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Objective: Helicobacter pylori (Hp) and Epstein-Barr virus (EBV) are involved in gastric cancer (GC) etiology. EBV/Hp co- infection was thought synergistically increase gastroduodenal disease occurence. We aimed to determine the presence of EBV/Hp co-infection in gastroduodenal diseases. Methods: The study group had 68 Hp (+) cases [25 GC, 13 IM (intestinal metaplasia), 30 PU (peptic ulcer)], and the control group had 40 NUD (non-ulcer dyspepsia) cases [20 Hp+, 20 Hp-]. EBV-DNA was detected by non-polymorphic EBNA-1 gene-based qPCR. EBV/EBNA-1 IgG levels were determined by quantitative and qualitative ELISA methods, respectively. Results: EBV-DNA positivity was 32% (8/25), 6.6% (2/30) and 5% (1/20) in GC, PU and NUD Hp (+) cases, respectively. There was a significant difference (p = 0.001) between GC (32%) and NUD Hp (+) (5%) cases in terms of EBV-DNA positivity. Mean EBV-DNA copy numbers were 6568.54 ± 20351, 30.60 ± 159.88 and 13.85 ± 61.93 for GC, PU, and NUD, respectively. In terms of the mean EBV-DNA copy number, a significant difference was found between the groups (p = 0.005). In terms of EBV/EBNA-1 IgG antibody positivity, no significant difference was found between GC and NUD cases (p = 0.248). EBV DNA positivity was found to be significant (odds ration [OR] = 26.71 (p=0.009, %95CI 2.286- 312.041) in multivariate logistic regression. Conclusioin: Although we had a small number of GC cases, it can be suggested that the estimated risk created by the synergistic effect based on the addition of EBV increased 26 times in the presence of Hp in GC.

Objective This study aimed to describe the prevalence of Epstein-Barr virus (EBV)-DNA among children in Suzhou, and to explore the association between plasma EBV load and disease diagnosis. Methods All children admitted to the Children's Hospital of Soochow University between January 2018 and September 2020 and subjected to the plasma EBV-DNA assay were included. The authors retrospectively collected demographic and discharge diagnostic information of the participants, and ascribed the disease distribution characteristics of children with positive plasma EBV-DNA by age and viral load. Results A total of 38,175 patients underwent plasma EBV-DNA PCR assay, of which 2786 (7.3%) had EBV-DNA in their plasma. Children aged 3–4 years had a high prevalence of EBV infection. Plasma EBV positivity was common with infectious mononucleosis (IM, 40.0%), respiratory infection (20.1%), atypical EBV infection (14.2%), acute leukemia (6.4%), hemophagocytic lymphohistiocytosis (HLH, 4.8%), and idiopathic thrombocytopenic purpura (ITP, 2.9%). With increasing age, plasma EBV positivity was more common in children with IM and atypical EBV infection. However, an inverse correlation was observed in children with respiratory infections and ITP. High levels of EBV loads were more likely to occur in HLH, IM, and atypical EBV infection, especially in HLH. However, lower viral loads were found in respiratory infection and acute leukemia. Conclusions This is a large sample study that revealed the prevalence of plasma EBV-DNA levels in children of various ages and presenting illnesses.

Immunodeficiency-associated lymphoproliferative disorders are associated with latent infection by Epstein-Barr virus (EBV). Most cases of EBV-positive immunodeficiency-associated lymphoproliferative disorders arise from B cells, although some are of T-cell or natural killer origin. Cutaneous involvement is unusual and sporadically reported in the literature. We describe a rare case of an EBV-positive T-cell lymphoma presenting in the skin of a 32-year-old woman using adalimumab for neurosarcoidosis.

Monoclonal gammopathy of undetermined significance (MGUS) is associated with several autoimmune conditions, including central nervous system (CNS) vasculitis. Epstein-Barr virus (EBV) is a pathogen capable of triggering a systemic immune response and is involved in the occurrence of a wide range of B-cell lymphoproliferative disorders. In systemic autoimmune diseases, EBV infection is suspected to play a central role in pathogenesis. Here, we present a case that was thought to be a systemic autoimmune disease and CNS vasculitis that developed after EBV infection, demonstrating that rituximab is effective for the treatment.

