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[Adult T-cell leukemia--from retrovirus-induced T-cell leukemia in dermatologic patients. Clinical histologic and epidemiologic studies].

In 1976, adult T-cell leukemia (ATL) was reported as a special form of T-cell leukemia. In such cases the following criteria are prominent: strong inclination to leukemic change, incidence of abnormal cells in the peripheral blood, and the existence of an endemic area at the time of the outbreak of the disease. The abnormal tissue infiltrating ATL cells originate from peripheral blood T-lymphocytes, and in these lymphocytes the causal retrovirus HTLV-I could be proven. Since pathognomonic cutaneous manifestations can be observed among almost 50% of the patients, knowledge of this disease is of great importance to dermatologists. Two cases are reported focussing on the clinical and histopathologic findings concerning the cutaneous manifestations. Epidemiologically, up to 1984, we collected and analyzed 153 Japanese cases. There is a minor difference in sex distribution, but the incidence of ATL is highest among people in their fifties. The region of Kyushu, especially the southwestern part, and of Okinawa proved to be the endemic centers of ATL.

Antineoplastic Combined Chemotherapy Protocols↗

Evidence for the interleukin-2 dependent expansion of leukemic cells in adult T cell leukemia.

Interleukin 2 (IL-2) receptor/Tac antigen is abnormally expressed on cells of patients with adult T cell leukemia (ATL) caused by infection with human T lymphotropic virus type I (HTLV-I). Twenty-five patients with ATL were examined to determine whether their leukemic cells continued to show IL-2-dependent proliferation. In 21 patients, the in vitro proliferation of HTLV-I-infected nonleukemic T cell clones was found to be dependent on IL-2. However, clonality analysis based on T cell receptor gene rearrangement profiles and the site of HTLV-I provirus integration revealed IL-2-dependent growth in leukemic cells in four patients with ATL. These results provide evidence for the IL-2-dependent proliferation of leukemic cells in some ATL patients.

Antigens, Surface↗

Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T cell leukemia-lymphoma. Fifth International Workshop on Chromosomes in Leukemia-Lymphoma.

To correlate cytogenetic findings with histology and immunophenotype, 260 newly diagnosed patients with non-Hodgkin's lymphoma (NHL) and 31 with adult T cell leukemia/lymphoma (ATL) were studied at the Fifth International Workshop on Chromosomes in Leukemia-Lymphoma. Clonal chromosome abnormalities were found in 85% of cases of NHL and in all cases of ATL. The most significant associations of histology with cytogenetics involved the 8q24 and 14;18 translocations. Of 23 NHL patients with an 8q24 translocation, 20 (87%) had small noncleaved cell (SNC) lymphoma. Of 57 NHL patients with a t(14;18)(q32;q21), 37 (65%) had a follicular lymphoma, and at least 13 others (23%) had a diffuse lymphoma of follicular center cell origin. Five others including two who also had an 8q24 translocation had SNC lymphoma; tumors in these patients lacked the monomorphic features seen in those with only an 8q24 translocation. The most striking associations of immunology with cytogenetics involved rearrangements of 14q11-13, abnormalities of 1p, trisomy 3, and trisomy 12. Abnormalities of 14q11-13 were correlated with T cell disease. Among 138 NHL and 24 ATL cases that lacked involvement of 8q24, t(14;18), or rearrangements of 14q11-13, abnormalities of 1p and trisomy 3 were significantly associated with the T cell phenotype (P less than .01) and trisomy 12 with the B cell phenotype (P less than .01). No karyotype difference was found between Japanese ATL and non-Japanese T cell lymphomas except that +3 occurred more often in the former (P = .06). Although the 8q24 translocations in 23 patients were distributed relatively equally among geographic regions (United States, ten; Europe, ten; Japan, three), the t(14;18) in 57 patients was much less frequently seen in Japan than in the other parts of the world (United States, 31; Europe, 21; Australia, four; Japan, one). Thirty-nine chromosome bands had breaks in five or more cases; a number of protooncogenes and genes related to lymphocyte function located in these bands are likely to be involved in the development of lymphoma. Thus, besides confirming the close association of particular chromosome abnormalities with histology, we have identified a number of new associations that merit molecular analysis.

Adolescent↗

Anticoagulant activity in cell homogenate of adult T cell leukemia.

