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1.
Rinsho Ketsueki ; 65(1): 41-46, 2024.
Artículo en Japonés | MEDLINE | ID: mdl-38311388

RESUMEN

The patient was a 21-year-old man who had been diagnosed with Crohn's disease and received infliximab and azathioprine six years earlier. He was admitted with fever and fatigue. Peripheral blood examination showed LDH 2,473 U/l and thrombocytopenia, and contrast-enhanced computed tomography (CT) showed hepatosplenomegaly. Bone marrow biopsy and liver biopsy showed CD4+CD56+TCRγδ+CD8- atypical cells, leading to a diagnosis of hepatosplenic T-cell lymphoma (HSTCL). The patient was refractory to CHOP and DA-EPOCH, and therefore received cord blood transplantation with myeloablative conditioning. CT showed reduced in hepatosplenomegaly and peripheral blood examination showed LDH 165 U/l and plt 180,000/µl, so the patient was discharged on day117. HSTCL is a tumor of immature γδT cells with a Vδ1 mutation in the spleen, and immunodeficiency has been implicated in its pathogenesis. Patients with inflammatory bowel disease treated with azathioprine are known to have an increased risk of lymphoproliferative disease. In this case, use of immunosuppressive drugs for Crohn's disease may have caused malignant transformation of γδ cells in the intestinal epithelium. Although the patient was refractory to chemotherapy, he was able to achieve remission with early cord blood transplantation and long-term survival is expected.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad de Crohn , Neoplasias Hepáticas , Linfoma de Células T , Neoplasias del Bazo , Masculino , Humanos , Adulto Joven , Adulto , Enfermedad de Crohn/inducido químicamente , Enfermedad de Crohn/tratamiento farmacológico , Azatioprina/efectos adversos , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Inmunosupresores/uso terapéutico , Linfoma de Células T/etiología , Linfoma de Células T/terapia , Linfoma de Células T/diagnóstico , Neoplasias del Bazo/etiología
2.
JAMA ; 331(5): 389-390, 2024 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-38206604

RESUMEN

This Viewpoint outlines a recent safety signal identified by the FDA concerning CAR T-cell therapy for pediatric cancer, including what is known and likely implications.


Asunto(s)
Inmunoterapia Adoptiva , Linfoma de Células T , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células T/etiología , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores Quiméricos de Antígenos/uso terapéutico
3.
Leuk Lymphoma ; 65(3): 301-311, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38093530

RESUMEN

Aggressive T-cell lymphomas (TCL) account for 10-15% of non-Hodgkin lymphomas (NHL) with weaker responses and shorter durations to chemotherapy than other types of NHL. Current therapies for patients with relapsed/refractory Cutaneous T-cell lymphoma (CTCL) have limited efficacy, and short durations of response. Gemcitabine and liposomal doxorubicin have shown single-agent activity in TCL and combined have activity in relapsed B-cell lymphomas. We evaluated outcomes of 18 patients with relapsed/refractory aggressive TCL (13 CTCL, 5 PTCL) treated with a gemcitabine plus liposomal doxorubicin (GemDox) combination and evaluated outcomes with a specific focus on CTCL patients. Significant responses were observed in CTCL patients with an overall response rate of over 80%. In all patients, objective responses were seen in eight patients (50%), with six patients (5 CTCL) able to proceed to allogeneic stem cell transplant. Given limited treatment options for r/r CTCL, GemDox should be considered a therapeutic option in relapsed/refractory CTCL.


