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1.
Blood ; 136(24): 2754-2763, 2020 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-32766875

RESUMEN

This study aimed to assess the efficacy and safety of treatment with avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with relapsed or refractory extranodal natural killer/T-cell lymphoma (ENKTL). In this phase 2 trial, 21 patients with relapsed or refractory ENKTL were treated with 10 mg/kg of avelumab on days 1 and 15 of a 28-day cycle. The primary end point was the complete response (CR) rate based on the best response. Targeted sequencing and immunohistochemistry were performed using pretreatment tumor tissue, and blood samples were drawn before and after treatment for measurement of cytokines and soluble programmed cell death protein 1 (PD1), PD-L1, and PD-L2. The CR rate was 24% (5 of 21), and the overall response rate was 38% (8 of 21). Although nonresponders showed early progression, 5 responders currently continue to receive treatment and have maintained their response. Most treatment-related adverse events were grade 1 or 2; no grade 4 adverse events were observed. Treatment responses did not correlate with mutation profiles, tumor mutation burden, serum levels of cytokines, or soluble PD1/PD-L1 and PD-L2. However, the response to avelumab was significantly associated with the expression of PD-L1 by tumor tissue (P = .001). Therefore, all patients achieving CR showed high PD-L1 expression, and their tumor subtyping based on PD-L1 expression correlated with treatment response. In summary, avelumab showed single-agent activity in a subset of patients with relapsed or refractory ENKTL. The assessment of PD-L1 expression on tumor cells might be helpful for identifying responders to avelumab. This trial was registered at www.clinicaltrials.gov as #NCT03439501.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/mortalidad , Anciano , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma Extranodal de Células NK-T/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Recurrencia , Tasa de Supervivencia
2.
Blood ; 136(22): 2548-2556, 2020 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-32584959

RESUMEN

Because non-anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline-based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies.


Asunto(s)
Neoplasias del Sistema Nervioso Central/prevención & control , Linfoma Extranodal de Células NK-T/prevención & control , Metotrexato/administración & dosificación , Modelos Biológicos , Anciano , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Femenino , Humanos , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Linfoma Extranodal de Células NK-T/metabolismo , Linfoma Extranodal de Células NK-T/patología , Masculino , Persona de Mediana Edad , Factores de Riesgo
3.
Haematologica ; 107(8): 1864-1879, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35021606

RESUMEN

Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copynumber aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfoma Extranodal de Células NK-T , Linfoma de Células T Periférico , MicroARNs , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Inestabilidad Genómica , Herpesvirus Humano 4/genética , Humanos , Linfoma Extranodal de Células NK-T/diagnóstico , Linfoma Extranodal de Células NK-T/genética , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/genética , MicroARNs/genética , Regulación hacia Arriba
4.
Ann Hematol ; 101(7): 1535-1543, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35639152

RESUMEN

In 2016, World Health Organization classification of lymphoid neoplasms separated firmly-follicular helper (Tfh) cell origin lymphomas from peripheral T-cell lymphoma-not specified (PTCL-NOS) based on their unique immunogenic characteristics. Generally, Tfh cell origin lymphoma, which has an approximately 25% incidence, is classified into three categories: angioimmunoblastic T-cell lymphoma (AITL), follicular peripheral T-cell lymphoma (F-PTCL), and nodal peripheral T-cell lymphoma with a T-follicular helper phenotype (nodal PTCL with Tfh cell phenotype). Their prognosis has been estimated using four traditional prognostic tools for T-cell lymphoid malignancies: the international prognostic index (IPI), the prognostic index for peripheral T-cell lymphoma unspecified (PIT), the modified PIT (mPIT) and the international T-cell lymphoma project index. In addition, the AITL score that reflects AITL characteristics well has been introduced recently. However, there are no clear guidelines for evaluating the prognosis of Tfh cell lymphoma. Thus, we performed a comparative analysis to determine which of these five indexes is most suitable for Tfh cell lymphoma. We evaluated the accuracy of classification according to risk score and predicted survival rate. Based on review by lymphoma pathology experts, we enrolled 198 patients diagnosed with Tfh cell lymphoma in this retrospective study. AITL was the most common subtype (n = 168), followed by F-PTCL (n = 21) and nodal PTCL with Tfh cell phenotype (n = 9). The median progression-free survival and overall survival with front-line treatment was 0.8 years (95% confidence interval [CI], 0.6-1.1 years) and 2.9 years (95% CI, 1.6-4.2 years), respectively. The AITL score showed better differentiation than other scoring systems in terms of classification according to risk score. However, for predicting PFS (concordance-index [C-index], IPI vs. PIT vs. modified PIT vs. international T-cell lymphoma project index vs. AITL score; 0.617 vs. 0.605 vs. 0.576 vs. 0.591 vs. 0.592) and OS (C-index, IPI vs. PIT vs. modified PIT vs. international T-cell lymphoma project index vs. AITL score; 0.663 vs. 0.651 vs. 0.612 vs. 0.672 vs. 0.583), the IPI, and the international T-cell lymphoma project index showed better performance. In conclusion, there are unmet needs to develop a prognostic index for Tfh cell lymphoma because its characteristics differ from PTCL-NOS. Although the AITL score reflects Tfh cell-origin lymphoma characteristics well and clearly shows their power of classification according to risk score, there are concerns about accurate prediction of survival outcomes. Therefore, it seems too early to settle on a single scoring system in Tfh cell origin lymphoma. In the future, along with classification, a more effective tool for survival prediction needs to be developed that reflects the specific characteristics of T-cell lymphoma.


