared with rates of increase of the mRNA and protein level in the cells, suggesting that the protein levels in plasma do not always reflect survivin expression in tumor cells. Our findings indicate the potential clinical relevance of survivin quantified by real-time PCR but not for the protein level in plasma as determined by ELISA, especially in cases of ATL and acute leukemias.

Acute Disease↗
PubMed2006

Adult T-cell leukemia in a liver transplant recipient that did not progress after onset of graft rejection.

A liver allograft recipient developed acute-type adult T-cell leukemia (ATL) during tacrolimus treatment, 2 years after undergoing transplantation for subacute fulminant hepatitis. Both donor and recipient were asymptomatic carriers of human T-cell lymphotropic virus type I (HTLV-I), but the ATL cells originated from the recipient. Tacrolimus treatment was discontinued, and combination chemotherapy was administered. The patient achieved complete remission, but the transplanted liver was acutely and chronically rejected. The patient did not respond to rescue therapy with tacrolimus, prednisolone, and mycophenolate mofetil and died of hepatic failure. Liver biopsies showed CD4+ ATL cell infiltration at the onset of ATL but not at the terminal stage. Moreover, Southern blotting revealed clonal integration of HTLV-I into the host genome of lymphoma cells at onset but not at the terminal stage. ATL after liver transplantation has not been previously described. The clinical course of the posttransplantational ATL was atypical, because it did not progress after the onset of rejection.

Fatal Outcome↗
PubMed2004

[Anti-tumor immunity in adult T-cell leukemia].

Adult T-cell leukemia (ATL) occurs in a small population of human T-cell leukemia virus type I (HTLV-I)-infected individuals. It has been noted that ATL is incidentally associated with mother-to-child infection which occurs mainly through breast-feeding, elevated levels of proviral load, and insufficiency in HTLV-I-specific cytotoxic T lymphocyte (CTL) responses. Among these, anti-tumor potentials of HTLV-I-specific CTL have been shown in ex vivo analysis of human HTLV-I-infected individuals and also in vivo experiments by using rat models of HTLV-I-infected lymphomas. In another rat model of HTLV-I-infection, orally infected rats showed significantly higher HTLV-I proviral load but lower HTLV-I-specific cellular immune responses than in intraperitoneally infected rats. As a result, persistent viral load was inversely correlated with levels of virus-specific T-cell responses. HTLV-I-specific T-cell responses in orally infected rats recovered by re-immunization. Conversion of Tax-specific T-cell responses from low to high levels was also observed in an ATL patient who obtained complete remission after hematopoietic stem cell transplantation. These findings suggest that HTLV-I-specific immune unresponsiveness associated with oral HTLV-I infection may be a potential risk factor for development of ATL, allowing expansion of the infected cell reservoir in vivo, and that immunological strategies targeting Tax may potentially reduce the risk of ATL and induce therapeutic effects on ATL.

Animals↗
PubMed2007

HTLV-1 Tax and adult T-cell leukemia.

Human T-lymphotropic virus type I (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 viral transactivator/oncoprotein, Tax, activates viral transcription and usurps regulatory mechanisms that are critical for cell growth and division to facilitate viral replication. The effects that Tax exerts on cells include potent NF-k B activation, cell cycle perturbation and cell transformation. How Tax influences ATL development is incompletely understood at present. While Tax-expression is needed at the early stages of cellular transformation, at later times most ATL cells do not express tax; therefore, genetic and epigenetic changes in HTLV-1-infected cells are believed to play an important role in the etiology of ATL. This review attempts to integrate recent literature on the biological activities of Tax and the properties of HTLV-1 transformed T-cells and ATL cells, and speculate on what cellular changes may collaborate with Tax to effect cell transformation and ATL development.

Adult↗
PubMed1992

Tumor necrosis factor-beta and hypercalcemia.

