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The aggressive lymphoma, extranodal natural killer/T-cell lymphoma-nasal type, is strongly associated with Epstein-Barr virus (EBV) and is most common in Asia and in South and Central America. By contrast, incidence is low in the United States and Europe, where extranodal natural killer/T-cell lymphoma represents only 0.2%-0.4% of all newly diagnos...
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Context 1
... the past, the International Prognostic Index and NK/T-cell lymphoma prognostic index were used for risk stratification. Following the introduction of nonanthracycline containing treatment regimens, these scoring systems were no longer adequate, and in 2016 the prognostic index of natural killer lymphoma (PINK) was introduced (Table 1). 17 This new scoring system attributes 1 point for every risk factor, and a modification of the PINK score is the prognostic index of natural killer lymphoma-EBV score that includes all factors from the PINK score together with EBV plasma load. ...Similar publications
The objectives of the study were to utilize tumor size data from 10 Phase II/III atezolizumab studies across five solid tumor types to estimate tumor growth inhibition (TGI) metrics and assess the impact of TGI metrics and baseline prognostic factors on overall survival (OS) for each tumor type. TGI metrics were estimated from bi‐exponential models...
Citations
... nose, nasal passages or paranasal sinuses [9][10][11][12]. Several studies have demonstrated that NKTCL is strongly associated with the infection of EBV [13,14]. ...
... The main therapeutic treatments for NKTCL include systemic chemotherapy, for examples, A-CHOP regimen (asparaginase, cyclophosphamide, doxorubicin, vincristine, prednisone), whereas external beam radiation therapy combined with concurrent chemotherapy was prescribed for localized NKTCL [8,[15][16][17][18]. Although asparaginase-based therapy has been demonstrated to increase response rate and clinical outcomes than conventional systemic chemotherapy for NKTCL, certain patients with NKTCL experienced recurrence or developed drug resistances [6,9,19]. Due to the poor prognosis of NKTCL despite the use of current treatment modalities, it is urgent to investigate the ...
... In contrast to our novel findings on the CNVs, the SNVs detected in our NKTCL subjects were in large part similar to previous studies in terms of gene identities and the functional pathways they mapped to, but with large variation in the mutation frequencies when compared to other cohorts [24,[26][27][28][29][30][31]45]. Consistent with large studies on Chinese subjects of NKTCL [24,31], we identified that recurrent mutations of JAK3 (8/36, 22%), JAK1 (17%), STAT3 which advances treatment response in about half of the patients but eventually fails in the relapse of resistant or refractory disease [4,6,9,40]. In our cohort of NKTCL, of whom most received L-asparaginase, the combined clinical factor, stage III and IV, and molecular factor, copy loss of LIFR gene, predicted the worse prognosis of this subtype of disease. ...
The molecular pathogenesis of extranodal NK/T-cell lymphoma (NKTCL) remains obscured despite the next-generation sequencing (NGS) studies explored on ever larger cohorts in the last decade. We addressed the highly variable mutation frequencies reported among previous studies with comprehensive amplicon coverage and enhanced sequencing depth to achieve higher genomic resolution for novel genetic discovery and comparative mutational profiling of the oncogenesis of NKTCL. Targeted exome sequencing was conducted to interrogate 415 cancer-related genes in a cohort of 36 patients with NKTCL, and a total of 548 single nucleotide variants (SNVs) and 600 Copy number variances (CNVs) were identified. Recurrent amplification of the MCL1 (67%) and PIM1 (56%) genes was detected in a dominant majority of patients in our cohort. Functional mapping of genetic aberrations revealed that an enrichment of mutations in the JAK-STAT signaling pathway, including the cytokine receptor LIFR (copy number loss) upstream of JAK3, STAT3 (activating SNVs), and downstream effectors of MYC, PIM1 and MCL1 (copy number gains). RNA in situ hybridization showed the significant consistence of MCL1 RNA level and copy number of MCL1 gene. We further correlated molecular and clinical parameters with overall survival (OS) of these patients. When correlations were analyzed by univariate followed by multivariate modelling, only copy number loss of LIFR gene and stage (III-IV) were independent prognostic factors of reduced OS. Our findings identified that novel loss of LIFR gene significantly correlated with the adverse clinical outcome of NKTCL patients and provided therapeutic opportunities for this disease through manipulating LIFR.
