Clinical Features and Survival Outcome in Aggressive-Type Adult T-Cell Leukemia/Lymphoma Patients: Real-Life Experience of a Single Center from an HTLV-1 Endemic Country.

Background and Objectives: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1). ATLL is a rare disease, found more frequently in HTLV-1-endemic areas, Romania being one of them. Despite treatment advances, the prognosis remains dismal. We aimed to describe the clinical, biological, and survival outcome features of Romanian patients with aggressive-type ATLL. Materials and Methods: We report the data of a prospective, observational, and unicentric study of all 20 patients diagnosed with lymphoma and acute types of ATLL at our center over the past 12 years. Data were collected from the patients' medical records. Results: Lymphoma-type ATLL (60%) was more common than acute-type ATLL (40%). Median age at diagnosis was 40.5 years, and most patients were female. Laboratory data revealed significant differences between acute and lymphoma-type ATLL, namely, higher leukocyte (p = 0.02) and lymphocyte counts (p = 0.02) and higher levels of corrected calcium (p = 0.001) in acute-type ATLL. All patients received chemotherapy, and only two underwent allogeneic stem cell transplantation. Only six patients obtained a complete or partial response to chemotherapy, mostly the lymphoma-type ones. The median survival for all patients was 6.37 months, with higher survival in the lymphoma-type ATLL (8.16 months) than in the acute-type (3.60 months). Normal calcium levels (p = 0.011), uric acid (p = 0.005), BUN score (p = 0.000), JCOG-PI moderate risk (p = 0.038), and obtaining complete or partial response (p = 0.037) were associated with higher survival. Conclusion: Aggressive-type ATLL among Romanian patients presents distinct characteristics, including younger age at diagnosis, female predominance, and higher incidence of lymphoma-type ATLL compared to currently reported data. Survival remains very low, with all subtypes experiencing a median survival of less than one year.

Advances in the treatment of human T-cell lymphotropic virus type-I associated myelopathy.

INTRODUCTION: Nearly 2-3% of those 10 to 20 million individuals infected with the Human T-cell lymphotropic virus type-1 (HTLV-1); are predisposed to developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is a neuro-inflammatory disease; differentiated from multiple sclerosis based on the presence of typical neurologic symptoms, confirmation of HTLV-1 infection, and other molecular biomarkers. AREAS COVERED: A brief review of the epidemiology, host immune responses, and molecular pathogenesis of HAM/TSP is followed by detailed discussions about the host-related risk factors for developing HAM/TSP and success/failure stories of the attempted management strategies. EXPERT OPINION: Currently, there is no effective treatment for HAM/TSP. Anti-retroviral therapy, peculiar cytokines (IFN-α), some anti-oxidants, and allograft bone marrow transplantation have been used for treating these patients with limited success. Under current conditions, asymptomatic carriers should be examined periodically by a neurologist for early signs of spinal cord injury. Then it is crucial to determine the progress rate to adapt the best management plan for each patient. Corticosteroid therapy is most beneficial in those with acute myelitis. However, slow-progressing patients are best managed using a combination of symptomatic and physical therapy. Additionally, preventive measures should be taken to decrease further spread of HTLV-1 infection.

[Retracted] Effects of nutrients on matrix metalloproteinases in human T­lymphotropic virus type 1 positive and negative malignant T­lymphocytes.

Subsequently to the publication of the above article, a concerned reader drew to the attention of the Editorial Office and the authors that certain pairings of the GAPDH western blotting control bands in Fig. 4 appeared to be strikingly similar to adjacent pairings of bands within the same gel slices; moreover, data bands featured in the HuT­2, C91­PL and Jurkat zymography blots in Fig. 5 also appeared to be remarkably similar, both comparing the bands within a given gel slice (as in the case of the Jurkat cell experiment in Fig. 5) or comparing between gel slices (as in the case of the Hut­2 cells compared with the C910PL cells in Fig. 5). The Editorial Office independently investigated these concerns, and reached the conclusion that the bands did appear strikingly similar; too similar for the appearance of the bands within these figures to have arisen by chance. Moreover, the application of a software analysis program revealed that certain of the data in Fig. 6 had also appeared in another paper published by several of the same authors in another journal at around the same time. As a result of this investigation, the Editor of International Journal of Oncology has decided that this paper should be retracted from the journal on account of a lack of confidence in the authenticity of the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 45: 2159­2166, 2014; DOI: 10.3892/ijo.2014.2638].

