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The Advanced Trauma Life Support Program in Manitoba: a 5-year review.

Twenty Advanced Trauma Life Support (ATLS) courses were conducted at the University of Manitoba between 1982 and 1987. There were 302 registrants, 95 of whom were from rural communities. Twelve registrants failed the course. The impact of the program was assessed by questionnaire (68.8% response overall). The response from department heads of surgery in urban hospitals was 87.5% and from surgeons in rural areas 50%. Fifty-eight percent of rural surgeons, 62.5% of urban surgeons and 75% of urban emergency-department directors claimed they could identify those who had attended an ATLS course by the increased confidence demonstrated and the use of more timely and appropriate consultation and treatment. Thirty percent of rural surgeons, 37% of urban surgeons and 42% of emergency-department directors claimed that mortality and morbidity were decreased when care was provided by ATLS-trained physicians. The remainder were undecided because of lack of information. Ninety-three percent of respondents indicated that the course increased their confidence, trauma capability and ability to communicate with consultant trauma surgeons. Fifty-two percent thought the course should be mandatory for all physicians, and 100% thought it should be mandatory for all emergency-department physicians. The data suggest that although most physicians treat fewer trauma patients 5 years after their ATLS training, the course is still highly recommended, and it has improved trauma care. Although the ATLS program was intended primarily for rural physicians, more urban-based physicians registered for it.

Education, Medical, Continuing↗

HTLV-I associated adult T cell leukemia/lymphoma: report of two cases from an Amerindian population in coastal northwest British Columbia.

Epidemiological studies of HTLV-I infection have demonstrated the presence of this virus in certain Amerindian populations in Central and South America. We have recently reported the first evidence of endemic HTLV-I infection in North American Amerindians from the coastal regions of British Columbia, Canada. While the predominant HTLV-I-associated disease observed in British Columbia Amerindians is the HTLV-I associated neurological disease (HTLV-I-associated myelopathy/tropical spastic paraparesis), we report here the first two cases of HTLV-I-associated adult T cell leukemia/lymphoma (ATL). Clinical and PCR evidence to support the diagnosis of HTLV-I-associated ATL in these two Amerindians is presented. Both cases of ATL were found in the same tribe although neither patient was directly related to each other. While reports of HTLV-I-associated ATL have been reported in Circumartic native peoples, reports of ATL in North American single ancestry Amerindians have not been previously made to our knowledge.

Adult↗

Interleukin-10 gene expression in adult T-cell leukemia.

We studied the serum levels of interleukin-10 (IL-10), in patients with adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) infection. Elevated IL-10 levels were observed in 33 of 45 patients with ATL. Fresh leukemic cells from ATL patients as well as HTLV-I-infected T-cell lines MT-2, SLB-1, and C10/MJ expressed IL-10 mRNA by reverse transcription-polymerase chain reaction analysis, whereas IL-10 mRNA was not detected in normal peripheral mononuclear cells and an uninfected T-cell line Jurkat. IL-10 protein was also detected in the culture medium of leukemic cells from ATL patients as well as these HTLV-I-infected cell lines, and in the extracellular fluids of ATL patients. Interestingly, MT-4 cells, which did not express Tax although transformed by HTLV-I, did not express IL-10 at either the mRNA or protein level. To elucidate the role of the HTLV-I encoded transactivator Tax in IL-10 gene expression, Jurkat cells were transfected with a Tax expression plasmid. In transiently transfected Jurkat cells, endogenous IL-10 mRNA expression was induced by Tax. Stably transfected Jurkat cell lines expressed IL-10 mRNA and secreted IL-10 protein into the culture medium. The nuclear factor (NF)-kappa B pathway is a target for Tax transactivation. We treated MT-2 cells with phosphorothioate antisense oligonucleotides to the p65 subunit of NF-kappa B. A reduction in the expression of p65 was accompanied by a reduction in IL-10 gene expression and IL-10 production. We showed that the IL-10 kappa B-like sites ( kappa B1,-2,034 to -2,025; kappa B2, -1,961 to -1,952; kappa B3, -452 to -443) specifically formed a complex with NF-kappa B-containing nuclear extract from MT-2 cells and that NF-kappa B bound with the highest affinity to the kappa B2 element (kappa B2 > kappa B3 > kappa B1). These data suggest a general role for NF-kappa B activation in the induction of IL-10 gene transcription. Activation of IL-10 in HTLV-I-infected cells may contribute to the pathology associated with HTLV-I infection.