... A biopsy is necessary to confirm the diagnosis using microscopy, immunohistochemistry, and Epstein -Barr encoding region (EBER) in situ hybridization [8]. Histopathologically, ENKTCL features variable sizes of atypical lymphocytes with plasmocytes, eosinophils, histiocytes [2] [3] [4] [7] and the presence of angiodestruction and angiocentricity [1] - [5] [7] [9]. The diagnosis is further reinforced with the presence of EBV by in situ hybridization as EBV has been implicated in disease pathogenesis [2] [5] - [9]. ...
... Histopathologically, ENKTCL features variable sizes of atypical lymphocytes with plasmocytes, eosinophils, histiocytes [2] [3] [4] [7] and the presence of angiodestruction and angiocentricity [1] - [5] [7] [9]. The diagnosis is further reinforced with the presence of EBV by in situ hybridization as EBV has been implicated in disease pathogenesis [2] [5] - [9]. High proliferation rate (Ki -67>60%) predicts a poorer prognosis. ...
... Immunohistochemistry, the natural killer (NK) cell marker CD56 and cytotoxic markers granzyme B and TIA -1 are expressed and detectable. T -cell markers demonstrates positive for CD2, cytoplasmic CD3+ and surface CD3 -ve [2] - [5] [7] [9]. T -cell markers CD4, CD8, CD5 and CD 7 are usually negative [2] [7] [9]. ...
Extranodal NK/T-cell Lymphoma of nasal type is a rare and highly aggressive subtype of non-Hodgkin lymphoma, closely associated with the Epstein-Barr virus. It exhibits a poor prognosis and limited responsiveness to available treatments irrespective of clinical stage and therapy. We report a case of a 54 years old gentleman who presented to the hospital after being unwell for one week. Histology study revealed lymphoma cells which are polymorphous, admixed with small lymphocytes, angiocentric growth invasion and positive immunohistochemistry for CD2, CD 56, cytoplasmic CD3+, surface CD3−ve. Patient was referred for further treatment however, died while ongoing treatment. This case study adds valuable insights into the clinical presentation, diagnosis, and challenges in managing Extranodal NKT-Cell Lymphoma, emphasizing the need for increased awareness and research in this area.
... To determine whether daratumumab treatment altered the clonal identity of B cells, a representative subgroup of 13 patients, including 2 responders and 2 nonresponders with post-treatment PBMC samples, underwent BCR and TCR sequencing. Since EBV-encoded RNA in situ hybridization positivity is a diagnostic criteria of NKTCL [34], we hypothesized that responders could have large numbers of baseline EBV-targeting B clones directed against the underlying EBV infection and would have a less diverse BCR repertoire. Sequencing of BCR IGH and TCRβ locus revealed lower BCR clonality in responders (measured by Simpson clonality), whereas TCR clonality was not affected (Fig. 5a). ...
Natural killer/T cell lymphoma (NKTCL) is a highly aggressive, heterogeneous non-Hodgkin lymphoma resulting from malignant proliferation of cytotoxic natural killer (NK) or T cells. Previous studies demonstrated variable expression of CD38 on NKTCL tumors. Daratumumab, a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, was hypothesized to be a novel therapeutic option for patients with relapsed or refractory (R/R) NKTCL. In the phase 2 NKT2001 study (ClinicalTrials.gov Identifier: NCT02927925) assessing the safety and efficacy of daratumumab, a suboptimal overall response rate was seen in R/R NKTCL patients. One patient, whose tumors did not express CD38, responded to treatment, suggesting that the immunomodulatory activities of daratumumab may be sufficient to confer clinical benefit. To understand the suboptimal response rate and short duration of response, we investigated the immune profile of NKTCL patients from NKT2001 in the context of daratumumab anti-tumor activity. Tumor tissue and whole blood were, respectively, analyzed for CD38 expression and patient immune landscapes, which were assessed via cytometry by time-of-flight (CyTOF), multiparameter flow cytometry (MPFC), clonal sequencing, and plasma Epstein-Barr virus (EBV)-DNA level measurements. Changes observed in the immune profiles of NKTCL patients from NKT2001, including differences in B and T cell populations between responders and nonresponders, suggest that modulation of the immune environment is crucial for daratumumab anti-tumor activities in NKTCL. In conclusion, these findings highlight that the clinical benefit of daratumumab in NKTCL may be enriched by B/T cell–related biomarkers.
... 17 While treatments vary based on the patient's status, pegaspargase/L-asparaginase-based regimens are currently first-line options for ENKTL patients. [18][19][20][21][22] However, there are still newly diagnosed patients experiencing disease progression, and the prognosis in patients with relapsed or refractory ENKTL remains unsatisfactory. 23 More effective treatment approaches deserve further exploration. ...