The hemostatic abnormality in 18 patients with adult T cell leukemia (ATL) was studied. Activated partial thromboplastin time (APTT) was slightly prolonged and prekallikrein activity was markedly low in these patients. The leukemic cell homogenate from these patients prolonged the recalcification time (RCT) of normal plasma; homogenates containing more than 3 x 10(3) cells/microliter prolonged it, although a lower cell concentration shortened it. The crude anticoagulant fraction from the gel filtration, with a molecular weight of about 34,000, prolonged RCT. The crude anticoagulant did not affect prothrombin time (PT), thrombin activity or activated X activity at any concentration, but prolonged the contact activation test, inhibited the activation of prekallikrein and prolonged RCT of Fletcher trait, Fitzgerald trait and F XII deficient plasma. These effects of ATL cell homogenate were stronger on platelet poor plasma than on platelet rich plasma. Although ATL cells had low procoagulant activity, increase of leukemic cells made anticoagulant activity predominant, might be the cause of hemostatic abnormality or amplify the bleeding tendency in patients with ATL.

Adult↗

[Recent progress in non-Hodgkin's lymphoma study in Japan].

Great progress has been made in clinical research on non-Hodgkin's lymphoma during the last 15 years. Surface marker and DNA analyses of immunoglobulin and T-cell receptor genes are essential for new classification of the disease according to the cellular origin of tumor cells. This approach resulted in the establishment of new disease entities such as adult T-cell leukemia/lymphoma(ATL), immunoblastic lymphoadenopathy (IBL)-like T-cell lymphoma, and the pleural B-lymphoma occurring in long-standing pyothorax. New retrovirus, HTLV-I, was found during studies on ATL. Prevention of HTLV-I infection is an important project. HTLV-I negative ATL was also found and is of particular interest in understanding leukemogenesis of ATL. An oncogen such as bcl-2 is important for characterization of follicular lymphoma. Prognostic factors of patients with T-lymphoma are completely different from those of B-lymphoma. Risk grouping by combination of major prognostic factors is useful for the selection of the best treatment modality and the accurate estimation of prognosis of patients at initial presentation. The effect of combination chemotherapy should be evaluated separately between T- and B-lymphomas because of the difference in response rate and prognostic factors.

B-Lymphocytes↗

Structural analysis of normal and mutant insulin receptors in fibroblasts cultured from families with leprechaunism.

Leprechaunism is an inherited disorder characterized by insulin resistance and intrauterine growth restriction. In this study we analyze insulin binding and subunit structure of the insulin receptor in dermal fibroblasts cultured from three unrelated families whose probands (Ark-1, Atl, and Minn) were affected by leprechaunism. Cells cultured from all three probands had markedly reduced insulin binding at equilibrium. Fibroblasts cultured from the parents of Ark-1 and Atl had partial and differing degrees of impairment in insulin binding. The structure of the alpha subunit of insulin receptors was analyzed by cross-linking 125I-insulin to plasma membranes. A major band of 350 kilodaltons (kD) (corresponding to the heterotetrameric insulin receptor alpha 2 beta 2) was observed in control and leprechaun fibroblasts. The relative amount of radioactivity cross-linked to plasma membranes reflected the genetic variations seen in insulin binding to intact cells. In reducing gels, 125I-insulin was cross-linked equally to a 250-kD (alpha-alpha dimer) and a 125-kD (alpha monomer) protein in cells from controls, the parents of Ark-1 and Atl, and probands Atl and Minn. By contrast, cells from the Ark-1 proband had diminished cross-linking of alpha-alpha dimers. The ratio of dimer to monomer in cells from controls was 0.93 +/- 0.06, and that in cells from Ark-1 was 0.31 +/- 0.19 (P less than .01). Beta-subunit structure and function was analyzed by studying insulin-enhanced autophosphorylation. Although maximal stimulation of beta-subunit phosphorylation was reduced to 30% in proband Ark-1 fibroblasts, this reduction was quantitatively related to reduced insulin binding. These results indicate that mutations causing severe insulin resistance and defective insulin binding are transmitted with autosomal recessive patterns of inheritance and that heterogeneity exists for these mutations. The mutation in pedigree Ark-1 most likely produces conformational changes in alpha-subunit interaction.

Cells, Cultured↗

Failure of regulation of Tac antigen/TCGF receptor on adult T-cell leukemia cells by anti-Tac monoclonal antibody.