Epstein-Barr virus (EBV) is associated with hematologic and solid tumors. In this study, we utilized a hybridization capture-based next generation sequencing (NGS) platform that targets 400 genes associated with hematological malignancies to detect and quantify non-targeted viral-derived EBV reads that aligned to the EBV reference contig (NC_007605). We evaluated 5,234 samples from 3,636 unique patients with hematological neoplasms and found that 100 samples (1.9%) in 93 unique patients had ≥ 6 EBV reads (range, 6-32,325; mean, 827.5; median, 54). The majority (n=73, 73%) represented known EBV-associated conditions, and the most common was post-transplant lymphoproliferative disorders (n=21, 29%). Documented EBV viremia accounted for a moderate quantity of EBV reads in 4/27 samples corresponding to conditions not known to be EBV-associated, while suspected viremia or low-level activation was likely the etiology in the remaining 23 samples. A good correlation (Spearman r=0.8, 95% CI 0.74-0.85) was found between EBV reads by NGS and systematic semi-quantitative EBER ISH assessment in 162 available samples, particularly at higher level of EBV-involvement. An optimal threshold for significant morphologic EBV-involvement was found to be ≥10 reads by the receiver operating characteristic (ROC) analysis (AUC 0.990 and 95% CI 0.9974-1.000%). Thus, in addition to mutational analysis, hybrid-capture-based NGS panels can be used to detect and quantitate off-target EBV-derived viral DNA, which correlates well with morphology.

Purpose: Epstein-Barr virus (EBV) is implicated in various neurological conditions. However, the relationship between EBV DNA in cerebrospinal fluid (CSF) and central nervous system (CNS) infection is unclear. We evaluated the clinical manifestation of patients with EBV DNA detected in CSF.Methods: We reviewed the medical records of patients admitted to Seoul National University Hospital from January 2000 to March 2021 who underwent EBV polymerase chain reaction (PCR) tests in CSF. The subjects were divided into positive and negative groups depending on the presence of EBV DNA, and further clinical information was obtained from positive patients.Results: CSF EBV PCR tests were performed in 807 patients, and 57 (7.1%) tested positive. Pleocytosis was common (81%) in CSF samples with EBV DNA detected, and the proportion was significantly higher than that in samples that were EBV PCR negative (44.5%, p < 0.0001). Among 57 patients with EBV DNA detected in CSF, 51 (89.5%) were diagnosed with CNS infection or inflammatory disorders. Of the 51 patients, 31 (60.8%) had possible etiologies other than EBV. Follow-up evaluation was conducted in 19 of 20 patients, and 63.2% showed a favorable outcome.Conclusion: Positive EBV PCR in CSF is mostly nonspecific and should be interpreted with caution. A comprehensive workup is needed to identify other etiologies before considering EBV as the sole culprit.

How Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) occasionally occurs following chronic inflammation remains to be elucidated. The case of a 57‐year‐old man who developed pulmonary EBV‐positive DLBCL from underlying silicosis lesions is presented. Immunohistochemical examination of the resected silicosis lesions showed predominant helper T cells and M1/M2 macrophages, with a lack of B cells, regulatory T cells, and resident memory T cells. Two years later, EBV‐positive DLBCL emerged unexpectedly from the silicosis. The imbalance of the immune cells in the microenvironment, at least in part, may help explain how chronic inflammation contributes to EBV‐positive DLBCL., The underlying silicosis lesions showed predominant Th cells and M1/M2 macrophages, with a lack of B cells, Treg cells, and TRM cells. The imbalance of the immune cells in the microenvironment, at least in part, may help to explain how chronic inflammation contributes to EBV‐positive diffuse large B‐cell lymphoma.