Background
The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T‐cell lymphoma (ENKTL) are considered to be different. However, the underlying features responsible for these differences are not well clarified especially in the era of asparaginase therapy.
Methods
In total, 1007 newly diagnosed ENKTL patients from 11 medical centers were included in this study. Clinicopathologic characteristics and survival data were collected. The chi‐squared test and Kruskal–Wallis test were utilized for the comparison of different groups. Univariable and multivariable Cox proportional hazards models were used to screen prognostic factors.
Results
Overall, 869 (86.3%) patients were nasal forms. Compared to patients with nasal ENKTL, nonnasal patients were at more advanced stages and had poor performance status, bone marrow involvement, elevated serum lactate dehydrogenase (LDH), and CD56‐negative status ( p < 0.05). The 5‐year overall survival (OS) for nasal and nonnasal patients were 65.6% and 45.0%, respectively. The OS of nasal forms patients were superior to nonnasal patients, especially in Eastern Cooperative Oncology Group performance status (ECOG PS) (≥2), advanced stage, KPI (HIR/HR), IPI (HIR/HR), PINK (HR), and high EBV DNA load groups. In patients treated with pegaspargase/L‐asparaginase‐based regimens, the OS of nasal patients was better than that of nonnasal patients. After adjusting the covariates of age, stage, ECOG PS score, LDH, B symptoms, and BM involvement, results showed that the nonnasal site was associated with poor survival of ENKTL.
Conclusions
The clinicopathologic characteristics and prognosis of nasal and nonnasal ENKTL patients are different. Nasal forms patients had superior OS than nonnasal patients, especially in the era of asparaginase.
... Extranodal natural killer /T cell lymphoma, nasal type (ENKTL-NT) is a distinct subtype of non-Hodgkin's lymphoma (NHL) and characterized by Epstein-Barr virus infection and clinical aggressiveness [1], mainly involving the nasal cavity and nasopharynx [2]. This lymphoma shows a prevalence in Asia and South America [2], accounting for more than 10% of all NHL cases [1], but is relatively rare in North America and Europe [3]. ...
... Extranodal natural killer /T cell lymphoma, nasal type (ENKTL-NT) is a distinct subtype of non-Hodgkin's lymphoma (NHL) and characterized by Epstein-Barr virus infection and clinical aggressiveness [1], mainly involving the nasal cavity and nasopharynx [2]. This lymphoma shows a prevalence in Asia and South America [2], accounting for more than 10% of all NHL cases [1], but is relatively rare in North America and Europe [3]. The prognosis for ENKTCL-NT has traditionally been considered poor, with a 5-year OS rate of less than 50% [3], regardless of stage or treatment [4,5]. ...
Sarcopenia is known to be associated with an increased risk of adverse outcomes in a variety of malignancies, but its impact in extranodal natural killer/T cell lymphoma, nasal type (ENKTL-NT) is unknown. The aim of this study was to explore the prognostic relevance of sarcopenia defined by MRI-based masticatory muscle index in ENKTL-NT patients. A total of 112 patients with newly diagnosed ENKTL-NT who underwent cranial magnetic resonance imaging (MRI) were enrolled. The masticatory skeletal muscle index (M-SMI) was measured based on T2-weighted MR images and sarcopenia was defined by M-SMI<5.5 cm2/ m2. The median M-SMI was 5.47 (4.91–5.96) cm2/m2; 58 were identified with sarcopenia in this cohort. On multivariate analyses, sarcopenia was the only independently risk factor predicting overall survival (HR, 4.590; 95% CI, 1.657–12.715; p = 0.003), progression-free survival (HR, 3.048; 95% CI, 1.515–6.130; p = 0.002), and treatment response (HR, 0.112; 95% CI, 0.042–0.301; p < 0.001). In addition, we found that integrating sarcopenia into prognostic indices could improve the discriminative power of the corresponding original model. Stratification analysis showed that sarcopenia was able to further identify survival differences in patients that could not be distinguished by prognostic models. In summary, our study suggests that sarcopenia defined by MRI-based M-SMI represents a new and routinely applicable prognostic indicator of clinical outcome or predictor of treatment response in ENKTL-NT patients, and may aid in risk stratification and treatment decisions.
... There is currently no standard chemotherapy regimen for the management of ENKTCL. Clinically, ENKTCL is managed by radiation +/-chemotherapy in stage I/II, and by chemotherapy +/-radiotherapy and autologous hematopoietic stem cell transplantation (ASCT) in stage III/IV [5]. Research has shown that radiotherapy provided an enrichment in the 5year overall survival (OS) by 48 % in patients who received chemotherapy only [6]. ...
