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Epigenetic modifications, particularly through methylation of DNA packaging histones, play a pivotal role in controlling gene expression. Aberrant patterns of histone methylation have been associated with the development and progression of hematological malignancies. Unraveling the impact of aberrant histone marks on gene expression and leukemogenesis has spurred a concerted effort to develop clinically effective epigenetic therapies. In malignancies associated with the accumulation of histone H3 lysine trimethylation (H3K27me3), one such intervention involves preventing the deposition of this repressive histone mark by inhibiting the histone-modifying enzymes EZH1 and EZH2. While inhibition of EZH1/2 has demonstrated efficacy in both preclinical studies and clinical trials in various cancers, studies delineating the dynamic effect of EZH1/2 inhibition on H3K27me3 and disease relapse in clinical samples are lacking. In a recent publication, Yamagishi et al. explore how responses of a patient with adult T-cell leukemia/lymphoma to valemetostat, an EZH1/2 inhibitor, are associated with changes in H3K27me3, chromatin accessibility and gene expression, and how these changes can be circumvented in relapsed disease.
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Epigénesis Genética , Histonas , Leucemia-Linfoma de Células T del Adulto , Animales , Humanos , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Histonas/metabolismo , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Complejo Represivo Polycomb 2/metabolismo , Complejo Represivo Polycomb 2/genéticaRESUMEN
BACKGROUND: Human T-lymphotropic virus (HTLV-1) is a neglected virus with worldwide distribution of over 10 million people and is the cause of two main associated diseases Adult T cell Leukemia-Lymphoma (ATLL), and HTLV-1-associated Myelopathy/Tropical Spastic paraparesis (HAM/TSP). The IL-17 cytokine family plays a crucial role in the host immunity against HTLV-1 and the development of associated disease. A systematic review was conducted to analyze all research reporting on the levels or expression of the IL-17 HTLV-1 infection and associated diseases. METHODS: The literature search was conducted in electronic databases including PubMed/Medline and Web of Sciences until January 31st, 2024, followed by the PRISMA guidelines. RESULTS: Our search revealed 20 eligible articles to be included in our study. The total number of cases studied was 1420, of which 386 were carriers without any symptoms, and were 176 ATLL and 237 HAM/TSP. The IL-17 cytokine family production or mRNA expression was higher in HAM/TSP patients but showed a trend toward reduction in the case of ATLL. CONCLUSIONS: Our results showed that while The IL-17 cytokine family plays a significant role in the immunopathogenesis of disease and clinical status of patients with inflammatory disorders such as HAM/TSP, IL-17 production is diminished and the RORC/IL-17 signaling pathway is downregulated during ATLL. Our data suggest that boosting the RORC/IL-17 signaling pathway in ATLL and using anti-IL-17 agents in HAM/TSP and other HTLV-related inflammatory conditions might benefit patients and improve their outcomes.
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We report a case of fulminant hepatitis in a hepatitis B surface antigen (HBsAg)-positive patient with aggressive adult T-cell leukemia-lymphoma who received monotherapy with an anti-CCR4 monoclonal antibody, mogamulizumab, with decreased hepatitis B virus (HBV)- DNA levels by entecavir prophylaxis. Although HBV reactivation-related hepatitis was considered in the differential diagnosis, the patient did not meet the conventional criteria for HBV reactivation and was finally diagnosed with drug-induced hepatitis. Considering that the immunoenhancing effects of mogamulizumab can lead to HBV reactivation-related hepatitis in HBsAg-positive patients, we should differentiate drug-induced hepatitis from HBV reactivation, especially in patients receiving immunomodulatory drugs, if HBV-DNA levels are reduced by antiviral prophylaxis.
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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.