Asunto(s)
Linfadenopatía Inmunoblástica , Linfoma de Células T Periférico , Linfoma de Células T , Humanos , Linfadenopatía Inmunoblástica/diagnóstico , Linfadenopatía Inmunoblástica/patología , Linfoma de Células T/patología , Pronóstico , Estudios Retrospectivos
5.
BMC Cancer ; 21(1): 972, 2021 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-34461835

RESUMEN

BACKGROUND: Tumor mutation burden is an emerging biomarker for immunotherapy. Although several clinical trials for immunotherapy in lymphoma have been carried out, the mutation burden of various lymphomas is not well known yet. Thus, the objective of this study was to compare tumor mutation burden of various non-Hodgkin lymphomas using panel based massively parallel sequencing. METHODS: We conducted 405 gene panel based massively parallel sequencing of 300 non-Hodgkin lymphomas and investigate the number of SNV/Indel in each lymphoma. RESULTS: The number of SNV/Indel was higher in mature B-cell lymphoma than in mature T- and NK-cell lymphoma. (P < 0.001) The number of SNV/Indel in primary mediastinal large B-cell lymphoma and primary diffuse large B-cell lymphoma of the central nervous system was the highest, which was significantly higher than that in diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS).(P = 0.030 and P = 0.008, respectively) The SNV/Indel number in EBV-positive DLBCL NOS was significantly lower than that in DLBCL NOS. (P = 0.048) Peripheral T-cell lymphoma, NOS showed no significant difference in the number of SNV/Indel from extranodal NK/T-cell lymphoma, nasal type (P = 0.942) or angioimmunoblastic T-cell lymphoma (P = 0.739). The number of SNV/Indel in anaplastic large cell lymphoma, ALK-positive was significantly lower than that in anaplastic large cell lymphoma, ALK-negative (P = 0.049). It was the lowest among all the lymphomas considered. CONCLUSION: Various lymphomas have different mutation burdens. Thus, tumor mutation burden can be used as a promising biomarker for immunotherapy in lymphomas.


Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto Joven
6.
BMC Cancer ; 21(1): 82, 2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33468080