Purpose: To evaluate the effect of baicalin on the proliferation of extranodal NK/T-cell lymphoma cells and the sensitivity of the cells to the drug. Methods: Cell-counting-kit (CCK) assay was used to determine cell activity, while the antagonistic, superimposed and synergistic effects of drug combinations were investigated by coefficient of drug interaction (CDI). Cell proliferation was assessed using 5-ethynyl-2’- deoxyuridine (EdU) test. Flow cytometry was carried out to determine the apoptosis of studied extranodal NK/T-cell lymphoma cells. Furthermore, western-blot was used to evaluate the expression levels of BCL2, BAX, cleaved-caspase3 and caspase3 of the cells. Results: Survival of SNK-6 and YTS cells decreased gradually in a concentration-dependent manner (r = -0.97 and -0.98). Cell viability at the same concentration diminished with time, but with increase in cisplatin concentration, cell viability at the same time point also decreased. At cisplatin concentrations of 5, 10, and 20 μmol/L, reduction in cell viability between the two groups were significantly different (p < 0.001). Furthermore, the proliferation of SNK-6 and YTS cells decreased with increasing baicalin concentrations while apoptosis of the cells increased with increasing baicalin concentration. Conclusion: Baicalin inhibits the proliferation but promotes the apoptosis of SNK-6 and YTS cells. Cisplatin plus baicalin lowers cell proliferation rate and increase the apoptosis rate of both SNK-6 and YTS cells compared with baicalin or cisplatin alone. This drug combination should be further explored for its apoptosis potential in animal models.
... Extranodal natural killer/T-cell lymphoma (NKTL) is an Epstein-Barr virus (EBV) associated, aggressive non-Hodgkin lymphoma (NHL) that is predominantly localizes to the upper aerodigestive tract but can involve non-nasal sites [1,2]. The incidence of NKTL shows a significant ethnic and geographic predilection, constituting approximate 10% of NHL in Asia and South America, but only 1% in North America and Western Europe [1,2]. ...
... Extranodal natural killer/T-cell lymphoma (NKTL) is an Epstein-Barr virus (EBV) associated, aggressive non-Hodgkin lymphoma (NHL) that is predominantly localizes to the upper aerodigestive tract but can involve non-nasal sites [1,2]. The incidence of NKTL shows a significant ethnic and geographic predilection, constituting approximate 10% of NHL in Asia and South America, but only 1% in North America and Western Europe [1,2]. Combined chemotherapy-radiotherapy is standard treatment for NKTL patients, but often associated with high relapse rate and serious side effects [3]. ...
Background:
Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL.
Methods:
We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo.
Results:
SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2, were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis.
Conclusions:
Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic.
... Se estima una supervivencia menor a los 5 meses en pacientes bajo tratamiento de segunda línea o en estadios avanzados. (4,5) Una de las principales razones del retraso en el diagnóstico del paciente presentado fue la implementación de un tratamiento inmunomodulador y antibiótico para la sinusopatía y egreso hospitalario por leve mejoría de los síntomas, pero hubo progreso de la enfermedad neoplásica. ...
... Se evidencia un crecimiento angiodestructivo con áreas de necrosis e infiltración linfocítica, conocida como reticulosis polimórfica. (4,5,7,8) Estos tumores muestran positividad para los marcadores de inmunohistoquímica CD2+, CD56+ y CD3ε+ citoplasmático. (8) El diagnóstico temprano de de los LTNE de tipo nasal permite la posibilidad de resección quirúrgica, sin embargo, en estadios en los cuales se dificulta la intervención quirúrgica se puede lograr un adecuado control local, con radioterapia junto con quimioterapia. ...
... (8) El diagnóstico temprano de de los LTNE de tipo nasal permite la posibilidad de resección quirúrgica, sin embargo, en estadios en los cuales se dificulta la intervención quirúrgica se puede lograr un adecuado control local, con radioterapia junto con quimioterapia. (4,8,9) En este caso, únicamente se realiza una intervención quirúrgica para la toma de la biopsia de las lesiones nasales y el traslado a un centro de atención médica especializada para su tratamiento complementario. ...
Introducción:
El linfoma de células T citotóxico/natural killer extranodal de tipo nasal es poco frecuente, pero con alta tasa de mortalidad. Las manifestaciones clínicas de la enfermedad pueden simular una infección de senos paranasales.