BACKGROUND Aggressive natural killer cell leukemia (ANKL) is a rare natural killer cell neoplasm characterized by systemic infiltration of Epstein–Barr virus and rapidly progressive clinical course. ANKL can be accompanied with hemophagocytic lymphohistiocytosis (HLH). Here, we report a case of ANKL with rare skin lesions as an earlier manifestation, accompanied with HLH, and review the literature in terms of etiology, clinical manifestation, diagnosis and treatment. CASE SUMMARY A 30-year-old woman from Northwest China presented with the clinical characteristics of jaundice, fever, erythema, splenomegaly, progressive hemocytopenia, liver failure, quantities of abnormal cells in bone marrow, and associated HLH. The immunophenotypes of abnormal cells were positive for CD2, cCD3, CD7, CD56, CD38 and negative for sCD3, CD8 and CD117. The diagnosis of ANKL complicated with HLH was confirmed. Following the initial diagnosis and supplementary treatment, the patient received chemotherapy with VDLP regimen (vincristine, daunorubicin, L-asparaginase and prednisone). However, the patient had severe adverse reactions and complication such as severe hematochezia, neutropenia, and multiple organ dysfunction syndrome, and died a few days later. CONCLUSION This is the first reported case of ANKL with rare skin lesions as an earlier manifestation and associated with HLH.

Epstein-Barr virus (EBV), discovered in 1964, is a double-stranded DNA virus belonging to the Herpesviridae family. EBV has a lymphoid tropism with transforming capacities using different oncogenic viral proteins. This virus has two replication cycles: a lytic cycle mainly occuring during primary infection and a latent cycle allowing viral persistence into host memory B cells. More than 90% of adults are seropositive for EBV worldwide, with a past history of asymptomatic or mild primary infection. EBV infection can sometimes cause life-threatening complications such as hemophagocytic lymphohistiocytosis, and lead to the development of lymphoproliferative disorders or cancers. Risk factors associated with these phenotypes have been recently described through the study of monogenic primary immune deficiencies with EBV susceptibility. We here review the virological and immunological aspects of EBV infection and EBV-related complications with an overview of current available treatments.

Background Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell lymphoma (DLBCL). Circular RNAs (circRNAs) play an essential role in lymphoma progression. However, the underlying mechanism of circRNA on DLBCL progression related to EBV remains largely unknown. Methods CircRNA was screened by high-throughput sequencing in tumor samples of 12 patients with DLBCL according to EBV infection status. Expression of circEAF2, as well as the relationship with clinical characteristics and prognosis, were further analyzed in tumor samples of 100 DLBCL patients using quantitative real-time PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of circEAF2 both in vitro and in vivo. The underlying mechanism of circRNA on DLBCL progression were further determined by RNA sequencing, RNA pull down assay, dual-luciferase reporter assay, rescue experiments and western blotting. Results We identified a novel circRNA circEAF2, which was downregulated in EBV + DLBCL and negatively correlated with EBV infection and DLBCL progression. In EBV-positive B lymphoma cells, circEAF2 overexpression induced lymphoma cell apoptosis and sensitized lymphoma cells to epirubicin. As mechanism of action, circEAF2 specifically targeted EBV-encoded miR-BART19-3p, upregulated APC, and suppressed downstream β-catenin expression, resulting in inactivation of Wnt signaling pathway and inhibition of EBV + DLBCL cell proliferation. In EBV-positive B-lymphoma murine models, xenografted tumors with circEAF2 overexpression presented decreased Ki-67 positivity, increased cell apoptosis and retarded tumor growth. Conclusions CircEAF2 counteracted EBV + DLBCL progression via miR-BART19-3p/APC/β-catenin axis, referring circEAF2 as a potential prognostic biomarker. Therapeutic targeting EBV-encoded miRNA may be a promising strategy in treating EBV-associated lymphoid malignancies.

Extra-nodal Natural killer/T cell lymphoma (ENKTL) is a well-defined and highly aggressive form of NonHodgkin’s lymphoma with a scarcity of cases reported in literature. The most common primary site of involvement is the nasal cavity followed by skin and the gastrointestinal tract (GIT). Cutaneous involvement is a rarity. More than 95% of cases are usually in association with Epstein Barr Virus (EBV) infection. EBV negative ENKTL can be similar in clinical, pathological, and prognostic characteristics with EBV positive ENKTL. This malignancy is usually characterized by its poor prognosis irrespective of clinical stage and therapy. We describe here, a 58-year-old man presenting with multiple nodular lesions over legs and trunk, had an ileal perforation later, and was diagnosed as ENKTL on the ileal biopsy specimen. This case is being reported in view of the fulminant clinical course of the disease, simultaneous involvement of the GIT and skin without nasal or midline involvement, the usefulness of immunohistochemistry in arriving at a diagnosis, and EBV negativity which is quite rare in the Asian population.