RESUMEN

BACKGROUND: BCOR acts as a corepressor of BCL6, a potent oncogenic protein in cancers of the lymphoid lineage. We have found the recurrent somatic mutation of BCOR occurred in mature T-cell lymphoma (TCL). The role of BCOR mutation in lymphoid malignancies is unknown. METHODS: Lymphoma patient samples were analyzed to identify missense mutations in BCOR using Sanger sequencing. Transfection, RNA interference, immunoprecipitation, western blotting, cell proliferation, cytokine assays and quantitative real-time PCR were employed to determine the functional relevance of the novel K607E mutation in BCOR. The significant transcriptional changes were analyzed by performing DNA microarray profiling in cells expressing BCOR K607E mutant. RESULTS: One hundred thirty-seven lymphoma patient samples were analyzed to identify K607E mutation of the BCOR gene. The BCOR K607E mutation was identified in 15 of 47 NK/T cell lymphoma cases (31.9%), 2 of 18 angioimmunoblastic T-cell lymphoma cases (11.1%), 10 of 30 peripheral T-cell lymphoma, not otherwise specified cases (33.3%), and 13 of 42 diffuse large B-cell lymphoma cases (30.9%). Molecular analysis of BCOR K607E mutation revealed that compared to the wild-type BCOR, the mutant BCOR bound to the BCL6, PCGF1, and RING1B proteins with lesser affinity. Ectopic expression of BCOR K607E mutant significantly enhanced cell proliferation, AKT phosphorylation and the expression of interleukin-2 (IL-2) with up-regulated expression of HOX and S100 protein genes in T cells. BCOR silencing also significantly enhanced cell proliferation, AKT phosphorylation, and IL-2 production. CONCLUSIONS: Functional analyses indicated that K607E mutation of BCOR is oncogenic in nature and can serve as a genetic marker of T-cell lymphoma.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinogénesis/genética , Linfoma de Células T/genética , Recurrencia Local de Neoplasia/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular/genética , Análisis Mutacional de ADN , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Células Jurkat , Linfoma de Células T/diagnóstico , Linfoma de Células T/epidemiología , Linfoma de Células T/terapia , Mutación , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & control , Proteínas Proto-Oncogénicas/metabolismo , Interferencia de ARN , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Represoras/metabolismo , Regulación hacia Arriba
7.
Mod Pathol ; 33(4): 603-615, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31653980

RESUMEN

Extranodal NK/T-cell lymphoma is an aggressive lymphoma that is strongly associated with Epstein-Barr virus infection. Although some extranodal NK/T-cell lymphoma patients have shown responses to immune checkpoint blockade, biomarkers for predicting extranodal NK/T-cell lymphoma patient response to immunotherapy have not yet been defined. To understand the tumor immune microenvironment, we analyzed the expression of 579 immune-related genes and characterized the immune cells using immunohistochemistries and in situ hybridization for EBER. Based on comprehensive analyses, we developed an immune subtyping model that classifies extranodal NK/T-cell lymphoma patients into four tumor immune microenvironment subgroups using three immunohistochemical markers (FoxP3, PD-L1, and CD68). The four tumor immune microenvironment subgroups were named immune tolerance, immune evasion-A, immune evasion-B, and immune silenced. The immune tolerance group was characterized by high-Treg counts and was frequently observed in early stage, and nasal extranodal NK/T-cell lymphoma. The immune evasion group showed high cytotoxic T-cell counts and high PD-L1 expression but low Treg counts. In the immune-silenced group, almost all immune responses were exhausted, most patients were at an advanced stage, and had the poorest disease prognosis among the tumor immune microenvironment subgroups. In some patients (n = 3), a shift in the tumor immune microenvironment subgroup classification was observed in sequential biopsies. The response rate to pembrolizumab, an anti-PD-1 antibody, was 100% (1/1) in the immune tolerance group, 60% (3/5) in the immune evasion group, and 0% (0/5) in the immune-silenced group. We classified extranodal NK/T-cell lymphoma into four tumor immune microenvironment subgroups using a new classification system. In conclusion, we propose that the tumor immune microenvironment of extranodal NK/T-cell lymphoma may change during disease progression and may serve as a useful biomarker for immunotherapy.


Asunto(s)
Biomarcadores de Tumor/análisis , Inmunofenotipificación , Linfocitos Infiltrantes de Tumor/inmunología , Linfoma Extranodal de Células NK-T/inmunología , Linfocitos T Reguladores/inmunología , Escape del Tumor , Microambiente Tumoral , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/análisis , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Femenino , Factores de Transcripción Forkhead/análisis , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/genética , Linfoma Extranodal de Células NK-T/patología , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/efectos de los fármacos , Resultado del Tratamiento
8.
Blood ; 131(17): 1931-1941, 2018 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-29475961

RESUMEN

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV+-DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV+-DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV+-DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV+-DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2, and Rho pathway transcriptomic activation. Targeting the Rho pathway using a Rho-associated protein kinase (ROCK) inhibitor, fasudil, markedly decreased tumor growth in EBV+-DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.