Asunto(s)
Doxorrubicina/análogos & derivados , Linfoma no Hodgkin , Linfoma de Células T , Humanos , Gemcitabina , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/etiología , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Polietilenglicoles
4.
Future Oncol ; 20(5): 245-256, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38018460

RESUMEN

Low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type has a favorable outcome with radiation therapy alone, and the addition of chemotherapy shows no survival benefit. Nonetheless, a proportion of patients will relapse or progress, with a dismal outcome, highlighting the need for a novel therapeutic strategy. Promising preliminary findings indicate the efficacy of PD-1/PD-L1 inhibitors in extranodal natural killer/T-cell lymphoma, nasal type, with good toxicity profiles. Here we describe the design of a phase II study (CLCG-NKT-2101), which is evaluating the safety and efficacy of adding anti-PD-1 antibody to the current radiation therapy regimen in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type patients. Tislelizumab will be added in an inductive and concurrent way to radiation therapy. The primary end point will be the complete response rate after induction immunotherapy. Clinical trial registration: ClinicalTrials.gov (NCT05149170).


Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células T , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estadificación de Neoplasias , Linfoma de Células T/etiología , Células Asesinas Naturales , Ensayos Clínicos Fase II como Asunto
5.
Leuk Lymphoma ; 65(1): 118-122, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37871127

RESUMEN

Epstein-Barr virus (EBV) associated T-cell and NK-cell lymphoproliferative diseases are lethal and extremely rare in Caucasians. We expand on the clinical, immunological and histogenetic characteristics associated with this second European case (19 years old, previously healthy, Caucasian boy) of systemic EBV positive T-cell lymphoma of childhood. We report, as novel findings, severe lympho-depletion and abrogation of thymopoiesis secondary to severe EBV activation and excessive immune activation. Similar to the first European case, we also detected a somatic missense variant in the proto-oncogene FYN. In the first European patient however, the FYN variant allele frequency (VAF) was 10% and the patient only experienced moderate leukopenia, whereas in our case, the VAF was 48% and the patient experienced severe leukopenia and lymphopenia. This could suggest a pathogenic role of these FYN variants in driving excessive T cell activation. If confirmed, FYN might become target in future treatments of this fatal disorder.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Leucopenia , Linfoma de Células T Periférico , Linfoma de Células T , Trastornos Linfoproliferativos , Masculino , Humanos , Adulto Joven , Adulto , Herpesvirus Humano 4 , Infecciones por Virus de Epstein-Barr/complicaciones , Linfocitos T/patología , Linfoma de Células T/etiología , Linfoma de Células T/genética , Linfoma de Células T Periférico/patología , Trastornos Linfoproliferativos/terapia
6.
Transpl Infect Dis ; 26(1): e14170, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37830407

RESUMEN

Hepatosplenic T-cell lymphoma (HSTCL) is an uncommon and highly aggressive subtype of peripheral T-cell lymphoma characterized by liver, spleen, and bone marrow involvement. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative treatment for HSTCL, but it carries a significant risk of relapse. Cytomegalovirus (CMV) reactivation is a frequent complication after alloHSCT, particularly in patients undergoing lymphocyte-toxic therapies. A 27-year-old man diagnosed with HSTCL underwent an alloHSCT with active disease after six lines of therapy. A CMV reactivation was successfully treated with foscarnet. A sudden reappearance of symptomatic lymphocytosis (15,550/µL) by day +20, prior to engraftment, raised suspicion of disease progression. A comprehensive diagnostic work-up revealed an oligoclonal expansion of donor lymphocytes along with complete donor chimerism, leading to an alternative diagnosis of a CMV-driven T-cell expansion. This was confirmed by an in vitro assay testing T-cell specificity against CMV. The patient achieved both complete response and complete donor chimerism despite persisting lymphocytosis, but ultimately relapsed. This case highlights the importance of diagnostic tools in understanding disease progression and guiding treatment decisions.