Outcome of Stem Cell Transplantation in HTLV-1-Associated North American Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) remains challenging to treat and has dismal outcome. Allogeneic stem-cell transplantation (allo-SCT) has promising results, but data remain scarce. In this single-center retrospective analysis of 100 patients with ATLL from north America (67 acute, 22 lymphomatous), 17 underwent allo-SCT and 5 autologous SCT (ASCT), with a median follow-up of 65 months. Post-transplant 3-years relapse incidence (RI) and non-relapse mortality (NRM) were 51% and 37%, respectively, and 3-year progression-free survival (PFS) and overall survival (OS) were 31% and 35%, respectively. ASCT 1-year RI was 80% compared to 30% in allo-SCT (p = 0.03). After adjusting for immortal-time bias, allo-SCT had significantly improved OS (HR = 0.4, p = 0.01). In exploratory multivariate analysis, patients achieving first complete response and Karnofsky score ≥ 90 had significantly better outcomes, as did Black patients, compared to Hispanics, who had worse outcome. In transplanted patients, 14 died within 2 years, 4 of which ASCT recipients. Our data are the largest ATLL transplant cohort presented to date outside of Japan and Europe. We show that allo-SCT, but not ASCT, is a valid option in select ATLL patients, and can induce long term survival, with 40% of patients alive after more than 5 years.

HTLV-1-Associated Lymphoma Presented as Massive Lymphadenopathy.

Adult T-cell leukemia/lymphoma is an aggressive T-cell malignancy caused by the long-term infection of human T-cell lymphotropic virus type 1 (HTLV-1). Our understanding of clinical features still largely relies on the Shimoyama classification developed 30 years ago, which described the 4 clinical subtypes (the smoldering, chronic, lymphoma, and acute types) based on the manifestations of lymphocytosis, elevated lactate dehydrogenase, hypercalcemia, lymphadenopathy, and involvement of the skin, lung, liver, spleen, central nervous system, bone, ascites, pleural effusion, and gastrointestinal tract. HTLV-1-associated lymphoma has a variety of presentations but the presentation of massive lymphadenopathy and compression symptoms is rare and has not been emphasized in the literature. In this article, we describe 2 cases of adult T-cell leukemia/lymphomas that presented with massive cervical nodes or mediastinal nodes with compressing symptoms as the major presenting clinical features. Clinicians should remain aware of this type of presentation by HTLV-1-associated lymphoma, especially in patients who came from endemic areas, even if not all clinical features are present and particularly with hypercalcemia and lytic bone lesions.

The Frequency and Risk Factors of Human T-cell Lymphotropic Virus Type I among Blood Donors in Khorasan-e Razavi, Iran, from 2002 to 2013.

INTRODUCTION: Human T-cell lymphotropic virus (HTLV-I) is the causative agent for adult T-cell lymphoma/leukemia (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis. The virus is endemic in the parts of Iran. This study is conducted to determine the trends in the frequency of HTLV-I in Mashhad, a city in Khorasan-e Razavi province, Iran, over 11 years. MATERIALS AND METHODS: Blood bank records of blood donors positive for HTLV-I were collected from different blood banks across Mashhad between 2002 and 2013. Obtained data were first entered into paper versions and then were analyzed by SPSS version 11.5. HTLV-I antibody was firstly measured by enzyme-linked immunosorbent assay (ELISA) method and later confirmed by the Western Blot (WB). RESULTS: During the study period, 983,000 donors were examined by ELISA and WB, among whom 2921 cases (0.297%) were positive HTLV-I carriers. The highest and lowest frequency of carriers was 0.451% and 0.098%, respectively. The most significant factor was related to marital status (85.2%) and the smallest significant factor was associated with the history of acupuncture (0.3%) according to the different risk factors. CONCLUSION: The frequency of HTLV-I carriers among blood donors was significantly decreased in this period. Screening of blood donors for HTLV-I infection played a significant role in this reduction.