Background Since azathioprine is associated with lymphoproliferative disorders in Epstein-Barr virus (EBV)-naive patients with inflammatory bowel disease, guidelines advise avoidance. No recommendations exist for autoimmune liver disease (AILD). Aims To evaluate EBV status and EBV-related complications in paediatric AILD. Methods Single-centre, retrospective, observational study of paediatric AILD. Results In 245 paediatric patients with AILD, azathioprine was used in 168 (68.6%) and mycophenolate mofetil in 69 (28.2%). EBV status was assessed in 18 (10.7%) prior to azathioprine and 6 (8.7%) MMF. Acute EBV infection was diagnosed in five patients while on immunosuppression, resulting in one transient hepatitis and one persistent hepatitis. There were no cases of lymphoproliferative disorder in native livers. Liver transplantation (LT) was performed in 39 (15.9%) patients, with 8 EBV IgG-negative at LT. Post-LT EBV viraemia developed in 29 (74.4%), first detected at median 26 days (IQR, 13-86). EBV IgG-negative recipients had higher peak viraemia (266 984 IU/mL [IQR, 41108-2429050] v 5333 [IQR, 2036-38770], P = .004) and longer time to peak viraemia (375 days [IQR, 251-884] v 70 [IQR, 21-604], P = .04). Early EBV-associated post-transplant lymphoproliferative disorder (PTLD) was diagnosed in two patients, both EBV-IgG negative with prior azathioprine. Conclusions Real-world data demonstrate that EBV serostatus is not routinely checked before immunosuppression for paediatric AILD. Lymphoproliferative disorder was not diagnosed in those with native livers; however, EBV IgG-negative LT recipients receiving EBV IgG-positive donor organs are at risk of early PTLD. Large multicentre studies with longer follow-up are required to further evaluate the risk.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome involving an uncontrolled immune response with variable triggers. HLH is rare but highly fatal, even with proper treatment; therefore, early recognition and diagnosis are crucial for management. Although the role of F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in HLH is poorly defined, it can provide valuable information on disease status and possible triggers. Herein, we report an F-18 FDG PET/CT study on a case of NK/T-cell lymphoma that progressed from Epstein-Barr virus-associated HLH.

Natural killer (NK) cells exert anti-viral effects after haematopoietic stem cell transplantation (HSCT). The balance between inhibition and activation of NK cells determined by the inherited repertoire of killer cell immunoglobulin-like receptors (KIR) genes may influence Epstein-Barr virus (EBV) reactivation after transplantation. To evaluate the relative contributions of KIR genotypes to EBV reactivation, we prospectively enrolled 300 patients with malignant haematological disease who were suitable for haploidentical HSCT. Univariate analysis showed that donors with KIR2DS1, KIR2DS3 or KIR3DS1 genes were associated with an increased risk of EBV reactivation [hazard ratio (HR) 1·86, 95% confidence interval (CI) 1·19-2·9, P = 0·0067; HR 1·78, 95% CI 1·07-2·97, P = 0·027; HR 1·86, 95% CI 1·19-2·91, P = 0·0065 respectively]. Multivariate analysis revealed that the presence of KIR2DS1, KIR2DS3 or KIR3DS1 genes was associated with increased EBV reactivation after HSCT. This effect was more evident in the absence of the cognate ligands for the corresponding activating receptors. Our present data firstly showed that donors with activating KIR genes, specifically activating KIR2DS1, KIR2DS3 and KIR3DS1, had an increased risk of EBV reactivation. Precaution for patients whose donors carry activating genes will help prevent EBV reactivation and improve patient prognosis after HSCT.

Herpesvirus reactivation affects the clinical course and outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). Epstein-Barr virus (EBV) is a herpesvirus, which sometimes causes pos...