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Leucemia-Linfoma de Células T del Adulto , Humanos , Femenino , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/terapia , Leucemia-Linfoma de Células T del Adulto/epidemiología , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Masculino , Adulto , Persona de Mediana Edad , Rumanía/epidemiología , Estudios Prospectivos , Virus Linfotrópico T Tipo 1 Humano , Infecciones por HTLV-I/mortalidad , Infecciones por HTLV-I/complicaciones , Anciano , Análisis de Supervivencia , Enfermedades Endémicas , PronósticoRESUMEN
A 63-year-old man with adult T-cell leukemia-lymphoma underwent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. On day 17 after transplantation, chest computed tomography (CT) showed nodules in the lower lobes of both lungs, and invasive pulmonary aspergillosis (IPA) was suspected. Treatment with liposomal amphotericin B was started, and improvement of infectious lesions was confirmed with CT on day 28. The antifungal agent was changed to voriconazole on day 52 because of progressive renal dysfunction. Disorders of consciousness and paralysis of the left upper and lower extremities developed on day 61. Brain CT showed subcortical hemorrhage in the right parietal and occipital lobes, and the patient died on day 62. An autopsy revealed filamentous fungi, suspected to be Aspergillus, in the pulmonary nodules and a ruptured cerebral aneurysm. Although IPA occurs in 10% of transplant recipients, vigilant monitoring for mycotic cerebral aneurysms is required to prevent hematogenous dissemination of Aspergillus, which is associated with a high mortality rate.
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Trasplante de Células Madre Hematopoyéticas , Aneurisma Intracraneal , Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Masculino , Humanos , Persona de Mediana Edad , Aneurisma Intracraneal/complicaciones , Aneurisma Intracraneal/terapia , Leucemia-Linfoma de Células T del Adulto/complicaciones , Leucemia-Linfoma de Células T del Adulto/terapia , Trasplante de Médula ÓseaRESUMEN
A 62-year-old woman with adult T-cell leukemia/lymphoma (ATL) received umbilical cord blood transplantation (CBT) in first complete remission. However, relapse of ATL was detected on day 74 post-transplantation, as evidenced by the rapid growth of lymphoma cells in peripheral blood and an increase in soluble interleukin-2 receptor (sIL2R) levels. Discontinuation of immunosuppressant therapy alone did not improve ATL findings, but treatment with lenalidomide caused lymphoma cells to disappear from the peripheral blood and sIL2R levels to return to normal. Pancytopenia was observed as a lenalidomide-associated adverse effect, but lymphocyte counts were not reduced. The patient was judged to be in complete remission based on results of Southern blot analysis and human T-cell leukemia virus 1 (HTLV-1)-infected cell analysis using flow cytometry (HAS-Flow). Flow cytometric analysis of peripheral blood and FISH analysis of X and Y chromosomes revealed that the therapeutic effect of lenalidomide was associated with an increase in the number of donor-derived peripheral natural killer cells. ATL relapse was not observed at 13 months into lenalidomide treatment. Our results suggest that lenalidomide is an effective option for the treatment of post-transplant relapsed ATL.
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Trasplante de Células Madre de Sangre del Cordón Umbilical , Lenalidomida , Leucemia-Linfoma de Células T del Adulto , Recurrencia , Inducción de Remisión , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/terapia , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Talidomida/análogos & derivados , Talidomida/uso terapéuticoRESUMEN
A 79-year-old man presented with respiratory distress associated with a mediastinal mass and pleural effusion, and was diagnosed as having adult T-cell leukemia/lymphoma. The patient was highly refractory to anticancer drugs and radiotherapy from the time of onset and had progressive respiratory deterioration. However, his condition became stable with the administration of valemetostat for 11 days, and subsequent low-dose-anticancer agents led to a rapid improvement accompanied by high fever and a surge in C-reactive protein. In this case, the in vivo priming effect of valemetostat on tumor cells may have increased the sensitivity of these cells to conventional anti-cancer drugs.
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Introduction: CC chemokine receptor 4 (CCR4), which is involved in leukocyte migration, is expressed in most tumor cells in patients with adult T-cell leukemia/lymphoma (ATLL). Case Presentation: Here we report the case of a 78-year-old man diagnosed with lymphoma-type ATLL expressing CCR4. The patient was administered two cycles of lenalidomide but died because of sepsis 5 months after the initial diagnosis. Autopsy revealed ATLL cells at several sites. Immunohistochemical analysis revealed that these ATLL cells had reduced CCR4 expression. Conclusion: The present case suggests that treatment should be carefully determined in ATLL with reference to a history of lenalidomide use and CCR4 expression.