Asunto(s)
Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Linfocitosis , Linfoma de Células T Periférico , Linfoma de Células T , Masculino , Humanos , Adulto , Citomegalovirus , Linfoma de Células T Periférico/etiología , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/etiología , Linfocitosis/etiología , Trasplante Homólogo/efectos adversos , Recurrencia Local de Neoplasia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfoma de Células T/etiología , Progresión de la Enfermedad
7.
Expert Opin Biol Ther ; 23(1): 37-47, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36453808

RESUMEN

INTRODUCTION: New methods in cancer immunotherapy, such as chimeric antigen receptor (CAR)-T cells, have shown promising results in destroying malignant cells. However, limitations and side effects of CAR-T cell therapy, such as graft-versus-host disease (GVHD), neurotoxicity, and cytokine release syndrome, have motivated researchers to investigate safer alternative cells like natural killer (NK) cells. AREA COVERED: NK cells can effectively recognize hematologic malignant cells and destroy them. Many clinical and preclinical studies investigate the efficacy of CAR-NK cells in treating lymphoma and other hematologic malignancies. The results of published clinical trials and preclinical studies have shown that CAR-NK cells could be an appropriate choice for treating lymphoma. In this review, we discuss the characteristics of CAR-NK cells, their role in treating B-cell and T-cell lymphoma, and the challenges faced by using them. We also highlight clinical trials using CAR-NK cells for treating lymphoma. EXPERT OPINION: CAR-NK cells have shown promising results in cancer therapy, especially B-cell lymphoma, with a much lower risk for GVHD, cytokine release syndrome, and neurotoxicity than CAR-T cells. Further investigations are required to overcome the obstacles of CAR-NK cell therapy, both generally, and in cancers like T-cell lymphoma.


Asunto(s)
Enfermedad Injerto contra Huésped , Linfoma de Células T , Linfoma , Humanos , Síndrome de Liberación de Citoquinas/etiología , Células Asesinas Naturales , Linfoma/terapia , Inmunoterapia/efectos adversos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfoma de Células T/etiología , Enfermedad Injerto contra Huésped/etiología
8.
J Cancer Res Clin Oncol ; 149(8): 5219-5230, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36374333

RESUMEN

PURPOSE: To investigate the prognostic value of gross tumor volume (GTV) in early-stage extranodal NK/T-cell lymphoma (ENKTCL) treated with intensity-modulated radiation therapy (IMRT) and explore the interactive effect of GTV and radiotherapy (RT) dose on locoregional recurrence (LRR). METHODS: The data of 319 early-stage ENKTCL patients who underwent IMRT were reviewed retrospectively. Overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) were estimated using Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards regression was performed to identify independent risk factors for survival outcomes. Penalized spline regression was used to flexibly model the association of continuous predictors (GTV and RT dose) with mortality, progression, and relapse. RESULTS: The 5-year OS, PFS, and LRC for the entire cohort were 72.9, 64.4, and 89.9%, respectively. The risks of disease mortality, progression, and recurrence increased steadily with increasing GTV. Patients with GTV < 35 mL had significantly higher 5-year OS (83.0% vs. 59.4%; P < 0.001), PFS (76.7% vs. 48.4%; P < 0.001), and lower 5-year cumulative LRR rate (4.9% vs. 14.5%; P = 0.004), than patients with GTV ≥ 35 mL. The risk of LRR was low with RT doses of 50-56 Gy, independent of GTV. For patients with GTV ≥ 35 mL, dose ≥ 56 Gy was not associated with decreased LRR. CONCLUSION: Larger GTV is associated with worse survival and higher LRR in early-stage ENKTCL patients treated with IMRT. A dose of 50-56 Gy may be appropriate to achieve lower risk of LRR, regardless of GTV.


Asunto(s)
Linfoma de Células T , Radioterapia de Intensidad Modulada , Humanos , Radioterapia de Intensidad Modulada/métodos , Estudios Retrospectivos , Carga Tumoral , Pronóstico , Dosis de Radiación , Recurrencia , Linfoma de Células T/etiología , Supervivencia sin Enfermedad
9.
Acta Vet Scand ; 64(1): 36, 2022 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-36503518