Adult T-cell leukemia/lymphoma and acquired immunodeficiency syndrome - CD4+ T-cell malignancy in CD4+ T-cell deficient status: A paradox.

CD4 counts along with viral loads are important parameters in the monitoring of human immunodeficiency virus (HIV) infection. Human T-cell lymphotropic virus type I (HTLV-I) is known to be an etiological agent for adult T-cell leukemia/lymphoma (ATLL). Coinfection of HTLV-I and HIV is well known in regions with high seroprevalence, and there is no published data in the Indian scenario. We present an interesting case of occurrence of CD4+ T-cell proliferation in a known beta thalassemia major with acquired HIV seropositivity accompanied by simultaneously increasing CD4+ counts and viral loads. Further workup revealed ATLL with an underlying HTLV infection.

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. OBJECTIVE: To identify factors associated with chronic pain in individuals with HTLV-1. METHODS: This cross-sectional study was conducted in a reference center for treatment of patients infected with HTLV-1 in Salvador, Bahia, Brazil. The study included individuals infected with HTLV-1, over 18 years, and excluded those with difficulty to respond the pain protocol. Data on sociodemographic, health behavior, and clinical characteristics were collected in a standardized way. The prevalence ratio (PR) of pain is described, as well as the factors independently associated with the presence of pain, which were assessed by multiple logistic regression. RESULTS: A total of 142 individuals were included in the study, mostly female (62.7%), aged 20-64 years (73.2%), married (61.3%), with less than eight years of education (54.2%), and with a steady income (79.6%). Multivariate analysis showed that being symptomatic for HTLV-1 - sensory manifestations, erectile dysfunction, overactive bladder, and/or HAM/TSP (PR=1.21, 95% CI: 1.05 to 1.38), self-medication (PR=1.29, 95% CI: 1.08-1.53), physiotherapy (PR=1.15, 95% CI: 1.02-1.28), and depression (PR=1.14, 95% CI: 1.01-1.29) were associated with an increased likelihood of presenting pain. On the other hand, physical activity (PR=0.79, 95% CI: 0.67-0.93) and religious practice (PR=0.83, 95% CI: 0.72-0.95) were associated with a decreased likelihood of having pain. CONCLUSION: The use of self-medication, physiotherapy and the presence of depression are independently associated with neurological symptoms in HTLV-1 infected patients. Religious practice and physical activity are both protective for the development of pain.

Metaanálisis de la validez del inmunodiagnóstico del virus linfotrópico de células T humanas i/ii en bancos de sangre, 2000-2018 / Meta-analysis regarding the validity of the immunodiagnosis of human T-cell lymphotropic virus I/II in blood banks, 2000-2018 / Meta-análise da validade do imunodiagnóstico do vírus linfotrópico de células t humanas I/II em bancos de sangue, 2000-2018

Resumen Objetivo: Evaluar la validez del inmunodiagnóstico del htlv i/ii en bancos de sangre, con base en estudios publicados en la literatura científica. Metodología: Se efectuó un metaanálisis de pruebas diagnósticas siguiendo la guía prisma y las recomendaciones de Cochrane. Se evaluó la calidad metodológica con quadas y se garantizó la reproducibilidad y la exhaustividad. Se realizó también un análisis de efectos aleatorios para la sensibilidad, la especificidad, los cocientes de probabilidad, la razón de momios diagnóstica y la curva característica operativa del receptor (roc) con sus intervalos de confianza (ic) del 95 %. Resultados: Se tamizaron 4604 estudios, de los cuales solo tres cumplieron el protocolo. Se evaluaron 548 infectados con htlv i/ii y 6643 sanos. El inmunodiagnóstico de htlv i/ii presentó una sensibilidad del 99 % (ic95 % = 98,0-99,0), especificidad del 100 % (ic95 % = 99,9-100), cocientes de probabilidad positivo de 315,8 (ic95 % = 128,2-778,5) y negativo de 0,02 (ic95 % = 0,01-0,04), razón de momios diagnóstica de 24373 (ic95 % = 6864-86545) y área bajo la curva roc del 99,9 %. Conclusión: Se dispone de pocos estudios en este campo del inmunodiagnóstico htlv i/ii. El elevado número de sujetos analizados evidenció alta validez del inmunodiagnóstico, lo que resulta determinante para garantizar la inocuidad de las unidades de sangre, la detección de portadores asintomáticos, la disminución de la transmisión y el inicio de tratamiento.

