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PubMed1993

Pulmonary manifestations in adult T-cell leukemia at the time of diagnosis.

Adult T-cell leukemia (ATL) is an underlying immunodeficient condition which often leads to various kinds of pulmonary diseases. We have analyzed 35 consecutive patients (18 male, 17 female) with ATL to see to what extent pulmonary complications were involved at the time of diagnosis. Over one-third presented with respiratory symptoms and 14 (40%) patients had significant findings on chest radiographs on the first admission in which reticulo-nodular shadows were predominant in 10 patients, suggesting that overt ATL is preceded by interstitial pulmonary disease. In addition, bacterial pneumonia and pneumocystosis were experienced in over two-thirds of the patients during the clinical course, and more than half of the patients subsequently died of pulmonary complications suggesting that early institution of diagnostic procedures and treatment for pulmonary conditions is needed in ATL patients.

Female↗
PubMed1995

Ten-year survey of incidence of infection as a cause of death in hematologic malignancies: study of 90 autopsied cases.

We investigated 90 autopsied cases with hematologic malignancy, including malignant lymphoma (ML), acute leukemia (AL), and adult T-cell leukemia (ATL) peculiar to our district, during the 10-year period 1982-1991 to determine the change in incidence of infection as a cause of death. We divided the cases into two groups representing the first half decade (1982-1986) and the second half decade (1987-1991) and compared the findings made in the two groups. Although infection was the major cause of death in those autopsied cases, the incidence of fatal infections decreased during the latter period. The incidence of fatal bacterial infections decreased, while fungal infections showed a relative increase. Pneumocystis carinii pneumonia and cytomegalovirus (CMV) infection occurred more frequently in patients with ATL than in those with ML or AL. Combined infection by more than three pathogens was observed in 2 cases of ATL. Our study revealed the characteristics of ATL specific to our district, and indicated the need to apply new strategies to prevent and treat fungal and viral infections in patients with hematologic malignancies.

Acute Disease↗
PubMed1987

Interleukin-2 receptor-inducing factor(s) in adult T cell leukemia.

The expression of the interleukin-2 receptor (IL-2-R) is regulated by transcriptional and post-transcriptional mechanisms. IL-2-R gene expression is induced by pharmacological agents including calcium ions, phorbol esters such as phorbol myristate acetate (PMA) and forskolin (FK), a direct activator of adenylate cyclase. HTLV-I(+) leukemic T cells and T cell lines from patients with adult T cell leukemia (ATL) continuously expressed IL-2-R without production of IL-2. However, there was no abnormality of the structural gene for IL-2-R in these cell lines as well as in fresh leukemic cells of ATL. We have detected that many HTLV-I(+) T4(+) T cell lines constitutively produce a non-IL-2 lymphokine named ATL-derived factor (ADF), which induced the expression of the high-affinity IL-2-R on a variety of cells including HTLV-I(+) T cells, myeloid leukemia cells and YT cells. IL-2-R-inducing agents such as ADF and FK were shown to induce elevation of the mRNA levels for IL-2-R through transcriptional enhancement of the IL-2-R gene. The possible involvement of IL-2-R-inducing cytokines in the physiological lymphocyte activation and the leukemogenesis in ATL and other T cell leukemias is discussed.

Antibodies, Monoclonal↗
PubMed1996

Comparison of surface antigens on eosinophils from patients with eosinophilia.

Recent studies have suggested that there may be heterogeneity among human eosinophils. To study this further, surface antigens on blood eosinophils from patients with eosinophilia (23 bronchial asthma, 6 eosinophilic pneumonia, 1 Kimura's disease and 1 adult T-cell leukemia) and from 8 control subjects were examined using a new direct method for fluorescence detection of eosinophils. HLA-DR+ and CD4+ eosinophil counts were higher in patients with bronchial asthma and adult T-cell leukemia (ATL) than in patients from other groups and in control subjects. CD11b+ eosinophil counts in Kimura's disease and ATL were smaller than those in the other groups. CD45RO+ eosinophil counts in bronchial asthma and eosinophilic pneumonia were significantly higher (p < 0.05) compared with Kimura's disease, ATL and control subjects. CD44+ eosinophil counts in eosinophilic pneumonia were significantly higher (p < 0.05) compared with the other groups and control subjects. These results suggest the existence of functional heterogeneity in the different eosinophilic diseases, with eosinophils in bronchial asthma and eosinophilic pneumonia being more highly activated in migration, activation and immunoregulation. On the other hand, eosinophils in Kimura's disease and ATL might be functionally down-regulated. This heterogeneity of eosinophils may reflect differences in the pathogenesis of various eosinophilic diseases.