Adult↗

[Soluble interleukin-2 receptor and macrophage colony-stimulating factor (M-CSF) in cerebrospinal fluid in patients with hematological malignancies: clinical significance in adult T-cell leukemia with meningeal infiltration].

We measured soluble interleukin-2 receptor (sIL-2R) and macrophage colony-stimulating factor (M-CSF) levels in the cerebrospinal fluid (CSF) of patients with hematological malignancies with or without meningeal infiltration and meningitis. Levels of sIL-2R and M-CSF in the CSF of adult T-cell leukemia (ATL) patients with meningeal infiltration were significantly higher than those of ATL patients without meningeal infiltration and non-ATL patients with meningeal infiltration. There was a significant positive correlation between sIL-2R levels and numbers of mononuclear cells in CSF of ATL patients with meningeal infiltration. However, M-CSF levels did not correlate with numbers of mononuclear cells. There was no correlation between CSF and serum levels of sIL-2R. There was also no correlation between sIL-2R and M-CSF in the CSF. Therefore, sIL-2R and M-CSF levels in the CSF may be useful in the diagnosis of meningeal infiltration in patients with ATL. In particular sIL-2R may be a sensitive marker.

Biomarkers, Tumor↗

OX40 expressed on fresh leukemic cells from adult T-cell leukemia patients mediates cell adhesion to vascular endothelial cells: implication for the possible involvement of OX40 in leukemic cell infiltration.

We demonstrated previously that OX40 and its ligand, gp34, directly mediate adhesion of activated normal CD4+ T cells, as well as human T-cell leukemia virus type I (HTLV-I)-transformed T cells to vascular endothelial cells. In the present study, we examined expression of OX40 on fresh leukemic cells from patients with adult T-cell leukemia (ATL) and its possible involvement in cell adhesion. Flow cytometric analysis showed that peripheral blood mononuclear cells (PBMC) or lymph node tumor cells from 15 of 17 cases expressed significant levels of OX40 without stimulation. On the other hand, gp34 was not expressed on these cells, although its expression is also known to be associated with HTLV-I-infection. In Western blot analysis, a 50-kD protein band was detected by anti-OX40 monoclonal antibody (MoAb) in two ATL cases examined, as well as phytohemagglutinin (PHA) blasts and Hut102, an HTLV-I-infected T-cell line, but not in resting PBMC or Jurkat. Expression of OX40 mRNA was shown by reverse transcriptase-polymerase chain reaction in all ATL cases tested, PHA-blasts, and Hut102, but not in resting PBMC or Jurkat. We could not detect expression of HTLV-I viral mRNA in any of the cases tested. Cell adhesion assay was performed and in at least three cases, fresh ATL cells exhibited adhesion to human umbilical vein endothelial cells that could be considerably inhibited by either anti-OX40 MoAb or anti-gp34 MoAb. Immunohistochemical staining of skin biopsy specimens indicated that infiltrating mononuclear cells express OX40 in vivo. Taken together, these data indicate that leukemic cells from most, but not all, ATL patients constitutively express OX40, which may play a role in leukemic cell infiltration in addition to cell adhesion in vivo.

Adult↗

Pleiotropic expression of heterologous cytokine/receptor genes in HTLV-1 associated diseases: candidate TRS for chimeric gene therapy.