Epstein-Barr virus (EBV) is associated with a range of epithelial and B cell malignancies as well as autoimmune disorders, for which there are still no specific treatments or effective vaccines. Here, we isolate EBV gH/gL-specific antibodies from an EBV-infected individual. One antibody, 1D8, efficiently neutralizes EBV infection of two major target cell types, B cells and epithelial cells. In humanized mice, 1D8 provides protection against a high-dose EBV challenge by substantially reducing viral loads and associated tumor burden. Crystal structure analysis reveals that 1D8 binds to a key vulnerable interface between the D-I/D-II domains of the viral gH/gL protein, especially the D-II of the gH, thereby interfering with the gH/gL-mediated membrane fusion and binding to target cells. Overall, we identify a potent and protective neutralizing antibody capable of reducing the EBV load. The novel vulnerable site represents an attractive target that is potentially important for antibody and vaccine intervention against EBV infection., Currently, there are no treatments or vaccines against Epstein-Barr virus (EBV) infection. Here, Zhu et al. isolate gH/gL-specific antibodies from infected donors and identify 1D8, that substantially reduces infection levels in both, B- and epithelial cells, and reduces tumor burdens in EBV-challanged humanized mice due to interferance with the gH/gL-mediated membrane fusion and binding.

X-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency disorder. A 13-month-old boy was diagnosed with pure red cell aplasia (PRCA) and treated with steroid and cyclosporine. Bone marrow showed diminished erythroid precursors, and positive results for Parvovirus B19 and Cytomegalovirus (CMV) infection. A genetic study of Diamond-Blackfan anemia was negative. Five months later, he was admitted due to fever and lymphadenopathy. PCR showed still positive for the Parvovirus, CMV, and Epstein-Barr virus (EBV). He was diagnosed with diffuse large B-cell lymphoma that was positive for EBV. The patient received chemotherapy with R-CHOP, and achieved complete remission. Immunoglobulin (Ig) levels were within an age-matched normal range until the completion of chemotherapy. Subsequently, he was admitted nine times due to recurrent pneumonia and acute otitis media between two and eight years old. We reanalyzed the Ig levels and lymphocyte subsets: IgG, IgA, and IgM were 30 mg/dL, below 1.0 mg/dL, and 36 mg/dL, respectively. Lymphocyte subsets showed nearly absent CD19 (+) cells, but T- and NK cell counts were within normal ranges. A genetic study showed a hemizygous inframe deletion mutation in exon 4 of the IAP gene without the SH2D1A mutation, consistent with a XIAP deficiency. Therefore, he was diagnosed with XIAP deficiency. Genetic analysis of his mother, aunt and elder sister showed that they were carriers of the same gene mutation. He receives intravenous Ig regularly with follow-up, and still requires a low dose steroid to maintain hemoglobin level. We report XIAP deficiency as initial presentation of PRCA.

Human is the host of the Epstein-Barr virus (EBV) especially in childhood and adolescence. Most of them are asymptomatic infection and self-limiting. However, for those patients who suffer from immune dysfunction, EBV infection will be life-threatening. Epstein-Barr virus-associated hemophagocytic lymphohistocytosis (EBV-HLH) is one of the severe effects. The diagnosis and differential diagnosis of EBV-HLH and other EBV infectious diseases are mentioned in this paper. The molecular biology mechanism and complications of EBV-HLH are equally briefly presented. It also provides a practical method for the genetic diagnosis of such diseases and the differential diagnosis with other human immunodeficiency diseases for medical scientists in routine clinical practice.

Background More than 90% of the adult population globally is chronically infected by the Epstein–Barr virus (EBV). It is well established that EBV is associated with a number of malignancies, and advances in knowledge of EBV-related malignancies are being made every year. Several studies have analysed the global epidemiology and geographic distribution of EBV-related cancers. However, most have only described a single cancer type or subtype in isolation or limited their study to the three or four most common EBV-related cancers. This review will present an overview on the spectrum of cancers linked to EBV based on observations of associations and proportions in the published literature while also using these observations to estimate the incidence and mortality burden of some of these cancers. Method We have reviewed the literature on defining features, distribution and outcomes across six cancers with a relatively large EBV-related case burden: Nasopharyngeal carcinoma (NPC), Gastric carcinoma (GC), Hodgkin lymphoma (HL), Burkitt lymphoma (BL), Diffuse large B-cell lymphoma (DLBCL) and Extranodal NK/T-cell lymphoma, Nasal type (ENKTL-NT). We retrieved published region-specific EBV-related case proportions for NPC, GC, HL and BL and performed meta-analyses on pooled region-specific studies of EBV-related case proportions for DLBCL and ENKTL-NT. We match these pooled proportions with their respective regional incidence and mortality numbers retrieved from a publicly available cancer database. Additionally, we also reviewed the literature on several other less common EBV-related cancers to summarize their key characteristics herein. Conclusion We estimated that EBV-related cases from these six cancers accounted for 239,700–357,900 new cases and 137,900–208,700 deaths in 2020. This review highlights the significant global impact of EBV-related cancers and extends the spectrum of disease that could benefit from an EBV-specific therapeutic.