Anti-Tac monoclonal antibody, which blocks the membrane binding and action of human T-cell growth factor (TCGF), is strongly proposed to recognize TCGF receptor. We have demonstrated that anti-Tac antibody reacted with leukemic cells from patients with adult T-cell leukemia (ATL) and reacted with T-cell lines established from ATL cells. Although antigenic modulation, or down-regulation, of Tac antigen on activated normal T cells was induced by anti-Tac antibody, the expression of Tac antigen on ATL cells or T-cell lines was not affected when examined by the fluorescence-activated cell sorter (FACS) and the radioassay using 125I-staphylococcal protein A. These results indicate that regulation of Tac antigen-TCGF receptor is different between normal and malignant T cells, suggesting that failure of down-regulation of Tac antigen on leukemic cells by anti-Tac antibody may play an important role in the malignant proliferation of ATL cells.

Animals↗

Localization of adult T-cell leukemia-associated antigens by the immunocolloidal gold method.

Adult T-cell leukemia-associated antigen (ATLA) and adult T-cell leukemia virus (ATLV) antigens were localized in the MT-2 cell system by the immunocolloidal gold method using 71 human sera having various anti-ATLA titers and rabbit anti-ATLV antisera. In the thin-section method with anti-ATLA-positive human sera and rabbit antisera, protein A-gold particles were preferentially observed on and around sectioned adult T-cell leukemia (ATL) virions located in pericellular aggregates and within the cytoplasmic vacuoles but nowhere else in a significant number. The number of gold particles per ATL virion was statistically well correlated with the anti-ATLA titers of human sera applied (p less than 0.005). The preembedding method showed that pericellular ATL virions were specifically tagged with protein A-gold, but the antigens in question were not expressed on the plasma membrane of MT-2 cells. The absence of ATLA and ATLV antigens on the plasma membrane constitutes a unique pathobiological feature of ATL and ATLV as compared with other retrovirus systems.

Adult↗

Association of the human type C retrovirus with a subset of adult T-cell cancers.

To determine whether the human T-cell lymphoma-leukemia virus (HTLV) is associated with particular cancers, patient sera were surveyed for HTLV-specific antibodies. An association was seen with aggressive cancers of mature T-cells, specifically Japanese adult T-cell leukemia (ATL) and T-cell lymphosarcoma cell leukemia (TLCL), a similar cancer of Caribbean blacks. Ninety to 100% of these patients possessed HTLV-specific antibody. Forty-seven and 20% of relatives of ATL and TLCL patients, respectively, and 12 and 4% of healthy donors from ATL and TLCL endemic areas were also antibody positive. Visceral organ involvement, hypercalcemia, and skin manifestation, features of ATL and TLCL, were often seen in other antibody-positive patients. Childhood cancers, most cutaneous T-cell and all non-T-cell leukemias and lymphomas, myeloid leukemias, Hodgkin's disease, and solid tumors were not associated with HTLV. Healthy United States donors and European patients with non-malignant diseases were antibody negative. HTLV is thus associated with a subtype of adult T-cell leukemia-lymphoma, clustered in viral endemic areas, with apparent racial and geographic predilection.

Adult↗

Case report of adult T-cell leukemia with preceding long-standing cutaneous involvement.

This report documents an unusual case of adult T-cell leukemia (ATL) with a preceding phase of long-standing cutaneous involvement. After nine months of an aleukemic phase, characteristic leukemic cells of ATL, possessing inducer/helper phenotype without helper function, had appeared. In addition, antibodies to ATL virus-associated antigen (ATLA) were found in the serum of the patient and her family. The patient died after an 18-month clinical course due to generalized cytomegalovirus infection in spite of strong chemotherapy. At autopsy, leukemic involvement was restricted to the skin. We postulate that ATL may originate not only from the lymph nodes but also from the skin.

Aged↗

[Adult T-cell leukemia virus--introduction--].

Attempts were made to find a putative virus causally related to ATL. A retrovirus was demonstrated in a T-cell line originating from leukemic cells of a patient with adult T-cell leukemia (ATL) in and subsequent virological and serological studies suggested that the virus be etiologically related to ATL. This retrovirus was named adult T-cell leukemia virus (ATLV). This article reports the general properties of ATLV and the possible etiological relation of ATLV to ATL.