DNA motifs that encode for specific transcriptional regulatory sequences (TRS) when engineered adjacent to the structural protein coding domain of a suicide enzyme can provide cell-lineage specific protein expression. The disparate up-regulation of several genes in adult T-cell leukemia (ATL) versus HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), seropositive carriers (SPC) and uninfected normals may reflect events at the molecular level related to leukemogenesis or to processes maintaining the heme-oncologic phenotype. Further, the genetic transduction of cytokine and receptor genes uniquely associated with ATL may provide targets for the development of leukemia-specific gene therapies aimed at exploiting differences in the production of certain growth factors and growth factor receptors. Comparisons of the transcriptional and translational levels of interleukin-2 receptor alpha chain (IL-2R alpha), transforming growth factor-beta 1 (TGF-beta 1) and intracellular adhesion molecule-1 (ICAM-1) in ATL, HAM/TSP, and SPC and in several control populations revealed selectively up-regulated expression in ATL. We evaluated the feasibility of using lymphoid-specific TRS to activate herpes simplex virus thymidine kinase (HSVtk) to achieve selective cytotoxicity in leukemias expressing terminal deoxynucleotidyl transferase (TdT). Selective and efficient leukemic cell killing was produced and suggests that similar chimeric gene constructs containing TRS elements for IL-2R alpha, TGF-beta 1, or ICAM-1 may prove useful in designing gene therapies to treat ATL.

Adult↗

Human T lymphotropic virus-type I Tax induction of CD21/Epstein-Barr virus receptor expression on T cells and its significance in leukemogenesis of adult T cell leukemia.

CD21, which is expressed on B cells, is also expressed on human T lymphotropic virus-type I (HTLV-I)-infected T cell lines. CD21 also serves as a receptor of Epstein-Barr virus (EBV). We evaluated the mechanism of CD21 induction on HTLV-I-infected T cells and its clinical significance in the leukemogenesis of adult T cell leukemia (ATL). CD21 induction was detected at very low levels in T cell lines (Jurkat and CEM cells), and in non- or low-Tax-producing HTLV-I-infected T cell lines (Oh13T, S1T, and Su9T01 cells). In contrast, marked induction of CD21 was detected in high-Tax-producing HTLV-I-infected T cell lines (K3T, F6T, and MT-2). A Jurkat T cell clone stably transfected with tax-expressing cDNA expressed a significant amount of CD21 on the cell surface. These results strongly suggest that HTLV-I Tax induces CD21 on T cells. On two-color analysis, CD21 expression was detected in CD4+ T cells of the primary ATL cells from a subset of patients, suggesting that EBV infection may be associated with the leukemogenesis of ATL, at least in part. However, no genome of EBV was detected in the genomic DNA of six HTLV-I-infected T cell lines or the primary ATL cells separated from all patients, indicating the irrelevance of EBV infection to ATL leukemogenesis.

DNA, Viral↗

A lymphokine-activated killer (LAK)-resistant cell line, and low expression of adhesion molecules LFA-3 and VCAM-1 on its cell surface.

Tumor cell lines are generally killed by lymphokine-activated killer (LAK) cells. In this study, however, we report a LAK-resistant cell line, OKM-2T. The OKM-2T is an adult T-cell leukemia (ATL) cell line, and was compared to other ATL cell lines and non-ATL cell lines. The LAK cells were generated from healthy volunteers. Cell surface markers were determined by a flow cytometry test. The ATL and non-ATL cell lines were killed by the LAK cells, markedly or moderately. However, the OKM-2T was scarcely killed. The adhesion tendency of the OKM-2T to the LAK cells was preserved at the same level as that of the other cell lines, whereas the OKM-2T showed low levels of adhesion molecules CD58 (LFA-3), CD86, and CD106 (VCAM-1). We determined blocking tests using specific antibodies. Anti-CD58 blocked the LAK lysis. Anti-CD54 and anti-CD106 enhanced the blocking effect of the anti-CD58; anti-CD86 did not show such an effect. These results suggest that the low expression of CD58 in the OKM-2T may have an intimate relationship with LAK resistance, and that the low expression of CD106 may also be responsible for it, in part.

Antibody-Dependent Cell Cytotoxicity↗

Mechanisms of bone lesions in multiple myeloma and lymphoma.