Asunto(s)
Adenocarcinoma/metabolismo , Transformación Celular Viral , Infecciones por Virus de Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/virología , Animales , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/genética , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/virología , Ratones , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/virología , Proteínas de Unión al GTP rho/genética
9.
Cytokine ; 129: 155048, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32135464

RESUMEN

BACKGROUND: As diffuse large B-cell lymphoma (DLBCL) is a very heterogeneous group of lymphomas, much effort has gone in trying to identify patients with increased risk for early death or secondary central nervous system (CNS) involvement. To better predict their outcomes, we measured the levels of various cytokines in serum samples of patients with DLBCL and analyzed their clinical outcomes. METHODS: We measured the levels of seven serum cytokines at diagnosis in 313 DLBCL patients who were treated with R-CHOP. Their impact on clinical outcomes, including time to secondary CNS involvement and the 3-year overall survival (OS) rate, were analyzed. RESULTS: The median age was 56 years (range, 16-86 years), and 177 patients (57%) were men. Secondary CNS involvement was found in 5.4% (16/294) cases, and time to secondary CNS involvement was significantly short in patients with elevated interleukin (IL)-10 (p = 0.012). With the 3-year OS rate of the whole cohort being 73.6%, serum levels of several cytokines, such as CCL3 > 4.0 pg/mL (54.3% vs. 76.1%, p = 0.001), CCL5 > 450 pg/mL (57.0% vs. 78.1%, p < 0.001), any expression of IL-6 (59.3% vs. 76.6%, p = 0.001), and any expression of IL-10 (68.2% vs. 84.5%, p = 0.001), showed prognostic impact. Higher expressions of these cytokines were associated with worse manifestations of clinical prognostic factors. CONCLUSIONS: Our study revealed that some cytokines impact OS and secondary CNS involvement. Future studies are required to elucidate how these findings can be incorporated to the conventional prognostic factors for more tailored approaches.


Asunto(s)
Sistema Nervioso Central/metabolismo , Interleucina-10/sangre , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sistema Nervioso Central/efectos de los fármacos , Quimiocina CCL3/sangre , Quimiocina CCL3/metabolismo , Quimiocina CCL5/sangre , Quimiocina CCL5/metabolismo , Ciclofosfamida/uso terapéutico , Citocinas/sangre , Citocinas/metabolismo , Doxorrubicina/uso terapéutico , Femenino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Rituximab/uso terapéutico , Tasa de Supervivencia , Vincristina/uso terapéutico , Adulto Joven
10.
BMC Cancer ; 20(1): 120, 2020 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-32054467

RESUMEN

BACKGROUND: The interaction of programmed death-1 protein (PD-1) and programmed death-1 ligand (PD-L1) produces immunosuppressive activity, protecting tumor cells from anti-tumor immunity and possibly releasing soluble PD-L1 (sPD-L1) from PD-L1 expressing tumor cells. Therefore, we measured serum levels of sPD-L1 in patients with primary central nervous system lymphoma (PCNSL) and explored its clinical implications. METHODS: Sixty-eight patients with newly diagnosed PCNSL had diffuse large B-cell lymphoma and were treated with high-dose methotrexate-containing chemotherapy. The measurement of sPD-L1 and cytokines was performed using serum samples archived at diagnosis, and the tissue expression of PD-L1 was also analyzed from archived paraffin-embedded tissue blocks. Disease relapse, progression-free survival (PFS), and overall survival (OS) were analyzed according to the extent of sPD-L1 in serum and PD-L1 in tissue. RESULTS: The median level of serum sPD-L1 (0.429 ng/mL) was higher than in healthy control patients (0.364 ng/mL). The occurrence of relapse was more frequent in the high sPD-L1 (78%) than the low sPD-L1 group (50%), though the groups did not have different clinical or pathological characteristics at diagnosis. As a result, the OS and PFS for the high sPD-L1 group were significantly lower than those in the low group. PD-L1-positive tumor cells were found in 35 patients (67%), and the extent of PD-L1-postive tumor cells was positively associated with serum sPD-L1 levels (r = 0.299, P = 0.031). Among the 34 cytokines analyzed, only the serum level of IL-7 correlated with the serum level of sPD-L1 (r = 0.521, P < 0.001). CONCLUSIONS: Serum levels of sPD-L1 could reflect the expression of PD-L1 in PCNSL tumor cells and predict patient survival outcomes. Therefore, sPD-L1 in serum could be a feasible biomarker for determining a risk-adapted treatment strategy for PCNSL patients. TRIAL REGISTRATION: The study population was patients who were diagnosed with PCNSL between January 2009 and February 2017 and registered for our prospective cohort studies after providing written informed consent (ClinicalTrials.gov: NCT00822731 [date of registration - January 14, 2009] and NCT01877109 [date of registration - June 13, 2013]).


