Serum levels of parathyroid hormone-related protein are not elevated in patients with T-cell prolymphocytic leukemia

 T-cell prolymphocytic leukemia (T-PLL) is a rare post-thymic T-cell neoplasm which shares most clinical features with adult T-cell leukemia (ATL). We measured serum level of C-terminal parathyroid hormone-related protein (C-PTHrP) in patients with T-PLL and ATL. Serum C-PTHrP levels of eight patients with T-PLL (median 36.8 pmol/l; range 27.0–50.2 pmol/l) did not differ from those of 30 human T-lymphotropic virus type I (HTLV-I)-seronegative blood donors (median 37.0 pmol/l; range 22.6–54.0 pmol/l). The C-PTHrP levels in ten ATL patients (median 69.6 pmol/l; range 42.5–899.4 pmol/l) were significantly higher than those in healthy controls (p<0.0001) or T-PLL patients (p=0.001). We suggest that the serum level of PTHrP can provide useful information for differentiating between T-PLL and ATL. Received: February 18, 1999 / Accepted: April 30, 1999     

Diffuse panbronchiolitis as a pulmonary complication in patients with adult T-cell leukemia

Forty-three cases of adult T-cell leukemia (ATL) admitted to our hospital between 1982 and 1987 were studied. Three of those were found to be complicated with diffuse panbronchiolitis (DPB). The incidence of DPB is considered to be significantly higher in patients with ATL. The three DPB-complicated cases composed one case each of the smoldering, chronic, and acute type of ATL. In each type, DPB preceded overt ATL and Candida albicans was found in sputa following detection for bacteria. The DPB complication apparently worsened the prognosis of the ATL patients. We have discussed a possible relationship between ATL and DPB.     

The occurrence of systemic lupus erythematosus in an asymptomatic carrier of human T-cell lymphotropic virus type I

A 63-year-old asymptomatic carrier of human T-cell lymphotropic virus type I (HTLV-1) infection was admitted because of chest oppression, a high-grade fever, polyarthralgia, and erythematous rashes. Laboratory examination revealed lymphocytopenia, proteinuria, and high titers of antinuclear antibodies and antidouble-stranded DNA antibody; thus, she was diagnosed as having systemic lupus erythematosus (SLE). This case indicates that HTLV-1 infection might be related with the pathogenesis of SLE.     

Ultrasonography and magnetic resonance imaging findings of rheumatoid arthritis-like arthritis in a patient with adult T-cell leukemia

A 43-year-old Japanese woman with adult T-cell leukemia (ATL) developed rheumatoid arthritis-like polyarthritis with dermatitis and skin erosion. Her rheumatoid factor and C-reactive protein results were positive. Musculoskeletal ultrasonography showed intra-articular and peritendinous power Doppler signal-positive synovitis. Plain magnetic resonance imaging showed synovitis of the above lesion and remarkable bone marrow edema/osteitis. She was diagnosed as having ATL-associated arthritis based on the invasion of ATL cells by skin biopsy at the arthritis lesion.     

Major prognostic factors of Japanese patients with lymphoma-type adult T-cell leukemia

Fifty-three Japanese patients with the lymphoma-type adult T-cell leukemia (ATL) were analyzed to study the prognostic value of various clinical findings recorded at the time of diagnosis. All patients were positive for human T-cell leukemia virus type I (HTLV-I) antibody and demonstrated monoclonal integration of HTLV-I proviral DNA in their malignant cells. The important individual variables detected in a previous univariate analysis were placed in a multiple regression model to identify the major prognostic factors for survival. This analysis showed that serum lactate dehydrogenase (LDH), calcium, and total protein levels had a strong predictive relationship with the length of survival (in descending order of importance). Among the 53 patients, 46 were dead at the time of analysis. The cause of death in relation to the duration of survival is also reviewed in this article.     

The time-sequential changes of risk factors for adult T-cell leukemia development in human T-cell leukemia virus-positive patients with rheumatoid arthritis: a retrospective cohort study

Abstract

Objective: This study aimed to investigate the time-sequential changes of risk factors for adult T-cell leukemia (ATL) development in human T-cell leukemia virus type 1 (HTLV-1)-positive rheumatoid arthritis (RA) patients.

Methods: HTLV-1 infection was screened using particle agglutination assay and confirmed via western blotting in 365 RA patients. Twenty-three HTLV-1-positive RA patients were included in the study cohort. Blood samples were obtained from these patients at each observation time point. The values of HTLV-1 proviral load (PVL) and serum soluble IL-2 receptor (sIL2-R), which are risk factors for ATL development, were measured using real-time PCR and enzyme immunoassay, respectively.