Abstract Objective: To evaluate the validity of the immunodiagnosis of htlv i/ii in blood banks, based on studies published in the scientific literature. Methodology: A meta-analysis of diagnostic tests was carried out following the PRISMA guidelines and Cochrane recommendations. The methodological quality was evaluated with QUADAS, and reproducibility and completeness were guaranteed. A random effects analysis was also performed with respect to sensitivity, specificity, likelihood ratios, diagnostic odds ratio, and receiver operating characteristic curve (ROC) with their 95 % confidence intervals (CI). Results: 4,604 studies were screened, of which only three complied with the protocol. 548 subjects infected with HTLV I/II and 6,643 healthy subjects were evaluated. The immunodiagnosis of HTLV I/II had a sensitivity of 99 % (95 % CI = 98.0-99.0), a specificity of 100 % (95 % CI = 99.9-100), a positive likelihood ratio of 315.8 (95 % CI = 128.2-778.5) and a negative likelihood ratio of 0.02 (95 % CI = 0.01-0.04), a diagnostic odds ratio of 24,373 (95 % CI = 6,864-86,545), and an area under the ROC curve of 99.9 %. Conclusion: Few studies are available in the field of HTLV I/II immunodiagnosis. The high number of subjects analyzed showed high validity of the immunodiagnosis, which is decisive to guarantee the safety of the blood units, the detection of asymptomatic carriers, the decrease in transmission, and the start of treatment.

Resumo Objetivo: Avaliar a validade do imunodiagnóstico do HTLV I/II nos bancos de sangue, baseados nos estudos publicados na literatura científica. Metodologia: Foi realizada uma meta-análise de testes diagnósticos seguindo a guia PRISMA e as recomendações de Cochrane. Foi avaliada a qualidade metodológica com QUADAS e garantiu-se a reprodutibilidade e a integridade. Realizou-se também uma análise de efeitos aleatórios para a sensibilidade, a especificidade, os quocientes de probabilidade, a razão de probabilidade diagnóstica e a Curva Característica de Operação do Receptor (Curva ROC) com seus Intervalos de Confiança (IC) de 95%. Resultados: Foram selecionados 4604 estudos, dos quais somente 3 cumpriram com o protocolo. Foram avaliados 548 infectados com o vírus HTLV I/II e 6.643 saudáveis. O imunodiagnóstico de HTLV I/II apresentou uma sensibilidade de 99% (IC95% = 98,0-99,0), especificidade de 100% (IC95%= 99,9-100), quocientes de probalidade positiva de 315,8 (IC95% = 128,2-778,5) e negativo de 0,02 (IC95% = 0,01-0,04), razão de probabilidade diagnóstica de 24373 (IC95% = 6864-86545) e área sob a curva ROC de 99,9%. Conclusão: São poucos os estudos disponíveis neste campo do imunodiagnóstico HTLV I/II. O elevado número de pessoas analisadas evidenciou alta validade do imunodiagnóstico, o que é decisivo para garantir a inocuidade das unidades de sangue, a detecção de portadores assintomáticos, a diminuição da transmissão e o início do tratamento.

Seroepidemiology of human T-cell lymphotropic virus type-I in blood donors of Northeastern Iran, Sabzevar.