Few data exist on Epstein-Barr virus (EBV) prevalence across the full spectrum of lymphoma subtypes, particularly in sub-Saharan Africa. The objective of our study was to test the presence of EBV in a nationally representative sample of malignant lymphomas diagnosed in the Butaro Cancer Center of Excellence (BCCOE) in Rwanda. Of 102 Hodgkin (HL) and 378 non-Hodgkin lymphomas (NHL) diagnosed in BCCOE between 2012 and 2018, 52 HL and 207 NHL were successfully tested by EBV-encoding RNA in situ hybridization. EBV prevalence was 54% in HL, being detected in all classical HL subtypes: mixed-cellularity (n = 3/8), nodular-sclerosis (n = 7/17) and lymphocyte-rich (n = 2/3). EBV prevalence was 9% in NHL, being 10% among 158 B-cell NHL, 3% among 35 T-cell NHL and the single NK-cell NHL was EBV-positive. Among B-cell NHL, EBV was present in the majority of Burkitt (n = 8/13), and was also rarely detected in follicular (n = 1/4) and acute B-cell lymphoblastic (n = 1/45) lymphomas. Five of the 45 (11%) diffuse large B-cell lymphomas (DLBCLs) were EBV-positive, including three out of five plasmablastic lymphoma (PBL). Of 39 HL and 163 NHL of known human immunodeficiency virus (HIV) status, 2 (5%) and 14 (9%) were HIV-positive, respectively, of which only four were also EBV-positive (2 PBL, 2 HL). In summary, we report rare regional-level data on the association of EBV with classical HL, Burkitt and DLBCLs, and report sporadic detection in other subtypes possibly related to EBV. Such data inform the burden of disease caused by EBV and can help guide application of future advances in EBV-specific prevention and therapeutics.

Epstein‐Barr virus‐associated lymphoproliferative disease (EBV‐LPD) is frequently fatal. Innate immunity plays a key role in protecting against pathogens and cancers. The stimulator of interferon genes (STING) is regarded as a key adaptor protein allowing DNA sensors recognizing exogenous cytosolic DNA to activate the type I interferon signaling cascade. In terms of EBV tumorigenicity, the role of STING remains elusive. Here we showed that treatment with the STING inhibitor, C‐176, suppressed EBV‐induced transformation in peripheral blood mononuclear cells. In an EBV‐LPD mouse model, C‐176 treatment also inhibited tumor formation and prolonged survival. Treatment with B cells alone did not affect EBV transformation, but suppression of EBV‐induced transformation was observed in the presence of T cells. Even without direct B cell‐T cell contact in a transwell system, the inhibitor reduced the transformation activity, indicating that intercellular communication by humoral factors was critical to prevent EBV‐induced transformation. These findings suggest that inhibition of STING signaling pathway with C‐176 could be a new therapeutic target of EBV‐LPD., Treatment with STING inhibitor, C‐176, suppressed the tumor formation in a mouse model of EBV LPDs. Although inhibitor treatment with B cells in vitro alone did not affect EBV transformation, the suppression of EBV‐induced transformation was observed in the presence of T cells

The pathogenesis of plasmablastic lymphoma (PBL) involves the Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and MYC gene aberrations. We aimed to determine the EBV latent infection pattern and frequency of MYC gene aberrations in PBLs. Immunohistochemistry was performed using antibodies for EBNA1, EBNA2, and LMP1 while fluorescence in situ hybridization was performed using a MYC probe. The patient cohort comprised 49 adult cases (44 were HIV-positive and three were HIV-negative). Forty-one cases were EBV-positive with 11 EBNA1-positive cases, all cases EBNA2-negative, and four LMP1-positive cases. Latency 0 was determined in 29 cases, latency I in eight cases, and latency II in four cases. The MYC gene was rearranged in eight cases, showed copy number alterations in 11 cases and, no rearrangement in 11 cases. This is the largest cohort of PBLs from South Africa to show a predominantly restricted EBV latency pattern with MYC gene aberrations as a common finding.