RESUMEN

BACKGROUND: High-grade lymphoma in dogs is a chemotherapy-responsive neoplasia with remission rates exceeding 80% under combination chemotherapy protocols. Usually these protocols are intensive and 24 + weeks. The objective of the present study was to investigate if a shorter protocol combined with an oral lomustine maintenance treatment (3 × in 8 weeks) would present an acceptable result, both for B- and T-cell lymphomas, and for the different types of lymphomas normally encountered in private veterinary practice. RESULTS: 144 dogs entered the study. Lymphoma types included multicentric (n = 123), alimentary (n = 13), miscellaneous (n = 7), and mediastinal lymphoma (n = 1). Overall response rate was 83.3% (B-cell: 86.6%, T-cell: 79.4%). Complete remission (CR) was achieved in 72.2% (B-cell: 77.3%, T-cell: 67.6%) and partial remission (PR) in 11.1% (B-cell: 9.3%, T-cell: 11.8%) of the dogs. Median duration of first CR amounted to 242 days (B-cell: 263 d, T-cell: 161 d). Median survival in dogs with CR was 374 days (B-cell: 436 d, T-cell: 252 d), and median overall survival time was 291 days (B-cell: 357d, T-cell: 210d). Immunophenotype demonstrated an independent significant influence on duration of remission and survival in the whole group. Findings of splenic and hepatic cytology were not significant associated with patient outcome. Treatment was well tolerated; the majority of adverse events were classified as grade 1 or 2. CONCLUSIONS: Short-term chemotherapy followed by lomustine consolidation leads to compara-ble remission and survival times compared to conventional protocols with cyclophosphamide, doxorubicin, vincristine and prednisolone with acceptable toxicosis in dogs with both B-cell and T-cell lymphoma.


Asunto(s)
Enfermedades de los Perros , Linfoma de Células T , Linfoma , Perros , Animales , Lomustina/uso terapéutico , Enfermedades de los Perros/patología , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/etiología , Linfoma de Células T/veterinaria , Linfoma/tratamiento farmacológico , Linfoma/patología , Linfoma/veterinaria , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
10.
Expert Opin Drug Saf ; 21(5): 653-660, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35129014

RESUMEN

INTRODUCTION: Peripheral T-Cell Lymphomas (PTCL) constitute a heterogeneous group of aggressive T - and natural killer (NK)-cell disorders and are associated with a poor prognosis. Frontline treatments often consist of anthracycline-based combination chemotherapy with the exception of NK-T cell lymphomas, where such combinations are ineffective due to the presence of P-glycoprotein which leads to multidrug resistance. Infectious and immune mediated side effects might be more pronounced in or unique to T-cell lymphomas due to the selection of agents which target multiple T-cell subtypes and also an immunocompromised state induced by the lymphomas themselves. AREAS COVERED: This review provides a comprehensive overview of safety considerations of treatment regimens used for peripheral T-cell lymphomas. We cover regimens used in both frontline and relapsed settings including combination chemotherapy, single agent chemotherapies and immunotherapies. EXPERT OPINION: Treatment of T-cell lymphomas often requires sequencing of several therapies due to lower efficacy of available treatment regimens in curing the disease compared to that seen in B-cell non-Hodgkin lymphomas. In addition, certain complications are more common in T-cell lymphomas due to their unique immunobiology. An understanding of these salient aspects is important for all providers who treat patients with this challenging disease group.


Asunto(s)
Linfoma de Células T Periférico , Linfoma de Células T , Humanos , Linfoma de Células T/etiología , Linfoma de Células T/patología , Linfoma de Células T/terapia , Linfoma de Células T Periférico/complicaciones , Linfoma de Células T Periférico/tratamiento farmacológico
11.
Br J Haematol ; 196(1): 31-44, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34169507

RESUMEN

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non-familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X-linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non-neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders and lymphomas can cause neoplasia-associated HLH. The present review will discern between EBV-associated familial and non-familial HLH and highlight diagnostic and therapeutic considerations. Non-familial EBV-associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non-neoplastic EBV-HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV-positive T-cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV-related complications is desperately needed to improve survival for patients with neoplasia-associated HLH.