Hypercalcemia in hematological malignancy is frequently encountered in lymphoid malignancies such as adult T-cell leukemia (ATL) and multiple myeloma and is difficult to manage. As a causative agent of hypercalcemia in ATL, tumor necrosis factor-beta (TNF-beta), previously known as lymphotoxin, has been carefully studied and reviewed here. Bone resorption studies showed the presence of activity in culture supernatants of HTLV-I infected cells. Enzyme linked immunosorbent assays (ELISA) for TNF-beta detected elevated TNF-beta in the sera of ATL patients with hypercalcemia. Immunostaining by monoclonal anti-TNF-beta antibody demonstrated the presence of TNF-beta in both HTLV-I infected cell lines and freshly isolated ATL cells. Furthermore biological TNF-beta activity assay including inhibition of anti-TNF-beta antibody confirmed the conventional documentation of TNF-beta activity in the sera and culture supernatants of HTLV-I infected cell lines. These studies showed that the TNF-beta secreted from ATL cells might be one of the factors contributing to the hypercalcemia in patients with ATL functioning as an osteoclast activating factor (OAF).

Animals↗
PubMed1993

Differences in clinicopathological characteristics and major prognostic factors between B-lymphoma and peripheral T-lymphoma excluding adult T-cell leukemia/lymphoma.

A total of 541 consecutive patients treated between 1975 and 1985, 449 with B-lymphoma and 92 with peripheral T-lymphoma, excluding adult T-cell leukemia/lymphoma (ATL), termed peripheral non-ATL T-lymphoma, were analysed. Clinicopathological features that were predominantly associated with B-lymphoma were low and intermediate grades (defined by the Working Formulation), diffuse large cell type, stage II disease, bulky disease, favourable extranodal sites that are defined as a group of primary tumors such as the eye, Waldeyer's ring, thyroid, and stomach, while other features predominantly associated with peripheral non-ATL T-lymphoma were high grade pathology, diffuse mixed-cell and immunoblastic type, systemic "B" symptoms, poor performance status (PS), generalized lymphadenopathy, involvement of organs such as liver, skin, and nose, leucocytosis, and a high levels of serum alkaline phosphatase. The survival curve for B-lymphoma was better (P < 0.01) than that for peripheral non-ATL T-lymphoma. Multivariate analysis revealed that the major prognostic factors were pathology, stage, and primary site for B-lymphoma, while stage, PS, and total protein levels were important for peripheral non-ATL T-lymphoma. These results indicate that B- and peripheral non-ATL T-lymphomas appear to have different biological characteristics.

Adult↗
PubMed1995

Adhesion properties of adult T cell leukemia cells.

The interaction between neoplastic as well as normal T cells and vascular endothelial cells which is mediated by adhesion molecules play a key role in their trafficking, localization and infiltration. This brief article reviews our studies on the expression of adhesion molecules on leukemic cells isolated from patients with adult T cell leukemia (ATL) and HTLV-I-infected T cell line cells and on their adhesion to human umbilical vein endothelial cells (HUVEC). Fresh ATL cells expressed lymphocyte function-associated antigen-1 (LFA-1), but the expression of very late antigen-4 (VLA-4) and sialyl-Lewis(x) (SLex) was variable. Sialyl Lewis(a) (SLea) was not detected. Cell adhesion assays using HUVEC and adhesion-blocking antibodies revealed the consistent E-selectin-mediated adhesion and variable VLA-4-mediated adhesion of ATL cells to HUVEC. The studies on HTLV-I-infected T cell lines confirmed the above data. These results, together with the detection of E-selectin expression on the endothelium of the skin infiltrated with ATL cells, indicate that E-selectin-mediated adhesion is the major pathway for the adherence of ATL cells to endothelial cells. The possible role of such adhesion in the formation of skin lesions and other clinical manifestations of ATL which result from the infiltration of leukemic cells is discussed.

Cell Adhesion↗
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↗
PubMed1998

Spontaneous acute tumor lysis syndrome in acute myeloid leukemia? A single case report with discussion of the literature.

Acute tumor lysis syndrome (ATLS), a condition which results from a rapid destruction of tumor cells with massive release of cellular breakdown products, has been well described following the treatment of various malignancies. However, only a handful of cases of spontaneous ATLS have been reported in the literature. We describe the first reported case of spontaneous ATLS in acute myeloid leukemia (AML). A previously healthy 63 year old woman presented with a two month history of fatigue and a one week history of easy bruising. On admission she had oliguric acute renal failure, with marked elevation in serum uric acid and phosphate. A bone marrow biopsy showed AML M7 with fibrosis. The renal failure resolved with supportive care and institution of allopurinol therapy. Following this, AML induction chemotherapy resulted in complete remission. Her biochemical and clinical course were very similar to the classical ATLS seen in patients after chemotherapy. Therefore, this case represents a rare instance of acute renal failure from spontaneous ATLS, and in our opinion the first reported occurrence of spontaneous ATLS associated with AML.