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Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis, and there is little data available from the Chinese population. This retrospective study included 115 patients diagnosed with ATLL who were treated across five hospitals in China from June 2011 to December 2022. The median age at diagnosis was 53 years. Several genes involved in T-cell receptor-induced nuclear factor κB (TCR-NF-κB) signaling were commonly mutated, including PLCG1, CIC, PRKCB, CARD11, and IRF4. Eighty-seven patients received chemotherapy. Of these, 13 received a hematopoietic stem cell transplant (HSCT) (allogeneic-HSCT, n=9; autologous-HSCT, n=4) after chemotherapy. Following initial multiagent chemotherapy using EPOCH/CHOEP and other regimens, the overall response rates were 80.6% (complete response [CR], 44.4%) and 42.8% (CR, 14.2%), respectively. The 4-year survival rates (median survival time in days) for EPOCH/CHOEP (n=43), HSCT (n=13), and CHOP-based regimens (n=31) were 12.7% (138), 30.8% (333), and 0% (66), respectively. Lymphadenopathy, EPOCH/CHOEP, and hematopoietic stem cell transplantation were independent prognostic protective factors in patients with aggressive ATLL. Chinese patients exhibit a higher incidence of aggressive-type ATLL, sharing similar genetic alterations with Japanese patients. Etoposide-based chemotherapy (EPOCH or CHOEP) remains the preferred choice for aggressive ATLL, and upfront allogeneic HSCT should be considered in all eligible patients.
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Sweden is a country with a low prevalence of human lymphotropic T-cell virus (HTLV) infection, estimated at < 0.005%, but the infection rate is notably higher in specific risk groups such as HTLV-2 among intravenous drug users (IVDU) and people originating from HTLV-1 highly endemic areas. Thus, in the most recent study from 2012, the prevalence of HTLV-2 among IVDU in Stockholm was 3.2%. However, much of the epidemiological data on HTLV in Sweden stems from studies conducted primarily between the 1990s and 2007, and the impact of migration to Sweden during the past 15 years has not been evaluated. Despite Sweden's status as a country with generally low prevalence of HTLV, it is prudent to anticipate and prepare for several potential challenges associated with HTLV infection in the future. Proactive measures to enhance awareness, alongside strategies to curtail transmission and mitigate complications, are crucial for addressing this relatively rare, but significant health issue. In this work, we review the current epidemiological knowledge about HTLV in Sweden and discuss future Swedish perspectives.
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Infecciones por VIH , Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Abuso de Sustancias por Vía Intravenosa , Humanos , Suecia/epidemiología , Infecciones por VIH/complicaciones , Abuso de Sustancias por Vía Intravenosa/complicaciones , Linfocitos T , Infecciones por HTLV-I/epidemiologíaRESUMEN
Adult T-cell leukemia/lymphoma (ATL) is a form of leukemia caused by the human T-cell leukemia virus type I (HTLV-1). Otolaryngologists often diagnose ATL based on cervical lymphadenopathy or Waldeyer ring lesions. However, there are few reports of ATL occurring in the nasal and paranasal cavity. Here, we report four such cases of ATL. Case 1: An 82-year-old man diagnosed with acute-type ATL with a tumor in the nasal cavity underwent 5 courses of THP-COP, but died after 36 months due to ATL. Case 2: A 62-year-old woman diagnosed with lymphoma-type ATL with a tumor in the frontal sinus was treated with 5 courses of VCAP-AMP-VECP, and has survived for more than 10 years. Case 3: A 64-year-old man diagnosed with lymphoma-type ATL with a tumor in the maxillary sinus underwent 8 courses of VCAP-AMP-VECP and 2 courses of mogamulizumab, but died after 34 months due to ATL. Case 4: A 52-year-old woman diagnosed with lymphoma-type ATL with tumors in both ethmoid sinuses received 2 courses of CHOP, 2 courses of DeVIC, radiotherapy (32 Gy) and 2 courses of mogamulizumab, but died after 9 months due to ATL.