Adolescent↗
PubMed1979

Early closure of the tricuspid valve in a case of Ebstein's anomaly with type B Wolff-Parkinson-White Syndrome.

Echocardiographic studies of a 19-year-old female with Ebstein's anomaly and type B Wolff-Parkinson-White syndrome showed an earlier closure of the anterior tricuspid leaflet (ATL) than of the anterior mitral leaflet (AML), contrary to the previous reports. The interval between the closure of the ATL and the AML was 20 msec and 30 msec, respectively, before and after administration of edrophonium chloride. However, closure of the AML preceded that of the ATL after administration of atropine sulfate and during supraventricular tachycardia by 10 msec and 60 msec, respectively, concomitant with the shortening of the duration of the QRS complex. We conclude that early closure of the ATL may depend on preexcitation of the right ventricle.

Adult↗
PubMed1999

Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion.

Polymorphonuclear neutrophil (PMN) activation is pivotal in acute inflammation and injury from reperfusion. To elucidate components controlling PMNs in vivo, we prepared novel transgenic mice with the human leukotriene (LT) B4 receptor (BLTR) for functional characterization. Overexpression of BLTR in leukocytes dramatically increased PMN trafficking to skin microabscesses and lungs after ischemia-reperfusion, whereas mice deficient in 5-lipoxygenase (5-LO) showed diminished PMN accumulation in reperfused lungs. Hence, both BLTR expression and LT biosynthesis are critical for PMN infiltration in reperfusion-initiated second-organ injury. Also, in BLTR transgenic mice, 5-LO expression and product formation were selectively increased in exudates, demonstrating that receptor overexpression amplifies proinflammatory circuits. Endogenous lipoxin (LX) A4 was produced in ischemic lungs and elevated by reperfusion. Because LXA4 and aspirin-triggered 15-epimeric LXA4 (ATL) selectively regulate leukocyte responses, they were tested in BLTR transgenic mice. Despite excessive PMN recruitment in BLTR transgenic mice, intravenous injection of ATL sharply diminished reperfusion-initiated PMN trafficking to remote organs, and topical application of LX was protective in acute dermal inflammation. These results demonstrate a direct role for BLTR with positive feedback, involving BLTR and 5-LO signaling in controlling PMNs. Moreover, LXA4 and ATL counter BLTR-amplified networks, revealing a novel protective role for LX and ATL in stress responses that has applications in perioperative medicine.

Animals↗
PubMed2002

Bay 11-7082 inhibits transcription factor NF-kappaB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells.

Human T-cell leukemia virus type I (HTLV-I) is the causative agent of an aggressive form of leukemia designated adult T-cell leukemia (ATL). We have previously demonstrated that all T-cell lines infected with HTLV-I and primary leukemic cells from ATL patients display constitutively high activity of transcription factor NF-kappaB. In this study we showed that Bay 11-7082, an inhibitor of NF-kappaB, induced apoptosis of HTLV-I-infected T-cell lines but only negligible apoptosis of HTLV-I-negative T cells. Bay 11-7082 rapidly and efficiently reduced the DNA binding of NF-kappaB in HTLV-I-infected T-cell lines and down-regulated the expression of the antiapoptotic gene, Bcl-x(L), regulated by NF-kappaB, whereas it had little effect on the DNA binding of another transcription factor, AP-1. Although the viral protein Tax is an activator of NF-kappaB, Bay 11-7082-induced apoptosis of HTLV-I-infected cells was not associated with reduced expression of Tax. Furthermore, Bay 11-7082- induced apoptosis of primary ATL cells was more prominent than that of normal peripheral blood mononuclear cells, and apoptosis of these cells was also associated with down-regulation of NF-kappaB activity. Our results indicate that NF-kappaB plays a crucial role in the pathogenesis and survival of HTLV-I-infected leukemic cells and that it is a suitable target for the prevention and treatment of ATL.

Adult↗
PubMed2003

Arsenic/interferon specifically reverses 2 distinct gene networks critical for the survival of HTLV-1-infected leukemic cells.