Asunto(s)
Antígeno B7-H1/sangre , Biomarcadores de Tumor , Neoplasias del Sistema Nervioso Central/sangre , Linfoma de Células B Grandes Difuso/sangre , Adulto , Anciano , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Nervioso Central/terapia , Citocinas/sangre , Femenino , Humanos , Inmunohistoquímica , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Estudios Retrospectivos , Adulto Joven
11.
Ann Hematol ; 99(9): 2095-2104, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32440790

RESUMEN

Secondary hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal condition with various underlying disorders in adult patients and is diagnosed based on the HLH-2004 criteria, which were established based on experience in pediatric patients. However, few studies have prospectively evaluated the treatment outcomes and diagnostic performance of HLH criteria in adult patients with secondary HLH. Thus, we performed a single-center, prospective cohort study of adult patients with suspected HLH, and we analyzed treatment outcomes of patients enrolled between 2017 and 2019 as an interim analysis ( ClinicalTrials.gov Identifier: NCT03117010). Of the 73 patients with suspected HLH, 70 patients completed the evaluation for ≥ 7 of the HLH-2004 criteria, and 55 patients were diagnosed with HLH (55/73, 75%). Although serum ferritin and fever had a sensitivity of more than 90%, both had exceptionally low specificity, whereas soluble CD25 had a sensitivity of more than 90% and specificity of 80%. Forty patients with malignancy-associated HLH had B cell (n = 19) or T- or NK-cell (n = 21) lymphoid malignancy, whereas 15 patients had non-malignant disorders. Non-malignancy-associated HLH had greater than 90% 1-year overall survival (OS) after diagnosis of HLH, whereas that for malignancy-associated HLH was less than 40%. In conclusion, our study showed promising treatment outcomes for patients enrolled in our prospective cohort study, and prospectively demonstrated the diagnostic performance of the HLH-2004 criteria in adult patients with suspected HLH. Given that lymphoma was the most common cause of HLH in adults, thorough evaluation for lymphoma should be performed in adults with suspected HLH.


Asunto(s)
Linfohistiocitosis Hemofagocítica/sangre , Linfohistiocitosis Hemofagocítica/diagnóstico , Admisión del Paciente/tendencias , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Prospectivos , Vincristina/administración & dosificación , Adulto Joven
12.
Ann Hematol ; 99(6): 1283-1291, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32333154

RESUMEN

Epstein-Barr virus (EBV) positivity in diffuse large B cell lymphoma (DLBCL) provokes a critical oncogenic mechanism to activate intracellular signaling by LMP1. LMP1 specifically mimics the role of BTK-dependent B cell receptor. Therefore, a trial considering RCHOP therapy along with ibrutinib (I-RCHOP) in combination was conducted among patients with EBV-positive DLBCL. This study was an open-label, single-arm, prospective multicenter phase II clinical trial. Patients received 560 mg of ibrutinib with RCHOP every 3 weeks until 6 cycles were completed or progression or unacceptable toxicity was observed. The primary endpoint was objective response, while secondary endpoints included toxicity, progression-free survival, and overall survival. A matched case-control analysis was completed to compare the efficacy and toxicity of I-RCHOP and RCHOP, respectively, in EBV-positive DLBCL patients. From September 2016 to August 2019, 24 patients proven to have EBV-positive DLBCL in the tissue were enrolled and received I-RCHOP. Their median age was 58 years (range, 28-84 years). The objective overall response was 66.7%, including 16 patients who achieved complete response after 6 cycles. Patients aged younger than 65 years presented a superior OR (87.5%) as compared with those older than 65 years (25.0%; p = 0.01). In a matched case-control study, I-RCHOP therapy provoked a more favorable complete response rate (87.3%) than did RCHOP (68.8%) in those younger than 65 years. Treatment-related mortality was linked most frequently with I-RCHOP therapy (four patients presented with unusual infection without Gr3/4 neutropenia) in the older age group (age ≥ 65 years). In conclusion, in this phase II trial for EBV-positive DLBCL, I-RCHOP was effective but did not show a significant improvement in response and survival in comparison with RCHOP. Also, I-RCHOP promoted serious toxicity and treatment-related death in older patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/epidemiología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/epidemiología , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Infecciones por Virus de Epstein-Barr/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Masculino , Persona de Mediana Edad , Piperidinas , Prednisona/administración & dosificación , Estudios Prospectivos , Rituximab/administración & dosificación , Vincristina/administración & dosificación
13.
Am J Hematol ; 95(2): 151-155, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31709579