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AIMS: T-follicular helper (TFH) cells are effector T-cells that are crucial for B-cell selection and differentiation. T-cell lymphomas derived from TFH cells have distinct characteristics. Additionally, in the World Health Organization (WHO) classification 5th edition, three lymphomas were introduced as independent disease entities with TFH cell origin. We aimed to investigate the clinicopathological features of adult T-cell leukemia/lymphoma (ATLL) with a TFH phenotype (TFHP). METHODS AND RESULTS: We performed TFH immunohistochemistry analysis of five biomarkers for the biopsy specimen, with TFHP being indicated by a positive result for more than two markers. Among 75 cases of ATLL, 37.3% of them showed TFHP. Compared with cases of ATLL without TFHP, cases of ATLL with TFHP showed higher C-reactive protein levels (p = 0.0219) and increased high endothelial venule proliferation (p = 0.024). However, there were no significant between-group differences in overall survival as well as other clinical and morphological findings. Furthermore, there was no significant between-group difference in TFH markers and FOXP3 expression. CONCLUSION: Some patients with ATLL may present a TFHP, which should not preclude the diagnosis of ATLL. Although presenting a TFHP does not affect prognosis, it is important to identify cases of ATLL with a TFHP since it may inform future treatment strategies.
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Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Humanos , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/genética , Linfoma/patología , Pronóstico , Fenotipo , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/patologíaRESUMEN
BACKGROUND: Primary central nervous system lymphoma is rare, and primary central nervous system T cell lymphoma is relatively uncommon, contributing to < 5% of all cases. Lymphomatosis cerebri, a rare subtype of primary central nervous system lymphoma, is characterized by extensive white-matter lesions on magnetic resonance imaging and nonspecific symptoms, such as cognitive decline and depression. Reports of lymphomatosis cerebri in adult T cell leukemia/lymphoma are limited. CASE PRESENTATION: A 49-year-old Japanese man gradually developed insomnia, anorexia, and weight loss over a 2-month period following work-related promotion. Initially diagnosed with depression, his condition rapidly deteriorated with cognitive decline and motor dysfunction. Despite various treatments, his symptoms persisted within a month. Upon admission, the presence of neurological abnormalities suggestive of a central nervous system disorder raised suspicion of a cerebral lesion. Diagnostic tests revealed extensive brain lesions on imaging and the presence of atypical lymphocytes (flower cells) in the cerebrospinal fluid. The patient was diagnosed with lymphomatosis cerebri due to adult T cell leukemia/lymphoma, a rare presentation in the literature. Due to irreversible brainstem damage and poor neurological prognosis, aggressive treatment was not initiated, and the patient died, with an autopsy confirming the diagnosis. CONCLUSION: Lymphomatosis cerebri with adult T cell leukemia/lymphoma is very rare. It is crucial to promptly consider lymphomatosis cerebri as a differential diagnosis, particularly in cases of rapid cognitive decline and poor treatment response. Recognition of lymphomatosis cerebri as an important differential diagnosis for cognitive decline, and depression is necessary for timely intervention and management. Further research is required to better understand this unique and rare presentation in adult T cell leukemia/lymphoma.