Adult T-cell leukemia (ATL) is a severe chemotherapy-resistant malignancy associated with prolonged infection by the human T cell-lymphotropic virus 1 (HTLV-1) retrovirus. Although the Tax viral transactivator is clearly an oncogene, the role of its continuous expression in the maintenance of the transformed phenotype is controversial. Because arsenic trioxide (As) and interferon alpha (IFN) synergize to induce cell cycle arrest and apoptosis of ATL cells both ex vivo and in vitro, we investigated the effects of As alone and As/IFN combination on gene networks in HTLV-1-infected leukemic cells. The As/IFN combination reduced Tax expression and, accordingly, reversed the Tax-induced constitutive nuclear factor kappaB (NF-kappaB) activation. Using DNA microarray analyses, we demonstrated that As rapidly and selectively blocks the transcription of NF-kappaB-dependent genes in HTLV-1-infected cells only. Reversal of NF-kappaB activation by As alone resulted from dramatic stabilization of IkappaB-alpha and IkappaB-epsilon, independently of IkappaB kinase (IKK) activity modulation or Tax degradation. In contrast, only the As/IFN combination induced late and massive down-regulation of cell cycle-regulated genes, concomitantly with Tax degradation by the proteasome and cell death induction, indicating the importance of continuous Tax expression for ATL cell survival. These 2 successive events likely account for the potent and specific effects of the As/IFN combination in ATL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Dual targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ, a potent and selective inhibitor of NF-kappaB, as a strategy for chemoprevention and therapy of adult T-cell leukemia.

Human T-cell leukemia virus type I (HTLV-1) causes adult T-cell leukemia (ATL), a fatal T-cell leukemia resistant to chemotherapy, after more than 50 years of clinical latency from transmission through breast-feeding. Polyclonal expansion of virus-infected T cells predisposes them to transformation. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in the leukemic cells is essential for their growth and survival. Blocking NF-kappaB has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), and also examined its application to chemoprevention by selective purging of the HTLV-1-infected cells. DHMEQ inhibited NF-kappaB activation in primary ATL cells and cell lines derived from them and induced apoptotic cell death. NF-kappaB inhibition down-regulated expression of genes involved in antiapoptosis or cell-cycle progression. DHMEQ protected severe combined immunodeficiency (SCID) mice inoculated with HTLV-1-transformed cells from death. In addition, DHMEQ selectively targeted HTLV-1-infected cells in the peripheral blood of virus carriers in vitro, resulting in a decreased number of infected cells. We conclude that NF-kappaB is a potential molecular target for treatment and prevention of ATL. As a potent NF-kappaB inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine.

Animals↗
PubMed2005

Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states.

Human T-cell leukemia virus type I (HTLV-I) is a causative agent of neoplastic disease, adult T-cell leukemia (ATL). Although the encoding viral proteins play an important role in oncogenesis, the role of the HTLV-I proviral integration site remains unsolved. We determined the integration sites of HTLV-I proviruses in ATL cells and HTLV-I-infected cells in asymptomatic carriers. In carrier and ATL cells, HTLV-I provirus was integrated into the transcriptional unit at frequencies of 26.8% (15/56) and 33.9% (20/59), respectively, which were equivalent to the frequency calculated based on random integration (33.2%). In addition, HTLV-I provirus was prone to integration near the transcriptional start sites in leukemic cells (P = .006), and the transcriptional direction of the provirus was in accordance with that of integrated cellular genes in 70% of cases. More importantly, the integration sites in the carrier cells favored the alphoid repetitive sequences (11/56; 20%) whereas in leukemic cells they disfavored these sequences (2/59; 3.4%). Taken together, during natural course from carrier to onset of ATL, HTLV-I-infected cells with integration sites favorable for viral gene transcription are susceptible to malignant transformation due to increased viral gene expression.

Base Sequence↗
PubMed2006

Emodin and DHA potently increase arsenic trioxide interferon-alpha-induced cell death of HTLV-I-transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1.

Adult T-cell leukemia (ATL) is an aggressive lymphoproliferative disease of poor clinical prognosis associated with infection by the human T-cell leukemia virus type I (HTLV-I). The use of arsenic trioxide (As2O3) has been shown to effectively treat acute promyelocytic leukemia (APL) with greater than 80% of patients achieving complete remission. The combination of arsenic and interferon has also shown promising results in the treatment of ATL. The requirement for slow dosage increases of arsenic and the time required to achieve a pharmacologic active dose in patients is a major obstacle because median survival of patients with ATL is about 6 months. In this study we report a potent synergistic effect of the combination of arsenic trioxide and interferon alpha (As/IFN-alpha) with emodin and DHA on cell-cycle arrest and cell death of HTLV-I-infected cells. Importantly, we found that clinically achievable doses of DHA and emodin allowed for reduced arsenic concentrations by 100-fold while still remaining highly toxic to tumor cells. Our data provide a rationale for combined use of As/IFN-alpha with emodin and DHA in patients with ATL refractory to conventional therapy.