BACKGROUND: Bone lesions and hypercalcemia occur rarely in patients with hematologic malignancies, except those patients with multiple myeloma and adult T-cell leukemia/lymphoma (ATL) associated with the human T-cell leukemia/lymphoma virus-1 (HTLV-1) virus. The primary mechanism for bone destruction in patients with myeloma and lymphoma is increased osteoclastic bone resorption. In patients with multiple myeloma, new bone formation is also inhibited. Mediators including lymphotoxin, interleukin-1beta, parathyroid hormone related protein (PTHrP), and interleukin-6, produced by the myeloma cells or by marrow stromal cells in response to myeloma cells, have been implicated as osteoclast-activating factors (OAF) in multiple myeloma. However, most studies to identify OAF produced by myeloma cells have been inconclusive. METHODS: To try to identify the OAF produced by myeloma cells, we developed an in vivo model of human myeloma bone disease using the ARH-77 myeloma cell line transplanted into severe combined immunodeficiency mice. RESULTS: We found that a novel cytokine(s) may be responsible for bone destruction. Interleukin-1 and PTHrP mediate bone destruction in patients with ATL. These factors can be detected in media conditioned by ATL cells or by lymphocytes infected with HTLV-1. Furthermore, serum PTHrP levels are increased in ATL patients. In patients with Hodgkin's disease or other types of non-Hodgkin's lymphoma, 1,25-(OH)2D3 or PTHrP is produced by the lymphoma cells and mediates bone destruction. Chemotherapy or resection of the lymphoma decreases 1,25-(OH)2D3 levels and hypercalcemia in these patients. CONCLUSION: Thus, OAF produced locally by the tumor or the marrow microenvironment play an important role in the bone destruction seen in patients with hematologic malignancies.

Animals↗

Antibody reactivities to tumor-suppressor protein p53 and HTLV-I Tof, Rex and Tax in HTLV-I-infected people with differing clinical status.

Since the presence of anti-p53 antibody has been correlated with the mutation and accumulation of p53, the aim of this study was to detect anti-p53 antibody and understand its correlations with anti-Tof, -Rex, or -Tax antibody reactivity in HTLV-I infected people differing in their clinical status. A plasmid (pGEX-Tof) was constructed to express Tof recombinant protein (RP) in Escherichia coli. Serum samples from 50 asymptomatic carriers (ACs), 50 adult T-cell leukemia (ATL) and 50 HTLV-I-associated myelopathyltropical spastic paraparesis (HAM/TSP) patients were assayed for reactivity with different RPs by Western immunoblotting. The results showed that 2% of ACs, 4% of ATL patients and 6% of HAM/TSP patients had anti-p53 antibody. Therefore, anti-p53 antibody is not a useful serological marker for clinical management of HTLV-I infected people. Only 1 HAM/TSP patient had anti-Tof antibody whose specificity was further confirmed by antibody competition enzyme immunoassay. This study demonstrates that Tof protein is immunogenic in vivo, suggesting that it plays a role in the life cycle and pathogenesis of HTLV-I. The rate of anti-Rex antibody among HAM/TSP patients was significantly higher than that of ACs or ATL patients. In addition, 50% of ACs, 42% of ATL and 98% of HAM/TSP patients had anti-Tax antibody. McNemar's test showed that the presence of anti-p53 antibody did not have any correlation with the anti-Tax antibody in HTLV-I-infected people, while the correlation between anti-p53 and anti-Rex antibodies or anti-p53 and anti-Tof antibodies cannot be ruled out in this study.

Animals↗

Clinicopathological studies of a patient with adult T-cell leukemia and pseudogynecomasty.

We present a rare case of adult T cell leukemia/lymphoma (ATL) in which leukemic T cells expressed CD4 and CD25 surface antigens and infiltrated mammary glands during clinical course of the disease. A 40-year-old male was admitted with long-standing skin lesions and leukocytosis. Peripheral blood lymphocytes were highly pleomorphic and presented CD2, CD4, CD25, CD38 membrane surface antigens. The patient proved to be seropositive for human T-cell lymphotropic virus type I (HTLV-I) antibodies. Monoclonal expansion of lymphoid cells integrated with HTLV-I genome was observed, and the diagnosis of ATL chronic type was made. He underwent a chemotherapy regimen, and skin lesions and leukocytosis improved markedly. He progressed with an indolent clinical course of ATL, when he was admitted with bilateral hyperplasia of breast, recurrent skin lesions, and leukocytosis. Breast biopsy revealed bilateral gynecomasty, extensive leukemic infiltration of typical ATL cells in the mammary glands, and the presence of mammary epithelial cells productively infected with HTLV-I. This is the first report describing invasion of the mammary tissue with HTLV-I-transformed T-cells and HTLV-I-associated breast disease.

Breast↗

Pulmonary complications in patients with adult T-cell leukemia.