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Neoplasias Encefálicas , Depresión , Leucemia-Linfoma de Células T del Adulto , Neurolinfomatosis , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/etiología , Depresión/diagnóstico , Depresión/etiología , Diagnóstico Diferencial , Resultado Fatal , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/complicaciones , Imagen por Resonancia Magnética , Neurolinfomatosis/diagnóstico , Neurolinfomatosis/etiologíaRESUMEN
The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1WT (wild type) and HTLV-1p12KO (Orf-1 knockout) infectivity, but seroconversion to either virus is not sustained over time, suggesting a progressive decrease in virus expression. These results raise the hypotheses that either HTLV-1 persistence depends on a monocyte reservoir or monocyte depletion provides a transient immune evasion benefit. To test these hypotheses, we simultaneously depleted NK cells, CD8+ T cells, and monocytes (triple depletion) prior to exposure to HTLV-1WT or HTLV-1p12KO. Remarkably, triple depletion resulted in exacerbation of infection by both viruses and complete rescue of HTLV-1p12KO infectivity. Following triple depletion, we observed rapid and sustained seroconversion, high titers of antibodies against HTLV-1 p24Gag, and frequent detection of viral DNA in the blood and tissues of all animals when compared with depletion of only CD8+ and NK cells, or monocytes alone. The infection of macaques with HTLV-1WT or HTLV-1p12KO was associated with higher plasma levels of IL-10 after 21 weeks, while IL-6, IFN-γ, IL-18, and IL-1ß were only elevated in animals infected with HTLV-1WT. The repeat depletion of monocytes, NK, and CD8+ cells seven months following the first exposure to HTLV-1 did not further exacerbate viral replication. These results underscore the contribution of monocytes in orchestrating anti-viral immunity. Indeed, the absence of orf-1 expression was fully compensated by the simultaneous depletion of CD8+ T cells, NK cells, and monocytes, underlining the primary role of orf-1 in hijacking host immunity.
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Infective dermatitis associated with human T-cell lymphotropic virus type-1 (HTLV-1) (IDH) is a severe form of chronically infected eczema occurring in early childhood, although very rarely cases have been reported in adults. Most of the cases are from Jamaica and Brazil and occur in individuals with low socioeconomic status. IDH is always associated with refractory Staphylococcus aureus or beta-hemolytic Streptococcus infection of the skin and nasal vestibules. Patients with IDH may develop other even more severe HTLV-1-associated diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) of early or late appearance and adult T-cell leukemia/lymphoma. In the context of the Brazilian experience, it has been observed that 54% of IDH patients exhibit the juvenile form of HAM/TSP while the estimated incidence of adult HAM/TSP is 3%. As there are no curative treatments for HTLV-1 infection (or vaccines) or most of its associated diseases, prevention of infection is fundamental, mainly by vertical transmission, as it is responsible for the development of IDH, infantojuvenile HAM/TSP, and ATL. Public measures to reduce this transmission must be implemented urgently. Furthermore, it is recommended, mainly in HTLV-1 endemic areas, to search for HTLV-1 infection in all patients with infected eczema, even in adults.
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Infecciones por HTLV-I , Virus Linfotrópico T Tipo 1 Humano , Humanos , Infecciones por HTLV-I/complicaciones , Infecciones por HTLV-I/diagnóstico , Infecciones por HTLV-I/epidemiología , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Brasil/epidemiología , Paraparesia Espástica Tropical/diagnóstico , Paraparesia Espástica Tropical/virología , Paraparesia Espástica Tropical/epidemiología , Adulto , Dermatitis/virología , Dermatitis/diagnósticoRESUMEN
DUSP22 rearrangements are genetic alterations observed in a subset of systemic anaplastic large cell lymphoma (S-ALCL), primary cutaneous anaplastic large cell lymphoma (C-ALCL), and lymphomatoid papulosis (LyP). Previous investigations have shown that the LEF1+/TIA1- immunoprofile and MSC E116K mutations are highly associated with DUSP22 rearrangement in ALCL. However, the existing literature primarily focuses on S-ALCL. Our understanding of the LEF1/TIA1 immunoprofile and MSC mutation status in C-ALCL/LyP is still limited. In this study, we aimed to assess LEF1/TIA1 expression and MSC mutations in a cohort of 23 C-ALCL/LyP cases, along with a control group of histological mimickers. DUSP22 rearrangements were detected by fluorescence in situ hybridization in eight cases (6/10 C-ALCL, 2/13 LyP). We found LEF1 expression in five out of eight (63%) DUSP22-rearranged cases (3/6 C-ALCL, 2/2 LyP), and none of the 15 cases lacking DUSP22 rearrangements. Furthermore, we also found frequent LEF1 expression in adult T-cell leukemia/lymphoma (ATLL; 10 of 11, 91%) within the control group. TIA1 expression was consistently negative in all DUSP22-rearranged C-ALCL/LyP and ATLL cases tested. MCS E116K mutation was identified in one of five DUSP22-rearranged C-ALCL cases. RNA sequencing of a DUSP22-rearranged C-ALCL revealed a novel DUSP22::SNHG fusion coexisting with a CD58::WNT2B fusion. In conclusion, our findings demonstrated a lower rate of LEF1 expression in DUSP22-rearranged C-ALCL/LyP compared to previous reports that predominantly focused on S-ALCL. Moreover, we observed that the majority of ATLL cases also expressed LEF1, suggesting that the LEF1+/TIA1- immunoprofile does not differentiate DUSP22-rearranged C-ALCL/LyP from ATLL.