RESUMEN

The T Cell Project was the largest prospective trial to explore the incidence, treatment patterns, and outcomes for T cell lymphomas. The rare subtypes of T cell lymphomas, including hepatosplenic T cell lymphoma (HSTCL), enteropathy associated T cell lymphoma (EATL), and peripheral gamma delta T cell lymphomas (PGDTCLs) are poorly represented in most studies and there is little data regarding treatment patterns. We report results from 115 patients with hepatosplenic (n = 31), enteropathy associated (n = 65), and PGDTCLs (n = 19). While anthracycline regimens were most commonly used as first line therapy, response rates ranged from 20%-40% and were suboptimal for all groups. Autologous stem cell transplantation was performed as a consolidation in first remission in a small number of patients (33% of HSTCL, 7% of EATL, and 12% of PGDTCL), and four patients with HSTCL underwent allogeneic stem cell transplantation in first remission. The progression free survival at 3 years ranged from 28%-40% for these rare subtypes, and the overall survival at 3 years was most favorable for PGDTCL (70%). These data highlight the need for novel treatment approaches for rare subtypes of T cell lymphomas and for their inclusion in clinical trials.


Asunto(s)
Linfoma de Células T Asociado a Enteropatía , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células T Periférico , Proteínas de Neoplasias/sangre , Receptores de Antígenos de Linfocitos T gamma-delta/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Linfoma de Células T Asociado a Enteropatía/sangre , Linfoma de Células T Asociado a Enteropatía/mortalidad , Linfoma de Células T Asociado a Enteropatía/terapia , Femenino , Humanos , Incidencia , Linfoma de Células T Periférico/sangre , Linfoma de Células T Periférico/mortalidad , Linfoma de Células T Periférico/terapia , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Trasplante Autólogo
14.
Cytokine ; 113: 371-379, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30327172

RESUMEN

To better predict the outcomes of patients with peripheral T-cell lymphoma (PTCL), we measured the levels of various cytokines in serum samples from patients with PTCL and analyzed their clinical outcomes. We measured 34 cytokines in samples from 121 PTCL patients (55 PTCL-not otherwise specified (NOS), 44 angioimmunoblastic T-cell lymphoma (AITL), and 22 ALK- anaplastic large cell lymphoma) at diagnosis. Their impact on clinical outcomes, including overall survival and complete response rate, were analyzed with other clinical variables. The median age of patients was 58 years (range, 20-85 years) and 81 patients (66.9%) were male. The median overall survival among all patients was 56.1 months (95% CI 21.4-90.8) and median progression-free survival was 19.3 months (95% CI 12.3-26.3). Patients with AITL were more likely to express higher levels of serum cytokines, and 7 cytokines showed mean levels that were significantly higher than those in other subtypes. In this subgroup, IL-10 higher than 3.8 pg/mL was associated with adverse outcomes. In patients with ALK- anaplastic large cell lymphoma, 9 cytokines showed a prognostic impact, with higher levels of interferon γ, interleukin (IL)-8, IL-10, IL-17, IL-23, IP-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1ß, and RANTES negatively affecting clinical outcomes. In PTCL-NOS, patients with elevated levels of interferon γ, IL-7, and IL-23 showed poor outcomes. The current analysis demonstrated different cytokine profiles according to histologic subtype, which revealed the heterogeneity of PTCL. In addition, cytokine levels can be used as prognostic markers and may be useful for therapeutic applications in PTCL patients.