Results: The study cohort comprised 79 person-years. The median HTLV-1 PVL and sIL2-R values of the HTLV-1-positive RA patients were 0.44 copies per 100 white blood cells (WBCs) and 406?U/mL, respectively. Three HTLV-1-positive RA patients showed a high PVL value. No remarkable changes were observed in the PVL and sIL2-R values during the observation period. However, one elderly HTLV-1-positive RA patient who had a high PVL value developed ATL during treatment with methotrexate and infliximab.

Conclusion: A thorough clinical assessment of the risk factors for ATL development may be necessary in daily clinical practice for RA patients in HTLV-1-endemic areas in Japan.     

Bisphosphonate incadronate inhibits growth of human T-cell leukaemia virus type I-infected T-cell lines and primary adult T-cell leukaemia cells by interfering with the mevalonate pathway

Anti-resorptive bisphosphonates are used for the treatment of hypercalcaemia and bone complications associated with malignancies and osteoporosis, but also have been shown to have anti-tumour effects in various cancers. Adult T-cell leukaemia (ATL) is a fatal T-cell malignancy caused by infection with human T-cell leukaemia virus type I (HTLV-I), and remains incurable. ATL is associated with osteolytic bone lesions and hypercalcaemia, both of which are major factors in the morbidity of ATL. Thus, the search for anti-ATL agents that have both anti-tumour and anti-resorptive activity is warranted. The bisphosphonate agent, incadronate, prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells, but not of non-infected T-cell lines or normal peripheral blood mononuclear cells. Incadronate induced S-phase cell cycle arrest and apoptosis in HTLV-I-infected T-cell lines, and treatment of these cells with substrates of the mevalonate pathway blocked the incadronate-mediated growth suppression. Incadronate also prevented the prenylation of Rap1A protein. These results demonstrated that incadronate-induced growth suppression occurs by interfering with the mevalonate pathway. Importantly, treatment with incadronate reduced tumour formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into severe combined immunodeficient mice. These findings suggest that incadronate could be potentially useful for the treatment of ATL.     

Defective human T-lymphotrophic virus type I provirus in T-cell prolymphocytic leukaemia

T-cell prolymphocytic leukaemia (T-PLL) is a rare form of post-thymic T-cell neoplasm, the aetiology of which remains unknown. We examined human T-lymphotropic virus (HTLV) provirus in five HTLV-I/II seronegative patients with T-PLL. Southern blotting did not show monoclonal integration of the HTLV-I genome in any of the DNA samples. However, two of the five DNA samples contained an HTLV-I tax sequence. Other sets of oligonucleotide primers for HTLV-I gag, pol, env and LTR regions were all negative. HTLV-I tax gene expression and p40tax antibody were not detected in samples from cases with HTLV-I tax sequence. Our findings suggest that there may be alternative mechanisms involved in HTLV-associated leukaemogenesis, in which HTLV-I genome insertion triggers T-PLL but the deletion of various regions of the integrated provirus subsequently prevents active replication and the expression of the virus.     

Treatment of adult T-cell leukemia/lymphoma: past, present, and future

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-cell lymphotrophic virus type I. Clinical manifestations of ATLL range from smoldering to chronic, lymphoma and acute. Patients with acute and lymphoma type ATLL require therapeutic intervention. Conventional chemotherapeutic regimens used against other malignant lymphoma have been administered to ATLL patients, but the therapeutic outcomes of acute and lymphoma type ATLL remain very poor. Promising results of allogeneic stem cell transplantation (SCT) for ATLL patients have recently been reported and the treatment outcome might be improved for some ATLL patients. Besides conventional chemotherapy and SCT, interferon, zidovudine, arsenic trioxide, targeted therapy against surface molecule on ATLL cells, retinoid derivatives, and bortezomib have been administered to ATLL patients in pilot or phase I/II studies. Further studies are required to confirm the clinical benefits of these novel therapeutics. This article reviews the current status and future directions of ATLL treatment.     