Arsenic Trioxide↗
PubMed1997

Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia.

PURPOSE: To determine the frequency of the deletions of p15/p16 genes in adult T-cell leukemia (ATL) cells and to evaluate their value in the diagnosis of clinical subtypes of ATL patients and the prediction of their clinical outcome. MATERIALS AND METHODS: Peripheral-blood samples from 114 patients with ATL were examined by Southern blot analysis. In five chronic-type patients who showed disease progression to acute type, serial samples also were examined. RESULTS: Among 114 patients, 28 (24.6%) showed the deletions of p15 and/or p16 genes. The results were well correlated with the clinical subtypes. Patients with deleted p15 and/or p16 genes had significantly shorter survival times than the patients in whom both genes were preserved (P < .0001). A similar decline in survival time was observed in the analyses within the same subtypes. In multivariate analysis using the Cox proportional hazard model, the deletions of p15 and/or p16 genes emerged as an independent prognostic indicator. Moreover, three of the five chronic-type patients who progressed to acute type lost the p16 gene alone or both the p15 and p16 genes at their exacerbation phase. CONCLUSION: The results suggest the following: (1) that the deletions of p15 and/or p16 genes play a key role in the progression of ATL; and (2) that these deletions are reliable prognostic factors that predict shortened survival times.

Adult↗
PubMed2005

Fucoidan extracted from Cladosiphon okamuranus Tokida induces apoptosis of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.

Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. The highest endemic area of HTLV-1 carriers in Japan is located in Okinawa, and novel treatments are urgently needed in this area. We extracted fucoidan, a sulfated polysaccharide, from the brown seaweed Cladosiphon okamuranus Tokida cultivated in Okinawa, Japan and examined its tumor-suppression activity against ATL. Fucoidan significantly inhibited the growth of peripheral blood mononuclear cells of ATL patients and HTLV-1-infected T-cell lines but not that of normal peripheral blood mononuclear cells. Fucoidan induced apoptosis of HTLV-1-infected T-cell lines mediated through downregulation of cellular inhibitor of apoptosis protein-2 and survivin and G1 phase accumulation through the downregulation of cyclin D2, c-myc, and hyperphosphorylated form of the retinoblastoma tumor suppressor protein. Further analysis showed that fucoidan inactivated NF-kappaB and activator protein-1 and inhibited NF-kappaB-inducible chemokine, C-C chemokine ligand 5 (regulated on activation, normal T expressed and secreted) production, and homotypic cell-cell adhesion of HTLV-1-infected T-cell lines. In vivo use of fucoidan resulted in partial inhibition of growth of tumors of an HTLV-1-infected T-cell line transplanted subcutaneously in severe combined immune deficient mice. Our results indicate that fucoidan is a potentially useful therapeutic agent for patients with ATL.

Animals↗
PubMed1997

Individual prediction of change in delayed recall of prose passages after left-sided anterior temporal lobectomy.

Prognostic variables for individual memory outcome after left anterior temporal lobectomy (ATL) were studied in 27 patients with refractory temporal lobe epilepsy. The difference between pre- and postoperative performance in the delayed recall of two prose passages (Story A and B) from the Wechsler Memory Scale served as measure of postoperative memory change. Fifteen independent clinical, neuropsychological, and electrophysiological variables were submitted to a multiple linear regression analysis. Preoperative immediate and delayed recall of story content and right hemisphere Wada memory performance for pictorial and verbal items explained very well postoperative memory changes in recall of Story B. Delayed recall of Story B, but not of Story A, had high concurrent validity to other measures of memory. Patients who became seizure-free did not differ in memory change from patients who continued to have seizures after ATL. The variables age at epilepsy onset and probable age at temporal lobe damage provided complementary information for individual prediction but with less effectiveness than Wada test data. Our model confirmed that good preoperative memory functioning and impaired right hemispheric Wada memory performance for pictorial items predict a high risk of memory loss after left ATL. The analyses demonstrate that the combination of independent measures delivers more information than Wada test performance or any other variable alone. The suggested function can be used routinely to estimate the individual severity of verbal episodic memory impairment that might occur after left-sided ATL and offers a rational basis for the counseling of patients.

Adolescent↗
PubMed1998

Predictors of outcome of anterior temporal lobectomy for intractable epilepsy: a multivariate study.