Asunto(s)
Citocinas/sangre , Linfoma de Células T Periférico/sangre , Linfoma de Células T Periférico/mortalidad , Proteínas de Neoplasias/sangre , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de Supervivencia
15.
BMC Cancer ; 19(1): 1080, 2019 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-31707975

RESUMEN

BACKGROUND: The upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib. METHODS: Relapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD). RESULTS: We analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable. CONCLUSIONS: Ruxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification. TRIAL REGISTRATION: The study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).


Asunto(s)
Enfermedad de Hodgkin/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Neoplasias del Mediastino/tratamiento farmacológico , Pirazoles/uso terapéutico , Adulto , Anciano , Femenino , Amplificación de Genes , Enfermedad de Hodgkin/enzimología , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Linfoma de Células B Grandes Difuso/enzimología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Neoplasias del Mediastino/enzimología , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/patología , Persona de Mediana Edad , Terapia Molecular Dirigida , Nitrilos , Proyectos Piloto , Estudios Prospectivos , Pirimidinas , Tasa de Supervivencia , Resultado del Tratamiento , Adulto Joven
16.
Cancer Sci ; 109(12): 3971-3980, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30343526

RESUMEN

Vitamin D deficiency is a common health issue; however, the effect of vitamin D deficiency on the survival of T-cell lymphoma is still not clear. We evaluated the impact of serum vitamin D level of patients with peripheral T-cell lymphoma (PTCL) and extranodal natural killer/T-cell lymphoma (ENKTL) on survival outcome. Pretreatment levels of 25-hydroxyvitamin D [25(OH)D] and inflammatory cytokines were measured in serum samples that were archived at diagnosis, and we evaluated their association with survival in newly diagnosed patients with PTCL (n = 137) and ENKTL (n = 114) at a university-based hospital in Korea. An independent cohort from Rui Jin Hospital (Shanghai, China) was used for validation. The median 25(OH)D serum level was 12.0 ng/mL (1.3-60.0 ng/mL), and 40% had less than 10 ng/mL, which was defined as vitamin D deficiency. Median serum 25(OH)D levels were similar between PTCL (11.5 ng/mL) and ENKTL (12.9 ng/mL); however, vitamin D deficiency was associated with inferior survival in ENKTL but not with PTCL. The independent validation cohort (n = 115) also showed a significant association of vitamin D deficiency with poor survival in ENKTL. The 25(OH)D level had an inverse relation with inflammatory cytokines; this association had a negative effect only on survival of ENKTL, and not on PTCL. In conclusion, vitamin D deficiency was associated with inferior survival outcome of patients with ENKTL.


Asunto(s)
Linfoma Extranodal de Células NK-T/metabolismo , Linfoma de Células T Periférico/metabolismo , Deficiencia de Vitamina D/diagnóstico , Vitamina D/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Citocinas/sangre , Femenino , Hospitales Universitarios , Humanos , Linfoma Extranodal de Células NK-T/sangre , Linfoma Extranodal de Células NK-T/mortalidad , Linfoma de Células T Periférico/sangre , Linfoma de Células T Periférico/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Supervivencia , Deficiencia de Vitamina D/sangre , Adulto Joven
17.
Cancer Sci ; 109(6): 2056-2062, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29601137

RESUMEN

Prognosis of patients with localized nasal extranodal natural killer/T-cell lymphoma, nasal type (ENKL) has been improved by non-anthracycline-containing treatments such as concurrent chemoradiotherapy (CCRT). However, some patients experience early disease progression. To clarify the clinical features and outcomes of these patients, data from 165 patients with localized nasal ENKL who were diagnosed between 2000 and 2013 at 31 institutes in Japan and who received radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) were retrospectively analyzed. Progression of disease within 2 years after diagnosis (POD24) was used as the definition of early progression. An independent dataset of 60 patients with localized nasal ENKL who received CCRT at Samsung Medical Center was used in the validation analysis. POD24 was documented in 23% of patients who received RT-DeVIC and in 25% of patients in the validation cohort. Overall survival (OS) from risk-defining events of the POD24 group was inferior to that of the reference group in both cohorts (P < .00001). In the RT-DeVIC cohort, pretreatment elevated levels of serum soluble interleukin-2 receptor (sIL-2R), lactate dehydrogenase, C-reactive protein, and detectable Epstein-Barr virus DNA in peripheral blood were associated with POD24. In the validation cohort, no pretreatment clinical factor associated with POD24 was identified. Our study indicates that POD24 is a strong indicator of survival in localized ENKL, despite the different CCRT regimens adopted. In the treatment of localized nasal ENKL, POD24 is useful for identifying patients who have unmet medical needs.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Extranodal de Células NK-T/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carboplatino/administración & dosificación , Quimioradioterapia , Estudios de Cohortes , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Linfoma Extranodal de Células NK-T/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Análisis de Supervivencia , Adulto Joven
18.
Br J Haematol ; 181(6): 760-769, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29672827