Association of human T-cell leukemia virus type 1 with prevalent rheumatoid arthritis among atomic bomb survivors: A cross-sectional study

Previous studies have suggested that human T-cell leukemia virus type 1 (HTLV-1) might act as a pathogen in rheumatoid arthritis (RA), but epidemiological evidence of an association is scarce. We measured anti-HTLV-1 antibodies among Nagasaki atomic bomb survivors to determine whether HTLV-1 is related to RA and whether radiation exposure is associated with HTLV-1 and RA prevalence.This is a cross-sectional study among atomic bomb survivors who participated in biennial health examinations from 2006 to 2010. Serum levels of anti-HTLV-1 antibodies were measured using a chemiluminescent enzyme immunoassay and confirmed by Western blotting. Association between HTLV-1 and RA was analyzed by a logistic regression model.Of 2091 participants (women 61.5%; median age, 73 years), 215 (10.3%) had anti-HTLV-1 antibodies. HTLV-1 prevalence was higher among women (13.1% vs 5.8%; P < .001). Twenty-two participants (1.1%) were diagnosed with RA. HTLV-1 prevalence among RA participants was significantly higher than that among non-RA participants (27.3% vs 10.1%; P = .020). After adjustment for age, sex, and hepatitis C virus infection, HTLV-1 was significantly associated with prevalent RA (odds ratio, 2.89; 95% confidence interval, 1.06, 7.03). There was no association between radiation dose and either the prevalence of HTLV-1 or RA.This study, among a well-defined group of atomic bomb survivors, suggests that HTLV-1 is associated with RA.     

Factors associated with pain in individuals infected by human T-cell lymphotropic virus type 1 (HTLV-1)

Introduction

Despite the high prevalence of chronic pain in individuals infected with HTLV-1, predictive and protective factors for its development are still unclear.

Adult T-cell leukemia/lymphoma with two distinct clones in the peripheral blood and lymph node

A case of adult T-cell leukemia/lymphoma (ATL) with two different clones in the peripheral blood and lymph nodes is reported here. When cellular DNA from the lymph node was digested with EcoRI, one band larger than 9 Kb was detected. Digestion of the cellular DNA with PstI resulted in one clear band in addition to three internal fragments. In contrast, when cellular DNA from malignant peripheral blood lymphocytes (PBL) was digested with the same endonucleases, distinct bands at positions different from those observed in the lymph node were detected, indicating two separate malignant clones in the patient. Monoclonality of the tumor cells was shown by T-cell receptor-β (TCR-β) gene rearrangement in both PBL and lymph node. Furthermore, there was a difference in the surface phenotype between tumor cells taken from peripheral blood (CD4+, CD8–) and lymph node (CD4+, CD8+). These findings suggest the presence of two different ATL clones in PBL and lymph node in a single patient simultaneously, which is distinguishable by the integration pattern of human T-cell leukemia virus type I (HTLV-I) proviral DNA.     

Depletion and impaired interferon-alpha-producing capacity of blood plasmacytoid dendritic cells in human T-cell leukaemia virus type I-infected individuals

Dendritic cells (DCs) play an important role in innate and adaptive immunity. There are two major populations of blood DCs, myeloid DCs (myDCs) and plasmacytoid DCs (pcDCs). pcDCs are particularly important in antiviral as well as in general host defence, as they are the principal producers of type I interferons (IFNs). In this study, we analysed myDCs and pcDCs in healthy controls, human T-cell leukaemia virus type I (HTLV-I)-infected asymptomatic carriers (ACs), and patients with adult T-cell leukaemia (ATL). ATL patients had significantly decreased number of pcDCs and myDCs compared with controls. IFN-alpha production by peripheral blood mononuclear cells (PBMCs) was markedly reduced in ATL patients. Purified pcDCs from ACs were found to have impaired IFN-alpha-producing capacity, suggesting a functional defect in pcDCs in HTLV-I-infected individuals. Interestingly, pcDCs were shown to be susceptible to HTLV-I infection. Thus, impaired IFN-alpha production by pcDCs may contribute to the immunodeficiency observed in ATL. Furthermore, IFN-alpha-producing capacity was inversely correlated with HTLV-I proviral load in PBMCs from ACs, suggesting a role for pcDCs in maintaining the carrier state. Taken together, we hypothesize that the depletion and impaired IFN-alpha-producing capacity of blood DCs may contribute to the immunodeficiency in ATL and/or the development of ATL.     