Asunto(s)
Susceptibilidad a Enfermedades , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/fisiología , Linfohistiocitosis Hemofagocítica/etiología , Linfohistiocitosis Hemofagocítica/metabolismo , Algoritmos , Biomarcadores , Biopsia , Médula Ósea/patología , Toma de Decisiones Clínicas , Citocinas/metabolismo , Manejo de la Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/etiología , Linfoma de Células T/metabolismo , Mutación , Perforina/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología
13.
J BUON ; 26(5): 2033-2039, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34761614

RESUMEN

PURPOSE: Natural killer/T cell lymphoma (NKTCL) is a malignant condition. The molecular pathological mechanism of NKTCL has not been well studied. In this article we tried to study the role of microRNA-188-5p (miR-188-5p) in NKTCL. METHODS: The expression level of miR-188-5p and XRCC5 was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8 (CCK-8) assay and colony formation assay were used to assess the ability of cell proliferation. Dual luciferase reporter assay was used to examine the down-stream target of miR-188-5p. Western blotting was utilized to determine XRCC5 expression level. RESULTS: miR-188-5p was down-regulated in NKTCL. High expression of miR-188-5p accelerated cell proliferation. XRCC5 was one of the down-stream targets. Our data indicated that miR-188-5p suppressed NKTCL progression via regulating XRCC5 expression. CONCLUSIONS: This research elucidated that miR-188-5p suppressed tumor progression in NKTCL by regulating XRCC5. Our data may provide more evidence in looking for novel therapeutic targets.


Asunto(s)
Células Asesinas Naturales , Autoantígeno Ku/fisiología , Linfoma de Células T/etiología , MicroARNs/fisiología , Progresión de la Enfermedad , Humanos , Células Tumorales Cultivadas
14.
Blood ; 138(9): 785-789, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-33822002

RESUMEN

Lymphoma survivors have a significantly higher risk of developing second primary lymphoma than the general population; however, bidirectional risks of developing B- and T-cell lymphomas (BCLs and TCLs) specifically are less well understood. We used population-based cancer registry data to estimate the subtype-specific risks of second primary lymphoma among patients with first BCL (n = 288 478) or TCL (n = 23 747). We observed nearly fivefold increased bidirectional risk between BCL and TCL overall (TCL following BCL: standardized incidence ratio [SIR] = 4.7, 95% confidence interval [CI] = 4.2-5.2; BCL following TCL: SIR = 4.7, 95% CI = 4.1-5.2), but the risk varied substantially by lymphoma subtype. The highest SIRs were observed between Hodgkin lymphoma (HL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (PTCL-NOS following HL: SIR = 27.5; HL following PTCL-NOS: SIR = 31.6). Strikingly elevated risks also were notable for angioimmunoblastic T-cell lymphoma (AITL) and diffuse large B-cell lymphoma (DLBCL) (AITL following DLBCL: SIR = 9.7; DLBCL following AITL: SIR = 15.3). These increased risks were strongest within the first year following diagnosis but remained persistently elevated even at ≥5 years. In contrast, SIRs were <5 for all associations of TCL with chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. These patterns support etiologic heterogeneity among lymphoma subtypes and provide further insights into lymphomagenesis.


Asunto(s)
Linfoma de Células B , Linfoma de Células T , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Linfoma de Células B/clasificación , Linfoma de Células B/epidemiología , Linfoma de Células B/etiología , Linfoma de Células T/clasificación , Linfoma de Células T/epidemiología , Linfoma de Células T/etiología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Programa de VERF
15.
Leukemia ; 35(4): 956-967, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33664464

RESUMEN

T-cell lymphomas (TCL) are a group of biologically and clinically heterogenous neoplasms derived from mature T lymphocytes. Recent findings in biology have advanced the classification of these neoplasms; however, clinical investigations based on biologic features have yet to be designed. Two biomarker-driven treatments for TCL are promising: brentuximab vedotin (BV) in combination with chemotherapy or as monotherapy is the standard treatment for newly diagnosed CD30-positive TCL and relapsed/refractory anaplastic large cell lymphoma (ALCL), while ALK inhibitors have induced responses in ALK+ ALCLs. Common genetic alterations in TCL, such as aberrations in PI3K/mTOR, JAK/STAT, and epigenetic regulators are also targetable by pathway inhibitors and HDAC/DNMT inhibitors; however, responses to these treatments as monotherapy are neither satisfactory nor durable, even in patients pre-stratified by several biomarkers. Additional work is needed to extend biology/biomarker-driven treatment in these neoplasms. As T-cell lymphomagenesis is multistep and multifactorial, trials are ongoing to evaluate combination treatments. The focus of this article is to summarize the status and the current role of targeted-based therapy in nodal TCL.