Animals↗

[Epidemiological analysis of adult T-cell leukemia].

Adult T-cell leukemia (ATL) is prevalent in the rural coastal areas of southwestern part of Japan. The geographical distribution of persons with antibody to ATLV which seems to be the decisive causal agent of ATL is very similar to that of ATL patients. The positive rate of anti-ATLA among healthy inhabitants older than 50 years was 32% (21% in males and 39% in females) in Goto Islands in Nagasaki Prefecture. However, positive rates are only 15% in the age group of 30 to 49 years and 4% under 29 years in the same area. From the epidemiological analyses of the mode of anti-ATLA reactivity among married couples and family members with positive and negative anti-ATLA, two routes of transmission of ATLV were suspected. One route is from parents to children and another is the horizontal transmission from new family to woman after marriage. The environmental and socioeconomic factors which had changed remarkably after the World War II and may have influenced the characteristic distribution of ATLV carriers by age and sex in these areas are discussed as the modifying factors for ATLV infection and ATL manifestation from the epidemiological view point.

Adolescent↗

Distinctive phorbol ester-induced morphological and surface antigen changes in mycosis fungoides, the Sézary syndrome, and adult T-cell leukemia.

Clinical and pathological studies of cutaneous T-cell lymphomas (CTCL) reveal variations in tumor cell morphology and surface membrane phenotype that are of diagnostic and prognostic importance. Our study investigates blastic transformation and surface antigen change on CTCL cells in vitro under the influence of tumor-promoting phorbol ester (TPA) and phytohemagglutinin. Both agents transformed tumor cells with cerebriform nuclei into blast cells within 5 days; however, Sézary cells were somewhat resistant to transformation with phytohemagglutinin. Multinucleated cells with prominent nucleoli resembled Reed-Sternberg cells of Hodgkin's disease. These morphological changes simulated the appearance of the aggressive tumor stage of mycosis fungoides. During blastic transformation, the erythrocyte rosette receptor was induced by TPA on sheep erythrocyte-rosette-negative Sézary cells from one patient. During the first 24 hr in vitro, Sézary and MF cells stimulated by TPA lost Leu 3a (T4) antigen while maintaining original high levels of Leu 1 antigen. In contrast, leukemia cells from patients with adult T-cell leukemia (ATL) were resistant to modulation of Leu 3a antigen by TPA; 3A1 antigen on CTCL and ATL cells was unaffected by TPA. Blastic transformation of CTCL cells was observed with both TPA and phytohemagglutinin, but helper T-cell antigen Leu 3a (T4) and erythrocyte rosette receptor changes occurred only with TPA. Thus, blastic transformation and surface differentiation were not directly related. These results provide a possible model for the study of blastic transformation and surface antigen/receptor variation in CTCL. They also may provide an independent test for the distinction of CTCL and ATL in vitro. Finally, they illustrate the relative resistance of ATL to surface antigen modulation as previously shown for Tac antigen modulation by anti-Tac antibody.

Adult↗

Effects of acute and chronic splenectomy on experimental acute renal tubular lesions.

The first half of this study describes the effects of acute splenectomy on epinephrine-induced ATL in the dog. Renal morphology and hematocrit were compared in 12 dogs without splenectomy (group I), six dogs with antecedent splenectomy (group II), and seven dogs with antecedent splenectomy after splenic contraction was induced by topical application of epinephrine (group III). Splenectomy was performed in groups II and III 20 to 30 min prior to epinephrine infusion; all three groups received equal infusions (4 microgram/kg/min) for 6 hr before the kidneys were harvested. ATL and renal congestion were consistently severe in group I but infrequent and less severe in groups II and III. The second half of this study describes the apparent protective effect of chronic (2-week) splenectomy on epinephrine-induced ATL. Renal morphology and hematocrits were compared in 13 intact dogs (group IV) and 10 dogs splenectomized 2 weeks before the epinephrine infusion (group V). The severity of the ATL and the degree of renal congestion were significantly less in the chronically splenectomized dogs. This chronic protection afforded by acute and chronic splenectomy observed after epinephrine infusion remains unclear.

Animals↗

Radioimmunotherapy of interleukin-2R alpha-expressing adult T-cell leukemia with Yttrium-90-labeled anti-Tac.