Acute Kidney Injury↗
PubMed1999

HUB1 is an autoantigen frequently eliciting humoral immune response in patients with adult T cell leukemia.

The immunological screening of a cDNA phage expression library prepared from an adult T cell leukemia (ATL) cell line, ST1, was performed with IgG class antibodies in the serum of an ATL patient by the SEREX method to analyze the repertoire of antigen molecules in ATL. Ten different cDNAs, 7 previously reported and 3 newly identified, were isolated. One of the identified cDNAs was homologous to the recently reported gene, HTLV-I U5RE binding protein 1 (HUB1) encoding a protein binding to a possible repressor element of the long terminal repeat of the human T lymphotropic virus type I (HTLV-I). The obtained cDNA was expressed as a fusion protein with glutathione S-transferase. HUB1 protein was prepared by subsequent treatment of the fusion protein with thrombin. Reactivity of IgG serum samples from ATL patients, asymptomatic HTLV-I carriers and normal donors against the purified protein was examined by Western blot analysis. Twenty-one out of 30 samples (70.0%) from ATL patients, 10/24 samples (41.7%) from HTLV-I carriers and 9/24 samples (37.5%) from healthy donors showed positive reactivity, indicating the autoantigenicity of HUB1. The development of ATL may be related to higher production of antibodies against HUB1.

Adult↗
PubMed1999

[Intracranial and orbital extension of a nasal cavity adult T-cell leukemia: a case report].

Adult T-cell leukemia (ATL) is one kind of leukemia induced by human T lymphotropic virus type I (HTLV-I) infection. An unusual case of ATL is presented. A fifty-one-year-old male patient was admitted to our hospital because of nasal obstruction and blindness in the left eye. Imaging study revealed a mass lesion in the nasal cavity, the left paranasal sinus extending to the left orbit and intracranial frontal base. Biopsy of the mass from the paranasal sinus was carried out and the histological diagnosis was a granulomatous lesion with non-specific inflammation. The clinical impression of the lesion was lethal midline granuloma. After steroid therapy and 50 Gy of local radiotherapy, the patient's symptoms disappeared except for his blindness in the left eye. Imaging study revealed that the mass lesion had become smaller. In spite of local improvement, new lesions such as cervical lymph node swelling and multiple nodular shadows in the lung fields appeared on CT scan. Histological diagnosis of the biopsied cervical lymph node was T-cell dominant non-Hodgkin's lymphoma of the diffuse type. Serologically, anti-HTLV-I antibody was positive. Southern blot analysis of lymph node biopsy showed monoclonal proliferation of ATL cells. We made the diagnosis of our case as ATL. The patient died 16 months later despite repeated systemic chemotherapy with cyclophosphamide, vincristine, adriamycin, and prednisolone. ATL can involve the central nervous system (CNS) and manifest CNS symptoms. The neurosurgeon also should consider the CNS involvement of ATL especially in Japan.

Brain Neoplasms↗
PubMed2003

Expression of the c-Met proto-oncogene and its possible involvement in liver invasion in adult T-cell leukemia.

c-Met is a tyrosine kinase receptor for hepatocyte growth factor and suggested to be involved in oncogenesis ormetastatic phenotypes in many malignancies. Adult T-cell leukemia (ATL) is a neoplasia characterized by massive invasion of the leukemic cells into various organs. Recently, we have reported frequent hepatic involvement and the relationship between liver invasion and the poor prognosis in ATL. In the present study, we investigated the expression of c-Met in ATL cells and its relation to liver dysfunction. In three of four human T-cell lymphotrophic virus-I-positive T-cell lines, c-Met was expressed both at mRNA and protein levels, whereas it was not expressed in human T-cell lymphoma virus-I-negative T-cell lines. The expressed c-Met should be functional, because hepatocyte growth factor could induce the autophosphorylation of c-Met. Although the viral-transactivating protein Tax has been shown to be involved in the deregulated expression of cellular genes, Tax mRNA was not detected in c-Met mRNA-expressed cell lines. From freshly isolated peripheral blood mononuclear cells, the expression of c-Met mRNA was detected in 10 of 16 ATL patients but not from healthy individuals. Finally, serum transaminase levels were significantly increased in c-Met-positive ATL cases, and all of the infiltrated c-Met-positive cells into liver were shown to be multilobularly nucleated phenotype. Taken together, these data suggest for the first time that c-Met is involved in the liver invasive phenotype of ATL.