Foxp3 expression on normal and leukemic CD4+CD25+ T cells implicated in human T-cell leukemia virus type-1 is inconsistent with Treg cells

Foxp3 is a master gene of Treg cells, a novel subset of CD4⁺ T cells primarily expressing CD25. We describe here different features in Foxp3 expression profile between normal and leukemic CD4⁺CD25⁺ T cells, using peripheral blood samples from healthy controls (HCs), human T-cell leukemia virus type-1 (HTLV-1)-infected asymptomatic carriers (ACs), patients with adult T-cell leukemia (ATL), and various hematopoietic cell lines. The majority of CD4⁺CD25⁺ T cells in HCs were positive for Foxp3, but not all CD4⁺CD25⁺ T cells in ACs were positive, indicating that Foxp3 expression is not always linked to CD25 expression in normal T cells. Leukemic (ATL) T cells constitutively expressing CD25 were characteristic of heterogeneous Foxp3 expression, such as intra- and inter-case heterogeneity in intensity, inconsistency with CD25 expression, and a discrepancy in the mRNA and its protein expression. Surprisingly, a discernible amount of Foxp3 mRNA was detectable even in most cell lines without CD25 expression, a small fraction of which was positive for the Foxp3 proteins. The subcellular localization of Foxp3 in HTLV-1-infected cell lines was mainly cytoplasmic, different from that of primary ATL cells. These findings indicate that Foxp3 has two facets: essential Treg identity and molecular mimicry secondary to tumorigenesis. Conclusively, Foxp3 in normal T cells, but not mRNA, is basically potent at discriminating a subset of Treg cells from CD25⁺ T-cell populations, whereas the modulation of Foxp3 expression in leukemic T cells could be implicated in oncogenesis and has a potentially useful clinical role.     

Serum dehydroepiandrosterone and DHEA-sulfate in patients with adult T-cell leukemia and human T-lymphotropic virus type I carriers

The serum levels of dehydroeplandrosterone (DHEA) and DHEA-sulfate (DHEA-S) were determined by radioimmunoassay in 38 patients with adult T-cell leukemia (ATL). Levels of serum DHEA and DHEA-S were also measured in 60 human T-lymphotropic virus type I (HTLV-I) carriers, and did not differ from those in 60 healthy control subjects. Serum levels in patients with ATL were lower than those in the age- and sex-matched healthy controls and in HTLV-I carriers with statistical significance. Serum DHEA and DHEA-S in male patients with acute and lymphoma-type ATL were 1.06 ± 0.77 ng/ml and 245.8 ± 192.9 ng/ml, respectively. Levels in male patients with chronic and smoldering-type ATL were 1.69 ± 0.68 ng/ml and 477.6 ± 251.5 ng/ml, respectively. Serum levels of DHEA and DHEA-S in patients with acute and lymphoma-type ATL were significantly lower than those in patients with chronic and smoldering-type ATL (P < 0.05). These data suggest that a decrease in serum levels of DHEA and DHEA-S may be associated with patients who have some clinical subtypes of ATL. Moreover, androgens may have a therapeutic role in patients with ATL, as administered in patients with hairy-cell leukemia. Because there is at present no curative chemotherapy for ATL, a trial combination of androgens and standard chemotherapy may be a reasonable therapeutic option in such patients. © 1996 Wiley-Liss, Inc.     

Quality of life,risk behaviors and depression among carriers of hepatitis C virus and human T-cell lymphotropic virus type 1: a comparative study

Human T-cell lymphotropic virus type 1 (HTLV-1) has low prevalence rates, but is endemic in some regions of the world. It is usually a chronic asymptomatic infection, but it can be associated with serious neurologic and urinary conditions. Hepatitis C virus (HCV) is broadly spread out worldwide. The majority of these infections have a chronic course that may progress to cirrhosis and hepatocellular carcinoma.ObjectivesTo compare sociodemographic and mental health (risk behaviors, depression, and suicide) aspects, and quality of life among patients with HCV or HTLV-1.MethodsObservational, comparative and cross-sectional study involving outpatients with HCV or HLTV-1 infection. Sociodemographic characteristics, risk behaviors and quality of life were assessed through the questionnaires Mini International Neuropsychiatric Interview – MINI Plus (depression and suicide) and Medical Outcomes Study 36-Item Short-Form Health Survey (quality of life). Univariate and multivariate statistical analyses (hierarchical logistic regression) were conducted.Results143 individuals with HCV and 113 individuals with HTLV-1 infection were included. Males were predominant in the HCV group (68.8%) and females in the HTLV-1 group (71.7%). The frequency of risk behaviors (sexual and drug use) was greater in those with HCV (p < 0.05). A past depressive episode was more common in the HTLV-1 group (p = 0.037). Quality of life was significantly worse in the physical functioning, vitality, mental health, and social functioning domains in those with HTLV-1 (p < 0.05). HTLV-1 infection remained independently associated with worse quality of life in multivariate analysis.ConclusionsRisk behaviors are frequent among those infected with HCV. Additionally, despite HTLV-1 being considered an infection with low morbidity, issues related to mental health (depressive episode) and decreased quality of life are relevant.