Asunto(s)
Ganglios Linfáticos/patología , Linfoma de Células T/diagnóstico , Linfoma de Células T/tratamiento farmacológico , Terapia Molecular Dirigida , Biomarcadores de Tumor , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Aprobación de Drogas , Predisposición Genética a la Enfermedad , Genómica/métodos , Humanos , Inmunofenotipificación , Ganglios Linfáticos/metabolismo , Linfoma de Células T/etiología , Linfoma de Células T/metabolismo , Terapia Molecular Dirigida/efectos adversos , Terapia Molecular Dirigida/métodos , Fenotipo , Transducción de Señal/efectos de los fármacos
16.
Sci Rep ; 11(1): 3962, 2021 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-33597573

RESUMEN

T-cell non-Hodgkin's lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin's lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin's T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma.


Asunto(s)
Linfoma Cutáneo de Células T/etiología , Linfoma Cutáneo de Células T/genética , Rayos Ultravioleta/efectos adversos , Linfocitos T CD4-Positivos/metabolismo , Bases de Datos Genéticas , Humanos , Factores Reguladores del Interferón , Linfoma de Células T/etiología , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Linfoma de Células T/patología , Linfoma Cutáneo de Células T/patología , Mutación/genética , Síndrome de Sézary/sangre , Neoplasias Cutáneas/patología
17.
Transplantation ; 105(8): 1858-1868, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-33560724

RESUMEN

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) encompass a spectrum of heterogeneous entities. Because the vast majority of cases PTLD arise from B cells, available data on PTLD of T or NK phenotype (T/NK-cell PTLD) are scarce, which limits the quality of the management of these patients. METHODS: All adult cases of PTLD diagnosed in France were prospectively recorded in the national registry between 1998 and 2007. Crosschecking the registry data with 2 other independent national databases identified 58 cases of T/NK-cell PTLD. This cohort was then compared with (i) the 395 cases of B-cell PTLD from the registry, and of (ii) a cohort of 148 T/NK-cell lymphomas diagnosed in nontransplanted patients. RESULTS: T/NK-cell PTLD occurred significantly later after transplantation and had a worse overall survival than B-cell PTLD. Two subtypes of T/NK-cell PTLD were distinguished: (i) cutaneous (28%) and (ii) systemic (72%), the latter being associated with a worse prognosis. Compared with T/NK-cell lymphomas of nontransplanted patients, overall survival of systemic T/NK-cell PTLD was worse (hazard ratio: 2.64 [1.76-3.94]; P < 0.00001). CONCLUSIONS: This difference, which persisted after adjustment on tumoral mass, histological subtype, and extension of the disease at diagnosis could be explained by the fact that transplanted patients were less intensively treated and responded less to chemotherapy.


Asunto(s)
Trasplante de Riñón/efectos adversos , Linfoma de Células T/etiología , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias Cutáneas/etiología
18.
Cell Mol Immunol ; 18(3): 644-659, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32868912