BACKGROUND AND OBJECTIVES: Human T-cell lymphotropic virus type-I (HTLV-I) infection is considered as a public health challenge in endemic areas. The virus is associated with severe diseases, such as adult T-cell leukemia/lymphoma, and HTLV-I-associated myelopathy/tropical spastic paraparesis. One of the major routes of the HTLV-I transmission includes blood transfusion. Sabzevar is located in the endemic region of HTLV-I infection. The aim of the present study was to determine the seroprevalence of HTLV-I infection in the blood donors in Sabzevar. MATERIALS AND METHODS: A total of 35,067 blood donors in Sabzevar from March 2009 to April 2012 who were screened with HTLV-I on the enzyme-linked immunosorbent assay screening test were included in this survey. Reactive samples that confirmed by western blot were considered to be seropositive cases. The required data were obtained from blood donors' database of blood transfusion service. RESULTS: The overall prevalence of HTLV-1 based on the positive result of western blot test was 0.14%. The seropositive donors aged 17-59 years with a mean age of 38.10 ± 11.82. The prevalence rates of HTLV-I infection in 3 years of study were 0.19%, 0.14%, and 0.09%, respectively. A significant relation between age, sex, educational level, and history of blood donation was observed with seropositivity of HTLV-I. CONCLUSION: The improvement of donor selection and laboratory screening caused a decline in the prevalence of infection in blood donors. Given the lower prevalence of infection in regular donors with lower age and higher educational level, more efforts should be done to attract blood donors from these populations.

Abundant expression of HMGB1 in human T-cell lymphotropic virus type I-infected T-cell lines and high plasma levels of HMGB1 in patients with adult T-cell leukemia.

High mobility group box 1 (HMGB1) functions as a chromatin-associated nuclear protein and an extracellular signaling molecule. The concentration of HMGB1 protein and the expression of HMGB1 mRNA were analyzed by ELISA and polymerase chain reaction (PCR), respectively. The present study reports high plasma HMGB1 levels in patients with adult T-cell leukemia [ATL; which is caused by infection with human T-cell lymphotropic virus type I (HTLV-I)] compared with normal controls. In addition, HMGB1 was highly expressed in HTLV-I-infected T-cell lines compared with uninfected T-cell lines. The HTLV-I oncoprotein, Tax, induced extracellular release of HMGB1 in T cells. The results suggest that HMGB1 is a potential biomarker and a therapeutic target for ATL.

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

Abstract Introduction Despite the high prevalence of chronic pain in individuals infected with HTLV-1, predictive and protective factors for its development are still unclear. Objective To identify factors associated with chronic pain in individuals with HTLV-1. Methods This cross-sectional study was conducted in a reference center for treatment of patients infected with HTLV-1 in Salvador, Bahia, Brazil. The study included individuals infected with HTLV-1, over 18 years, and excluded those with difficulty to respond the pain protocol. Data on sociodemographic, health behavior, and clinical characteristics were collected in a standardized way. The prevalence ratio (PR) of pain is described, as well as the factors independently associated with the presence of pain, which were assessed by multiple logistic regression. Results A total of 142 individuals were included in the study, mostly female (62.7%), aged 20–64 years (73.2%), married (61.3%), with less than eight years of education (54.2%), and with a steady income (79.6%). Multivariate analysis showed that being symptomatic for HTLV-1 – sensory manifestations, erectile dysfunction, overactive bladder, and/or HAM/TSP (PR = 1.21, 95% CI: 1.05 to 1.38), self-medication (PR = 1.29, 95% CI: 1.08–1.53), physiotherapy (PR = 1.15, 95% CI: 1.02–1.28), and depression (PR = 1.14, 95% CI: 1.01–1.29) were associated with an increased likelihood of presenting pain. On the other hand, physical activity (PR = 0.79, 95% CI: 0.67–0.93) and religious practice (PR = 0.83, 95% CI: 0.72–0.95) were associated with a decreased likelihood of having pain. Conclusion The use of self-medication, physiotherapy and the presence of depression are independently associated with neurological symptoms in HTLV-1 infected patients. Religious practice and physical activity are both protective for the development of pain.