A survey of 360 patients with various hematologic diseases revealed a high frequency of respiratory complications in patients with adult T-cell leukemia (ATL) compared to others. Among 29 patients with ATL, pulmonary complications were seen in 26 patients; leukemic pulmonary infiltration in 13, bleeding in 1, interstitial pneumonitis in 1, and pulmonary infection in 13. The incidence of Pneumocystis carinii and bacterial pneumonias were high despite adequate neutrophil count. Even in chronic and smoldering ATL, respiratory diseases were found in high frequency. Many of those were leukemic cell infiltration. In ten of 13 patients with pulmonary infiltration it occurred in the early stage and 6 of them were diagnosed as having "chronic lung disease" before the diagnosis of ATL. Its histology was accompanied by fibrosis in greater or lesser degree in almost all cases. Transbroncheal lung biopsy (TBLB) is of value in diagnosis (8 of 13 cases).

Adult↗

Adult T-cell leukemia/lymphoma in Taiwan. A clinicopathologic observation.

The retrovirus-associated adult T-cell leukemia/lymphoma (ATL) has not been previously documented in Taiwan. Five cases identified recently by the authors are reported. Three of the patients were women, and their ages ranged from 36 to 60 years. The most important diagnostic clue was the observation of polylobated lymphoid cells in the peripheral blood. Other variably observed significant features included hypercalcemia, cutaneous eruptions, osteolytic bone lesion, hepatomegaly, and lymphadenopathy. Surface marker studies revealed that the leukemic or lymphoma cells were T-helper cells. Histopathologic examination revealed one case of pleomorphic type and three cases of medium-sized cell type. No tissue was available for study in one case. The diagnosis of ATL was confirmed by the indirect immunofluorescence test on MT-1 cell for antibodies to adult T-cell leukemia virus-associated antigen (ATLA). Three patients were dead within 6 months, and two patients had been in clinical remission for 7 and 10 months, respectively. These two latter cases were similar to the so-called smoldering type of ATL. Two descendents among nine relatives of the patients were also positive for anti-ATLA (22%). Two husbands were negative. Four of the five patients lived in the same county in northeastern coastal Taiwan, which suggested a possible clustering of ATL in that region.

Adult↗

Characterization of the spectrum of postthymic T-cell malignancies in Taiwan. A clinicopathologic study of HTLV-1-positive and HTLV-1-negative cases.

Postthymic T-cell malignancy shows marked geographic, clinicopathologic, and prognostic diversity. The frequency and spectrum of T-cell malignancies in Taiwan were investigated. Fifty-two patients (35 male and 17 female) with a median age of 49 years, were consecutively encountered between October 1983 and April 1987; these accounted for 39% of non-Hodgkin's lymphoma cases seen in our institutions. Ten patients (19.3%) had adult T-cell leukemia/lymphoma (ATL) associated with human T-cell leukemia virus (HTLV-1). Patients with ATL had disease similar to that reported from southwestern Japan and the Caribbean. They had frequent skin lesions (60%), hypercalcemia (40%), and a rapid clinical course with a median survival of 1.3 years. The 35 HTLV-1-negative peripheral T-cell lymphomas (PTL) were similar to PTL in western countries, manifesting frequent visceral, cutaneous, and vascular tropisms. Marrow involvement was documented at presentation in 39% and Stage III/IV disease in 80% of the PTL patients. The histology of PTL usually expressed prominent reactive features which is distinct from that in ATL. Several subcategories could be defined: Hodgkin's-like PTL in nine patients, T-zone lymphoma in three, angioimmunoblastic lymphadenopathy-like lymphoma in one, Lennert's lymphoma in three, and angioinvasive lymphoma in four. Two HTLV-1-negative PTL had neoplastic cells with clover-shaped nuclei and were designated as ATL-like. Morphologic classification based on the modified Working Formulation showed prognostic correlation, with median survival of less than 6 months for large cell/immunoblastic PTL, compared with 5 years for patients with small/medium cell PTL. Both low- and high-grade PTL seem to represent an incurable disease. Classical cutaneous T-cell lymphoma (seven cases) is relatively unusual in Taiwan, compared with the frequency of PTL. Post-thymic T-cell malignancies in Taiwan include HTLV-1-positive and HTLV-1-negative diseases, both of which have a poor prognosis and resemble similar T-cell malignancies in the East and West.