RESUMEN

Tcf-1 (encoded by Tcf7) not only plays critical roles in promoting T cell development and differentiation but also has been identified as a tumor suppressor involved in preventing T cell malignancy. However, the comprehensive mechanisms of Tcf-1 involved in T cell transformation remain poorly understood. In this study, Tcf7fl/fl mice were crossed with Vav-cre, Lck-cre, or Cd4-cre mice to delete Tcf-1 conditionally at the beginning of the HSC, DN2-DN3, or DP stage, respectively. The defective T cell development phenotypes became gradually less severe as the deletion stage became more advanced in distinct mouse models. Interestingly, consistent with Tcf7-/- mice, Tcf7fl/flVav-cre mice developed aggressive T cell lymphoma within 45 weeks, but no tumors were generated in Tcf7fl/flLck-cre or Tcf7fl/flCd4-cre mice. Single-cell RNA-seq (ScRNA-seq) indicated that ablation of Tcf-1 at distinct phases can subdivide DN1 cells into three clusters (C1, C2, and C3) and DN2-DN3 cells into three clusters (C4, C5, and C6). Moreover, Tcf-1 deficiency redirects bifurcation among divergent cell fates, and clusters C1 and C4 exhibit high potential for leukemic transformation. Mechanistically, we found that Tcf-1 directly binds and mediates chromatin accessibility for both typical T cell regulators and proto-oncogenes, including Myb, Mycn, Runx1, and Lyl1 in the DN1 phase and Lef1, Id2, Dtx1, Fyn, Bcl11b, and Zfp36l2 in the DN2-DN3 phase. The aberrant expression of these genes due to Tcf-1 deficiency in very early T cells contributes to subsequent tumorigenesis. Thus, we demonstrated that Tcf-1 plays stage-specific roles in regulating early thymocyte development and transformation, providing new insights and evidence for clinical trials on T-ALL leukemia.


Asunto(s)
Biomarcadores de Tumor/genética , Transformación Celular Neoplásica/patología , Factor Nuclear 1-alfa del Hepatocito/fisiología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/fisiología , Linfoma de Células T/patología , Análisis de la Célula Individual/métodos , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Perfilación de la Expresión Génica , Activación de Linfocitos , Linfoma de Células T/etiología , Linfoma de Células T/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
19.
J Pediatr Hematol Oncol ; 42(6): e463-e465, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-31259827

RESUMEN

Ataxia-telangiectasia is a rare autosomal recessive neurodegenerative disease characterized by ataxia, radiosensitivity, telangiectases, and increased risk for hematologic malignancies. We present a case of a female individual diagnosed with T-cell acute lymphocytic leukemia at 13 years and subsequently with αß subtype of hepatosplenic T-cell lymphoma (HSTCL) at 20 years. During her diagnostic work up for HSTCL, paired tumor-germline sequencing identified a diagnosis of ataxia-telangiectasia. We also describe a very refractory clinical course of her αß HSTCL, including only a brief response to multiagent chemotherapy and an allogenic bone marrow transplant.


Asunto(s)
Ataxia Telangiectasia/complicaciones , Neoplasias Hepáticas/patología , Linfoma de Células T/patología , Neoplasias Primarias Secundarias/patología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Neoplasias del Bazo/patología , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/etiología , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/etiología , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/etiología , Pronóstico , Neoplasias del Bazo/tratamiento farmacológico , Neoplasias del Bazo/etiología , Adulto Joven
20.
J Neuroimmunol ; 338: 577092, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31706113

RESUMEN

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory condition associated with antibodies against aquaporin-4 (AQP4). To date, 4 cases of B-cell lymphomas have been reported in patients with NMOSD. Here we describe two individuals with AQP4+ NMOSD and T-cell lymphomas (TCL). CONCLUSION: Possible mechanisms that may explain co-existence of NMOSD with TCL include a paraneoplastic syndrome leading to AQP4 antibody production, or a generalized dysfunction of the adaptive immune system. Both patients were diagnosed with NMOSD and initiated on anti-CD20 agents prior to lymphoma diagnosis, though the short duration of exposure argues against a direct role. Further research is needed to examine the rate of lymphoproliferative disorders in NMOSD.


Asunto(s)
Acuaporina 4/inmunología , Autoanticuerpos/análisis , Linfoma de Células T/etiología , Neuromielitis Óptica/inmunología , Adolescente , Adulto , Femenino , Humanos , Neuromielitis Óptica/complicaciones
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