The Seroepidemiologic Study for Human T-cell Lymphotropic Virus Type I(HTLV-I) Infection in Residents of Cheju-Do / 감염

BACKGROUND: Human T-cell lymphotropic virus type I (HTLV-I) is a retrovirus that has been identified as a cause of adult T-cell leukemia/lymphoma and tropical spastic paraparesis. HTLV-I infection is highly endemic in the southwestern islands of Japan, Caribbean basin, South America, and Africa. In 1993, we showed that the seroprevalence of antibodies to HTLV-I was 0.13% among blood donors in Korea, but surprisingly, 0.80% in Cheju-Do adjacent to endemic areas of Japan. So this study was designed to reevaluate the seroprevalence of antibodies to HTLV-I among residents in Cheju-Do. METHODS: Total 2,372 residents in Cheju-Do were tested from December 1995 to March 1996. Anti-HTLV-I antibodies were detected by the microtiter particle agglutination test. RESULTS: Among total 2,372 residents, 19 were anti-HTLV-I positive. So the overall positive rate of anti-HTLV-I antibodies was 0.80%. The positive rate in females was higher than in males (0.82% vs 0.78%). The positive rate was 1.45% in the age group of 20-29 years, 1.41% in 40-49 years, 0.91% in 0-9 years, 0.70% in 30-39 years, and 0.54% in 50-59 years. The mean age of seropositive cases is 35.2 in males and 35.4 in females, with a mean of 35.3. Geographically, high positive rate was observed in Sogwipo-City (1.37%) and Namcheju-Gun (0.83%) compared to those of Pukcheju-Gun (0.64%) and Cheju-City (0.61%), which showed high seroprevalence in districts adjacent to endemic areas of Japan. Any specific risk factors or associated disorders of HTLV-I infection could not be found among the seropositive cases. CONCLUSION: The seroprevalence of antibodies to HTLV-I in Cheju-Do was noted to be very high by the microtiter particle agglutination test. So henceforth serosurvey by confirmative laboratory tests is needed, and if high seroprevalence is showed from it, screening of blood donors for HTLV-I in Cheju-Do should be considered to prevent transfusion-associated HTLV-I infection.

Adult T-cell leukemia/lymphoma in a Korean: a case report

The clinicopathologic features of a Korean patient with adult T-cell leukemia/lymphoma(ATLL) are presented. A 51-year-old man, who has lived in Korea since birth, had multiple cutaneous nodules and multiple lymphadenopathy for the previous two months. A histopathologic study of the lymph node and skin lesion revealed T-cell non-Hodgkin's lymphoma of pleomorphic type, medium and large cell type. Peripheral blood examination showed leukemic features with 30% of abnormal lymphoid cells. HTLV-I proviral DNA pX region was detected in the DNA from peripheral blood mononuclear cells(PBMC) and the specific gag, pol, and env HTLV-I sequences were detected in the lymph node using polymerase chain reaction technique. Human T-cell leukemia/lymphoma type I(HTLV-I) antibodies were present in the serum. An immunophenotypic study of the lymph node revealed CD4 positive and CD8 negative helper/inducer T cell type surface markers. This case is the acute type, i.e. prototypic ATLL. He was treated with an intensive chemotherapy including cyclophosphamide, etoposide, doxorubicin, vincristine, and prednisone. Despite initial transient improvement, the tumor progressed after three cycles of the regimen and became refractory to further chemotherapy. These clinicopathologic findings, including the immunophenotypic analysis, established with certainty the diagnosis of HTLV-I-induced adult T-cell leukemia/lymphoma.

A Case of Human T-cell Lymphotropic Virus Type I Associated Myelopathy Treated with Sho-saiko-to / 日本東洋医学雑誌

We introduce the successful treatment of intractable symptoms of 52-year-old female patient with HTLV-I-associated myelopathy (HAM) by Kampo medicine. She showed spastic paraplegia, urinary incontinence, sensory disturbance of extremities and nocturnal myoclonus.<br>Neurological examination proved to be hyperactive deep tendon reflexes and positive pathological reflexes in legs. The viral antibody titer of HTLV-I was elevated both in cerebrospinal fluid and serum. After treatment with Sho-saiko-to, symptoms were improved. The effect is considered to be immunomodulation of Sho-saiko-to.