Adult T-cell leukemia (ATL) is a malignancy of mature lymphocytes caused by the retrovirus human T-cell lymphotropic virus-I. It is an aggressive leukemia with a median survival time of 9 months; no chemotherapy regimen appears successful in inducing long-term disease-free survival. The scientific basis of the present study is that ATL cells express high-affinity interleukin-2 receptors identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this difference, we administered anti-Tac armed with Yttrium-90 (90Y) to 18 patients with ATL initially (first 9 patients) in a phase I dose-escalation trial and subsequently (second group of 9 patients) in a phase II trial involving a uniform 10-mCi dose of 90Y-labeled anti-Tac. Patients undergoing a remission were permitted to receive up to eight additional doses. At the 5- to 15-mCi doses used, 9 of 16 evaluable patients responded to 90Y anti-Tac with a partial (7 patients) or complete (2 patients) remission. The responses observed represent improved efficacy in terms of length of remission when compared with previous results with unmodified anti-Tac. Clinically meaningful (> or = grade 3) toxicity was largely limited to the hematopoietic system. In conclusion, radioimmunotherapy with 90Y anti-Tac directed toward the IL-2R expressed on ATL cells may provide a useful approach for treatment of this aggressive malignancy.

Adult↗

[Double cancer in patients with adult T cell leukemia].

We have studied the incidence and characteristics of associated neoplasms in 210 ATL patients. Twelve patients had other primary neoplasms and the incidence of double cancer was 5.7%. The additional malignancies in ATL patients consisted of 4 cases of stomach, 3 cases of colon and one of each lung, ovary, uterus, liver and bladder cancer. In metachronous double cancer patients, the neoplasm was found before the time of diagnosis of ATL in 5 out of 6 patients. Immunodeficiency due to HTLV-I infection as well as chemotherapy for the preceding neoplasm are suggested to be related to the leukemogenesis of ATL.

Aged↗

[Inhibitory effects of menogaril to the proliferation of HTLV-I infected T-cell lines and fresh tumor cells from adult T-cell leukemia patients].

Anti-cancer effect of anthracyclines are well established. In vitro inhibitory effects of a new anthracyclin-derivative drug, menogaril (TUT-7) which is developed for oral administration, on three human T-cell leukemia virus type-I (HTLV-I) infected T-cell lines, a HTLV-I non-infected T cell line, and fresh tumor cells from four adult T-cell leukemia (ATL) cases are evaluated and compared to those of doxorubicin. The inhibitory effects of TUT-7 is almost as much as those of doxorubicin. Both TUT-7 and doxorubicin induced apoptosis to a HTLV-I infected cell line and inhibited proliferation of fresh tumor cells from ATL of chronic, acute and lymphoma type in a dose dependent manner. We have already reported that skin eruption of ATL patient improved by oral administration of TUT-7. This new anthracyclin-derivative would be useful in treating ATL patients even in out-patients clinic keeping a good quality of life.

Apoptosis↗

[Recent progress in the chemotherapy of malignant lymphoma].

Recent progress in the chemotherapy of malignant lymphoma is described from the viewpoint of survival advantage. Malignant lymphoma is classified into the following five major categories: aggressive lymphoma, indolent B-lymphoma, Hodgkin's disease, T-lymphoblastic lymphoma and adult T-cell leukemia-lymphoma (ATL). In aggressive lymphoma of advanced stages, recent multicenter phase III studies revealed that first-generation CHOP therapy remains the best available treatment. By multivariate analysis on prognostic factors of non-ATL lymphoma patients who were treated by the second generation LSG 4 protocol, CRP and total number of involved lesions were found to be significantly unfavorable factors. In non-ATL lymphoma, mainly B-lymphoma, three risk groups (low, intermediate and high) were identified. Similarly, the International Non-Hodgkin's Lymphoma Prognostic Factors Project proposed a new predictive model for survival of aggressive lymphoma patients. Such predictive models would be very useful in the design of future chemotherapy trials for aggressive lymphoma. In advanced-stage Hodgkin's disease, about two-thirds of patients are expected to be long-term survivors, thanks to state-of-the-art chemotherapy. A recent phase III study conducted by CALGB disclosed that MOPP/ABVD and ABVD are superior to MOPP. In ATL and indolent B-lymphoma, no state-of-the-art chemotherapy has been established. In order to improve the prognosis of both diseases, innovative treatment strategies should be pursued.

Antineoplastic Combined Chemotherapy Protocols↗