Objetivo:
Presentar las manifestaciones clínicas de un paciente de 34 años de edad con diagnóstico de linfoma de células T citotóxico/natural killer extranodal de tipo nasal.
Caso clínico:
Se presenta un paciente masculino de 34 años de edad con rinorrea verdosa fétida recurrente y obstrucción en fosa nasal derecha. En la evaluación inicial sugiere sinusitis crónica, sin embargo, debido al empeoramiento de las manifestaciones clínicas se realiza una tomografía computarizada que muestra lesiones sugestivas de infiltración neoplásica, una biopsia de la lesión confirma el diagnóstico de linfoma de células T/natural killer extranodal de tipo nasal.
Conclusiones:
Los linfomas de células T citotóxico/natural killer extranodal de tipo nasal son considerados neoplasias poco frecuentes, caracterizadas por el patrón rápidamente progresivo con afectación ósea; en su etapa inicial presenta manifestaciones clínicas similares a una sinusitis. La tomografía computarizada y la histopatología, son indispensables en el diagnóstico de la enfermedad.
... Extranodal NK/T-cell lymphoma (ENKTL) is a rare extranodal non-Hodgkin lymphoma (NHL) that primarily occurs in the upper aerodigestive tract and has an aggressive presentation, with locoregional invasion in the nasopharynx causing necrosis, hemorrhage, and impingement on anatomic structures including the orbits [1][2][3]. The incidence of ENKTL is much higher in East Asia and Latin America than in Europe and North America, representing up to 15% of all NHL diagnoses, likely due to underlying geodemographic differences in human leukocyte antigen (HLA) genes and genetic susceptibility [4][5][6][7]. ...
Simple Summary
Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive blood cancer with poor survival rates, particularly for patients with advanced-stage and relapsed disease. Emerging research on the genetic and molecular causes of ENKTL have revealed new potential treatment strategies. In this review, we summarize how research on the biological causes of ENKTL has translated to new targets for the treatment of ENKTL, as well as the identification of new bi-omarkers which may predict prognosis and responses to specific anti-cancer therapies and enable a personalized medicine approach towards ENKTL therapy.
Abstract
Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated oncogenesis. In addition, we highlight prognostic and predictive biomarkers which may enable a personalized medicine approach toward ENKTL therapy.
... Studies have shown that high pretreatment PEDL is a poor prognostic marker in HIV-associated, EBV-negative diffuse large B cell lymphoma (DLBCL) [8]. Additionally, during treatment and follow-up, PEDL should also be monitored as a marker of extranodal natural killer/T cell lymphoma (ENK-TCL) [9]. Researches have reported that DLBCL and peripheral T cell lymphomas (PTCL) are most often associated with detectable PEDL [10]. ...
... Studies also reported that high PEDL was an adverse prognostic marker for patients with DLBCL [8]. Previous studies concluded that serial measurement of PEDL was strongly recommended [9], as any sign of an increase in PEDL indicated that relapse was inventible, even when a patient had been in remission for years [24]. However, so far, we have found no reports on the relationship between EBER status and the duration of dynamic PEDL changes among lymphoma patients during early lymphoma treatment. ...
The relationship between plasma EBV-DNA load (PEDL) and Epstein–Barr virus (EBV)-encoded small RNA (EBER) during the early treatment of lymphoma remains unclear. We explored discrepancies in PEDL and variables associated with EBER and evaluated the consistency between EBER and qualitative analysis of PEDL (qPEDL). Serial measurements of PEDL were performed to determine the dynamic changes of PEDL in early treatment of lymphoma. As a result, the median PEDL of non-Hodgkin’s lymphoma NKT cell subtype (NHL-NKT) was higher than that of non-Hodgkin’s lymphoma B cell subtype (NHL-B), the median PEDL of extranodal NK/T cell lymphoma (ENKTCL) was higher than that of diffuse large B cell lymphoma (DLBCL), and the median PEDL of EBER positive was higher than that of EBER negative. Age, Ki-67 ≧ 80%, Bcl-2 ≧ 80%, p53, and qPEDL were related to EBER. The PEDL could distinguish NHL-B, DLBCL, NHL-NKT, and ENKTCL from other lymphoma subtypes. EBER-positive patients spent more time with viral “turn negative (TN)” and “continuous positive (CP)” and less time with viral “continuous negative (CN).” The median PEDL of CP was higher than that of TN. In conclusion, although EBER affects the levels of PEDL in general, it has poor concordance with qPEDL. Our results show, for the first time, that high PEDL and positive EBER present a strong association with viral recurrence and persistent infection in the early treatment of lymphoma.