OBJECTIVE: To identify presurgical and postsurgical factors that are independently predictive of the outcome of anterior temporal lobectomy (ATL) for intractable epilepsy. BACKGROUND: There have been reports of prognostic factors in epilepsy surgery, but little is known about factors that independently predict outcome of ATL. METHODS: We studied 175 consecutive ATL patients who had at least 2 years of postsurgical follow-up. Significant factors on univariate analyses were subjected to stepwise logistic regression analysis. RESULTS: On univariate analyses, two presurgical conditions were significantly associated with excellent seizure control at last follow-up: (1) unilateral hippocampal formation atrophy as detected on MRI and (2) all scalp interictal epileptiform discharges concordant with the location of ictal onset (p < 0.05). Three postsurgical factors that occurred during the first year were associated with excellent seizure outcome: the absence of interictal epileptiform discharges at 3 months, complete seizure control, and having only nondisabling seizures for those who did not become seizure free. Logistic regression analysis revealed the following to be independently predictive of excellent seizure control: MRI-detected unilateral hippocampal formation atrophy, concordant interictal epileptiform discharges, complete seizure control during the first postsurgical year, and having only nondisabling seizures during the first postsurgical year for those who did not become seizure free. CONCLUSIONS: Presurgical identification of unilateral hippocampal formation atrophy, or of interictal epileptiform discharges that are all concordant with the location of ictal onset, predict excellent outcome of ATL. However, the probability of excellent outcome is highest (94%) when both factors are present.

Adolescent↗
PubMed2002

Age of meningitis or encephalitis is independently predictive of outcome from anterior temporal lobectomy.

BACKGROUND: The occurrence of meningitis or encephalitis in early childhood, i.e., < or =4 years of age, may be associated with both the development of medial temporal lobe epilepsy (MTLE) and an excellent operative outcome following an anterior temporal lobectomy (ATL). However, whether the predictive value of this risk factor for partial epilepsy is independent of the finding of mesial temporal sclerosis (MTS) on MRI is not known. METHODS: Consecutive patients (n = 39) with a remote history of meningitis or encephalitis who underwent an ATL were compared with 78 sex- and age-matched control subjects who had not experienced a CNS infection before ATL. All patients in both groups had nonlesional temporal lobe epilepsy and were followed up for at least 12 months postoperatively. RESULTS: There was a trend for the patients with a history of meningitis or encephalitis to have a lower frequency of class I postoperative outcome (61.5% vs 73.1%, p = 0.21). In the meningitis or encephalitis group, a class I outcome was more frequent in those with a history of meningitis or encephalitis at a young age (<4 years) (19/23 vs 5/16, p = 0.002), those with MTS detected on a preoperative MRI (22/31 vs 2/8, p = 0.04), and those with a history of meningitis (16/21 vs 8/18, p = 0.05). Multivariate logistic regression analysis found that a history of meningitis or encephalitis at a young age (b = 2.0, O.R. = 7.5, p = 0.048) was predictive of a class I outcome independent of the presence of MRI-identified MTS (b = 2.0, O.R. = 7.3, p = 0.07). CONCLUSION: The age of occurrence of a remote history of meningitis or encephalitis, but not the type of infection, is predictive of outcome after an ATL independent of the finding of MTS on the preoperative MRI.

Adolescent↗
PubMed1999

Acute tumor lysis syndrome: considerations of cause and prevention.

The need for better chemotherapeutic interventional modalities with adjunctive biotherapy and/or immunotherapy to confront oncologic disease processes will continue into the new millennium. Unfortunately, existing problems encountered as a consequence to chemotherapy centering on acute tumor lysis syndrome (ATLS) will also continue. ATLS results when cytotoxic agents lyse, or lacerate, outer plasma membranes of numerous cancerous cells. Eventually, their contents spill into the bloodstream, indirectly causing kidney damage. This article reviews the induction of ATLS caused by cytotoxic agents and its prevention and/or control. The association of ATLS with the administration of chemotherapeutic agents must be considered when treating various types of cancer.

Journal Article↗
PubMed2005

Acute tumor lysis syndrome induced by rituximab in diffuse large B-cell lymphoma.

Acute tumor lysis syndrome (ATLS) is a well-known complication of chemotherapy in patients with rapidly proliferative hematopoietic malignancies such as lymphoma and leukemia. Rituximab anti-CD20 monoclonal antibody, an alternative to chemotherapy in the treatment of low-grade follicular lymphoma, also has been associated with ATLS. Rituximab-induced ATLS has been reported in 2 patients with chronic lymphocytic leukemia and in 2 patients with non-Hodgkin's lymphoma. I report another case of rituximab-induced ATLS in a patient with diffuse large B-cell lymphoma and review the cases in the literature.

Acute Disease↗