RESUMEN

Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL-NOS were retained for study. At a median follow-up of 46 months, the median overall survival (OS) and progression-free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1-2), and high risk (HiR, 74 patients, 24%, score 3-4), having a 3-year OS of 76% [95% confidence interval 61-88], 43% [35-51], and 11% [4-21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes.


Asunto(s)
Linfoma de Células T Periférico/mortalidad , Modelos Biológicos , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células T Periférico/terapia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Tasa de Supervivencia
19.
Mod Pathol ; 31(9): 1418-1428, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29765142

RESUMEN

Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-κB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-κB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma.


Asunto(s)
Reordenamiento Génico , Linfoma de Células B de la Zona Marginal/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Neoplasias Gástricas/genética , Factor 3 Asociado a Receptor de TNF/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Adulto , Proteína 10 de la LLC-Linfoma de Células B/genética , Femenino , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Mutación , FN-kappa B/genética , Estadificación de Neoplasias , Estudios Retrospectivos , Transducción de Señal/genética , Neoplasias Gástricas/patología
20.
Haematologica ; 103(2): 278-287, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29097495

RESUMEN

The molecular biology of primary nodal T- and NK-cell lymphoma and its relationship with extranodal NK/T-cell lymphoma, nasal type is poorly understood. In this study, we assessed the relationship between nodal and extranodal Epstein-Barr virus-positive T/NK-cell lymphomas using gene expression profiling and copy number aberration analyses. We performed gene expression profiling and copy number aberration analysis on 66 cases of Epstein-Barr virus-associated T/NK-cell lymphoma from nodal and extranodal sites, and correlated the molecular signatures with clinicopathological features. Three distinct molecular clusters were identified with one enriched for nodal presentation and loss of 14q11.2 (TCRA loci). T/NK-cell lymphomas with a nodal presentation (nodal-group) were significantly associated with older age, lack of nasal involvement, and T-cell lineage compared to those with an extranodal presentation (extranodal-group). On multivariate analysis, nodal presentation was an independent factor associated with short survival. Comparing the molecular signatures of the nodal and extranodal groups it was seen that the former was characterized by upregulation of PD-L1 and T-cell-related genes, including CD2 and CD8, and downregulation of CD56, consistent with the CD8+/CD56-immunophenotype. PD-L1 and CD2 protein expression levels were validated using multiplexed immunofluorescence. Interestingly, nodal group lymphomas were associated with 14q11.2 loss which correlated with loss of TCR loci and T-cell origin. Overall, our results suggest that T/NK-cell lymphoma with nodal presentation is distinct and deserves to be classified separately from T/NK-cell lymphoma with extranodal presentation. Upregulation of PD-L1 indicates that it may be possible to use anti-PD1 immunotherapy in this distinctive entity. In addition, loss of 14q11.2 may be a potentially useful diagnostic marker of T-cell lineage.


Asunto(s)
Variaciones en el Número de Copia de ADN , Infecciones por Virus de Epstein-Barr , Regulación Neoplásica de la Expresión Génica , Linfoma Extranodal de Células NK-T/genética , Linfoma de Células T Periférico/genética , Adulto , Anciano , Linaje de la Célula , Cromosomas Humanos Par 14/genética , Femenino , Humanos , Linfoma Extranodal de Células NK-T/clasificación , Linfoma Extranodal de Células NK-T/virología , Linfoma de Células T Periférico/clasificación , Linfoma de Células T Periférico/virología , Masculino , Persona de Mediana Edad , Eliminación de Secuencia/genética
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