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Fosfatasas de Especificidad Dual , Reordenamiento Génico , Inmunofenotipificación , Factor de Unión 1 al Potenciador Linfoide , Fosfatasas de la Proteína Quinasa Activada por Mitógenos , Neoplasias Cutáneas , Humanos , Fosfatasas de Especificidad Dual/genética , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Masculino , Femenino , Persona de Mediana Edad , Factor de Unión 1 al Potenciador Linfoide/genética , Factor de Unión 1 al Potenciador Linfoide/análisis , Adulto , Anciano , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Antígeno Ki-1/genética , Antígeno Ki-1/análisis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Anciano de 80 o más Años , Hibridación Fluorescente in Situ , Mutación , Papulosis Linfomatoide/genética , Papulosis Linfomatoide/patología , Adulto Joven , Fenotipo , Linfoma Anaplásico Cutáneo Primario de Células Grandes/genética , Linfoma Anaplásico Cutáneo Primario de Células Grandes/patología , Inmunohistoquímica , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Linfoma Anaplásico de Células Grandes/inmunologíaRESUMEN
γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia-lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.
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Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Adulto , Anciano , Humanos , Leucemia-Linfoma de Células T del Adulto/terapia , Interleucina-18 , Interleucina-2 , Leucocitos Mononucleares , Inmunoterapia , Anticuerpos MonoclonalesRESUMEN
Abstract Hodgkin-like ATLL is a rare variant of adult T-cell leukemia/lymphoma (ATLL), a disease caused by human T-cell lymphotropic virus type-1 (HTLV-1). At admission, a 46-year-old female presented with lymphadenomegaly, lymphocytosis, slight elevation of LDH blood level, and acid-alcohol resistant bacilli in sputum and was being treated for pulmonary tuberculosis (Tb). She had lymphocytosis in the previous 20 months. Serology for HTLV-1 was positive. Lymph node was infiltrated by medium-sized lymphocytes with scattered Hodgkin and Reed-Sternberg-like cells CD30+, CS1-4+, and CD79a+. Background cells were CD4+ and CD25+. A clinical diagnosis of favorable chronic ATLL was given. She was treated with chemotherapy but later progressed to acute ATLL and ultimately died. Hodgkin-like ATLL should be considered in the histological differential diagnosis with Hodgkin lymphoma since treatment and prognosis of these diseases are distinct. It is also important to search for HTLV-1 infection in patients with unexplained prolonged lymphocytosis.