Blotting, Western↗
PubMed1992

[Endoscopic analysis of gastric mucosal lesions in patients with adult T-cell leukemia during chemotherapy].

Gastric mucosal lesions in 13 patients with adult T-cell leukemia (ATL) were endoscopically studied at least at 2 occasions during chemotherapy for these patients. X-ray examinations by using barium meal showed deformities in 10 patients and abnormal mucosal pattern in 11 out of 13 patients with ATL. The endoscopic examinations revealed gastric ulcers in 5 patients, erosion in 8, diffuse bleeding in 2, tumorous mucosal folds in one, and submucosal tumor in one patient. In 9 out of 12 ATL patients, pathological study revealed that ATL cells had invaded the mucosal area of the stomach. The ulcers and erosions were improved by chemotherapy in 3 out of 5 and 5 out of 8 patients, respectively, whereas the erosion was not reduced in 2 and even aggravated in one patient. Interestingly, the gastric lesions formed by ATL cell invasion were improved by the administration of anticancer agents in 5 out of 9 patients. However, these lesions reappeared together with systemic lesions of ATL.

Adult↗
PubMed2003

Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD52 monoclonal antibody, Campath-1H.

Adult T-cell leukemia (ATL) develops in a small proportion of human T-cell leukemia virus I-infected individuals. Presently, there is no effective therapy for ATL. A murine model of ATL was produced by introducing leukemic cells (MET-1) from an ATL patient into nonobese diabetic/severe combined immunodeficient mice. The MET-1 cells are activated T cells that express CD2, CD3, CD4, CD25, CD122, and CD52. We evaluated the efficacy of Campath-1H (alemtuzumab; a humanized monoclonal antibody directed to CD52), alone and in combination with humanized anti-Tac (HAT) directed to CD25 (interleukin 2 receptor alpha) or with MEDI-507 directed to CD2. We observed that four weekly treatments with 4 mg/kg HAT significantly prolonged survival of MET-1-bearing mice. However, the survival of mice receiving 4 weeks of 4 mg/kg Campath-1H was significantly longer than that of the group receiving four weekly treatments with HAT (P < 0.001). Treatment with Campath-1H for 4 weeks led to a striking prolongation of the survival of MET-1 ATL-bearing mice that was comparable with that of tumor-free nontreated controls. Using Fc receptor (FcR) gamma(-/-) mice, we found that FcRgammas on polymorphonuclear leukocytes and monocytes are required for Campath-1H-mediated tumor killing in vivo. These results demonstrate that Campath-1H has therapeutic efficacy on ATL in vivo in that the life span of the Campath-1H treatment group was comparable with that of mice that did not receive a tumor or therapy. The main tumor killing mechanism with Campath-1H in vivo involves FcRgamma-containing receptors (e.g., FcRgammaIII) on polymorphonuclear leukocytes and macrophages that mediate antibody-dependent cellular cytotoxicity and/or trigger cross-linking induced apoptosis. This study provides support for a clinical trial of Campath-1H in the treatment of patients with T-cell leukemias and lymphomas.

Alemtuzumab↗
PubMed1992

Urinary excretion of parathyroid hormone-related protein as a predictor of hypercalcemia in patients with adult T-cell leukemia.