Adult↗

Eosinophilia associated with adult T-cell leukemia/lymphoma.

Eosinophilia is associated with a number of disorders including malignancies. A patient is described who had eosinophilia associated with adult T-cell leukemia/lymphoma (ATL) induced by human T-lymphotropic virus type I (HTLV-I). Both tissue and peripheral blood eosinophilia and high titers of HTLV-I antibody were present. The eosinophilia was most likely caused by the malignant cells producing one or more lymphokines. The patient has achieved a durable complete remission from combination chemotherapy. Because durable remissions in ATL are rare with any known therapy and eosinophilia has not previously been associated with ATL, it is possible that the tumor in this patient was derived from a T-cell subset not usually transformed by HTLV-I. ATL is another malignancy now known to cause eosinophilia.

Adult↗

Differences in prognostic factors between leukemia and lymphoma type of adult T-cell leukemia.

Prognostic factors affecting the survival of adult T-cell leukemia (ATL) patients were analyzed in three groups: total cases, leukemia type cases, and lymphoma type cases. Factors found to be important overall, i.e. for total cases, were leukocyte count, ATL cell ratio in the peripheral blood, serum calcium levels and lactate dehydrogenase (LDH) level. Of those, LDH level proved not significant when evaluated separately for leukemia type or lymphoma type cases. Leukocyte count and ATL cell ratio were significant in leukemia type patients, whereas it was serum calcium level that was significant in lymphoma type; there were mutually exclusive sets of factors for the two groups. Thus, prognostic factors for ATL patients should be considered separately for each type of the disease.

Adult↗

Adult T-cell lymphoma in Israeli patients of Iranian origin.

The clinical and laboratory features of four Israeli patients with adult T-cell lymphoma-leukemia (ATL) are presented. In three of them evidence for human T-cell lymphotropic leukemia virus (HTLV-I) infection was obtained. Interestingly, all of the patients immigrated to Israel from the same regions in Iran. Except for lack of skin involvement, the clinical course was typical for ATL as described worldwide. This is the first report of ATL in an Iranian cohort. This observation suggests that Iranian patients with ATL-like illness should be studied for the presence of HTLV-I infection.

Aged↗

Sibling adult T-cell leukemia/lymphoma and clustering of human T-cell lymphotropic virus type I infection in a Jamaican family.

BACKGROUND: Human T-cell lymphotropic virus type I (HTLV-I) infection is endemic in Jamaica, with an estimated crude seroprevalence of 5%. Adult T-cell lymphoma/leukemia (ATL), a disease caused by HTLV-I, has an incidence of 1-2/100,000 in the Jamaican population. Familial ATL has not previously been reported from Jamaica. METHODS: Hospital records and histologic specimens of the two cases were reviewed. HTLV-I infection was confirmed by antibody testing and by polymerase chain reaction on paraffin-embedded tissue, where serum was unavailable. Family members were identified by the patients' parents. After giving informed consent, family members were asked to complete an interviewer-administered questionnaire and to agree to phlebotomy. RESULTS: ATL developed 10 years apart in two siblings from a Jamaican family at age 16 and 24 years. A study of 19 members of their extended family, including both parents, 2 grandparents, and 3 siblings, revealed an overall HTLV-I seroprevalence of 17%. This compared with 75% among parents and siblings living in the same household as the patients. HTLV-I antibody-positive (HTLV-I-positive) and negative family members had similar mean age. Three of 3 HTLV-I-positive subjects were breast-fed, compared with 10 of 15 HTLV-I-negative subjects. Intravenous drug abuse, sex with prostitutes, homosexuality, and blood transfusion were not reported. The mean number of sexual partners were similar. Both parents, who were antibody-positive, had polylobated atypical lymphocytes in their peripheral blood. CONCLUSION: The HTLV-I antibody seroprevalence is greater in the family than in the general population, consistent with the modes of transmission. The antibody seronegativity of both grandmothers suggests sexual transmission between parents. The development of ATL at age 16 and 24 years is consistent with maternal-infant transmission and a long latent period, as reported by other authors.

Adolescent↗