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Humanos , Femenino , Persona de Mediana Edad , Enfermedad de Hodgkin/patología , Infecciones por HTLV-I/patología , Leucemia-Linfoma de Células T del Adulto/patología , Linfocitosis/patología , Biopsia , Ensayo de Inmunoadsorción Enzimática , Enfermedad de Hodgkin/virología , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Leucemia-Linfoma de Células T del Adulto/virología , Resultado Fatal , Linfocitosis/virología , Ganglios Linfáticos/patologíaRESUMEN
Abstract Background: Adult T-cell leukemia/lymphoma is a peripheral disease associated with human T-cell lymphotropic virus type 1. Treatment is carried out according to clinical type with watchful waiting being recommended for less aggressive types. Aggressive adult T-cell leukemia/lymphoma is generally treated with chemotherapy and/or antivirals. The objective of this study was to correlate the survival of patients diagnosed in Bahia, Brazil, with the therapeutic approaches employed and to evaluate what issues existed in their treatment processes. Methods: Eighty-three adult T-cell leukemia/lymphoma patients (26 smoldering, 23 chronic, 16 acute, 13 lymphoma and five primary cutaneous tumoral) with available data were included in this study. Results: Complete response was achieved in seven smoldering patients with symptomatic treatment, in two with chronic disease using antivirals/chemotherapy, in one with acute disease using antivirals and in one lymphoma using the LSG15 regimen [vincristine, cyclophosphamide, doxorubicin, and prednisolone (VCAP); doxorubicin, ranimustine, and prednisolone (AMP); and vindesine, etoposide, carboplatin, and prednisolone (VECP)]. Smoldering patients who received symptomatic treatment presented longer survival. Favorable chronic patients treated with antivirals presented longer survival compared to the unfavorable subtype. However, for the acute form, first-line chemotherapy was better, albeit without significance, than antivirals. Only one of the patients with lymphoma and primary cutaneous tumors responded. Conclusions: Watchful waiting associated with phototherapy represents the best option for smoldering adult T-cell leukemia/lymphoma with survival in Bahia being superior to that described in Japan. There was a trend of better results with zidovudine/interferon-alpha in favorable chronic disease. Excellent results were achieved in the lymphoma type treated with the LSG15 protocol. Patients are diagnosed late probably due to lack of knowledge of adult T-cell leukemia/lymphoma by primary healthcare doctors and a Brazilian treatment protocol needs to be established.
Asunto(s)
Humanos , Masculino , Femenino , Preescolar , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Virus Linfotrópico T Tipo 1 Humano , Infecciones por HTLV-I , Leucemia-Linfoma de Células T del Adulto , Zidovudina , Leucemia , Linfoma de Células T PeriféricoRESUMEN
Summary Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T-cells caused by human T-cell lymphotropic virus type 1 (HTLV-1). Twenty million people are believed to be infected throughout the world, mostly in Japan, Africa, the Caribbean, and South America, particularly in Brazil and Peru. ATL affects about 5% of infected individuals and is classified in the following clinical forms: acute, lymphoma, primary cutaneous tumoral, chronic (favorable and unfavorable), and smoldering (leukemic and non-leukemic). Although it is considered an aggressive disease, there are cases with a long progression. We emphasize the importance of clinical classification as an indispensable element for evaluating prognosis and appropriate therapeutic approach. Since several cases have been published in Brazil and this disease is still poorly known, we decided to make a review paper for dissemination of clinical, hematological and pathological aspects, diagnosis, and therapy. The best way to reduce the occurrence of ATL would be halting the transmission of the virus through breastfeeding.
Resumo A leucemia/linfoma de células T do adulto (LLcTA) é uma neoplasia de células T maduras CD4+ causada pelo vírus linfotrópico para células T humanas tipo 1 (HTLV-1). Acredita-se que existem cerca de 20 milhões de pessoas infectadas em todo o mundo, principalmente no Japão, na África, no Caribe e na América do Sul, particularmen te no Brasil e no Peru. A LLcTA acomete cerca de 5% dos indivíduos infectados e classifica-se nas seguintes formas clínicas: aguda, linfomatosa, tumoral primária de pele, crônica (favorável e desfavorável) e indolente (leucêmica e não leucêmica). Embora seja considerada uma doença agressiva, há casos com longa evolução. Salientamos a importância da classificação clínica como elemento im prescindível para avaliação do prognóstico e conduta terapêutica adequada. Como já foram publicados vários casos no Brasil e essa doença ainda é pouco conhecida, decidimos fazer um trabalho de revisão para divulgar os seus aspectos clínicos, hematológicos, anatomopatológi cos, diagnósticos e terapêuticos. O melhor meio de redu zir a ocorrência de LLcTA seria sustando a transmissão vertical do vírus pela amamentação.