Hypercalcemia with adult T-cell leukemia (ATL) is chiefly caused by an excessive production by tumor cells of parathyroid hormone-related protein (PTHrP). We have previously reported hypercalcemic patients with solid tumors to excrete a large amount of the C-terminal fragments of PTHrP (C-PTHrP) into their urine. To elucidate whether PTHrP production correlates with or predicts the development of hypercalcemia, we studied the urinary excretion of C-PTHrP in 36 ATL patients. The urinary excretion of C-PTHrP was in the normal range (< 0.40 nmol equivalent to PTHrP (109-141)/g creatinine) in HTLV-1-positive carriers (n 3), ATL patients in complete remission (n 2) and chronic type ATL patients (n 2). It was marginally increased in seven patients in partial remission, and gradually increased as the disease progressed. In 20 patients who died without or with hypercalcemia, it was increased to 1.98 +/- 0.69 (n 9) and 7.6 +/- 2.1 nmol/g creatinine (mean +/- SD, n 11, P < 0.01), respectively. Urinary C-PTHrP excretion was significantly correlated with serum calcium and LDH levels as well as with CD25-positive cells in the peripheral blood. In four patients whose urinary excretion had been serially determined, it increased prior to the development of hypercalcemia. The findings suggest the urinary excretion of C-PTHrP to be of use as a predictor of the development of hypercalcemia in ATL patients. In ATL patients whose urinary excretion of C-PTHrP is progressively increasing, the serum calcium concentration should be carefully monitored to prevent hypercalcemic crisis.

Adult↗
PubMed1991

[Serum deoxythymidine kinase activity in adult T-cell leukemia].

Serum deoxythymidine kinase activities (s-TK) of the patients with adult T-cell leukemia (ATL), carriers and healthy persons were measured, using a recently developed TK assay with 125I-iodo-deoxyuridine as a substrate. The mean s-TK values were 3.3 +/- 2.7 U/l (n = 21) in normal subjects (HTLV-1(-)), 4.7 +/- 5.0 U/l (n = 35) in carriers, 9.8 U/l (n = 3) in smoldering ATL and 26.7 U/l (n = 6) in chronic ATL. In the patients with acute ATL, the mean s-TK values before and after chemotherapy were 80.9 U/l (n = 2) and 11.6 U/l (n = 4), respectively. In the follow-up studies of the patients with acute ATL, the changes of s-TK levels revealed earlier than those of serum LDH levels. It is suggested that s-TK activity is more useful than LDH as a parameter of monitoring treatment in ATL.

Biomarkers, Tumor↗
PubMed1991

Instability of the hindfoot after lesion of the lateral ankle ligaments: investigations of the anterior drawer and adduction maneuvers in autopsy specimens.

The mobility patterns in the tibiotalocalcaneal joint complex with a solitary lesion of the anterior talofibular ligament (ATL) and a combined lesion of the ATL and calcaneofibular ligament (CFL) were studied in 22 human lower-extremity autopsy specimens mounted in a kinesiologic testing device. A solitary lesion of the ATL increased the anteroposterior (AP) laxity in the ankle joint in the entire range of flexion, with a maximum median of 3.1 mm in neutral flexion. Further cutting of the CFL increased AP laxity most obviously in dorsiflexion. A solitary lesion of the ATL resulted in a minor instability in adduction, whereas further lesion to the CFL increased adduction in the entire range of flexion, with a maximum median of 14.2 degrees in dorsiflexion. The anterior drawer maneuver can reveal a combined lesion of the ATL and CFL if performed with the tibiotalocalcaneal joint complex in dorsiflexion. Significant clinical instability in adduction will only take place when a combined lesion of the ATL and CFL is present.

Adolescent↗
PubMed1990

[Human T-cell leukemia virus type I and adult T-cell leukemia-lymphoma].

Adult T-cell leukemia-lymphoma (ATL) is a unique T-cell leukemia-lymphoma that is closely associated with human T-cell leukemia virus type I (HTLV-I). HTLV-I is also associated with a benign disease, HTLV-I associated myelopathy. Main routes of the infection is through breast milk feeding from carrier mother to her baby, from carrier husband to wife, and by blood transfusion of carrier blood to recipient patients. The presence of anti-HTLV-I antibody is a definite sign of the carrier of HTLV-I, then screening of the antibody has been introduced with success to prevent the HTLV-I infection. Mechanism of leukemogenesis by the virus is not known. It is important to note that age-dependent occurrence of HTLV-I associated ATL can be simply described by a Weibull model. This suggests that ATL leukemogenesis might be the result of accumulation of numerous critical events, most likely somatic mutations, which are estimated to be five from the analysis. Although HTLV-I infection plays a primary role in the pathogenesis of ATL as an initiator, it may be only a prerequisite for accumulation of later events. The presence of HTLV-I negative ATL suggests that factor(s) other than HTLV-I infection may be involved in the leukemogenic process of ATL.

Adult↗