Sporadic Burkitt lymphoma (BL) is the most frequent tumour of children and adolescents but a rare subtype of lymphomas in adults. To date most molecular data have been obtained from lymphomas arising in the young. Recently, Epstein-Barr virus (EBV) positive and negative BL in young patients was shown to differ in molecular features. In the present study, we present a large age-overarching cohort of sporadic BL (n = 162) analysed by immunohistochemistry, translocations of MYC proto-oncogene, basic helix-loop-helix transcription factor (MYC), B-cell leukaemia/lymphoma 2 (BCL2) and B-cell leukaemia/lymphoma 6 (BCL6) and by targeted sequencing. We illustrate an age-associated inter-tumoral molecular heterogeneity in this disease. Mutations affecting inhibitor of DNA binding 3, HLH protein (ID3), transcription factor 3 (TCF3) and cyclin D3 (CCND3), which are highly recurrent in paediatric BL, and expression of sex determining region Y-box transcription factor 11 (SOX11) declined with patient age at diagnosis (P = 0·0204 and P = 0·0197 respectively). In contrast, EBV was more frequently detected in adult patients (P = 0·0262). Irrespective of age, EBV-positive sporadic BL showed significantly less frequent mutations in ID3/TCF3/CCND3 (P = 0·0088) but more often mutations of G protein subunit alpha 13 (GNA13; P = 0·0368) and forkhead box O1 (FOXO1; P = 0·0044) compared to EBV-negative tumours. Our findings suggest that among sporadic BL an EBV-positive subgroup of lymphomas increases with patient age that shows distinct pathogenic features reminiscent of EBV-positive endemic BL.

Epstein-Barr virus (EBV; human herpesvirus 4; HHV-4) and Kaposi sarcoma-associated herpesvirus (KSHV; human herpesvirus 8; HHV-8) are human gammaherpesviruses that have oncogenic properties. EBV is a lymphocryptovirus, whereas HHV-8/KSHV is a rhadinovirus. As lymphotropic viruses, EBV and KSHV are associated with several lymphoproliferative diseases or plasmacytic/plasmablastic neoplasms. Interestingly, these viruses can also infect epithelial cells causing carcinomas and, in the case of KSHV, endothelial cells, causing sarcoma. EBV is associated with Burkitt lymphoma, classic Hodgkin lymphoma, nasopharyngeal carcinoma, plasmablastic lymphoma, lymphomatoid granulomatosis, leiomyosarcoma, and subsets of diffuse large B-cell lymphoma, post-transplant lymphoproliferative disorder, and gastric carcinoma. KSHV is implicated in Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman disease, and KSHV-positive diffuse large B-cell lymphoma. Pathogenesis by these two herpesviruses is intrinsically linked to viral proteins expressed during the lytic and latent lifecycles. This comprehensive review intends to provide an overview of the EBV and KSHV viral cycles, viral proteins that contribute to oncogenesis, and the current understanding of the pathogenesis and clinicopathology of their related neoplastic entities.

Hypersensitivity to mosquito bites (HMB) is a rare disease characterized by transient intense skin reaction and systemic inflammation. Clinical presentation of HMB resembles other mosquito allergic responses, and it can also be difficult to clinically distinguish HMB from other severe allergic reactions. However, a distinctive pathophysiology underlies HMB. HMB belongs to a category of Epstein-Barr virus (EBV)-associated natural killer (NK) cell lymphoproliferative disorders (LPD). Hence, HMB may progress to systemic diseases, such as hemophagocytic lymphohistiocytosis, chronic active EBV disease, and EBV-associated malignancies. A triad of elevated serum IgE, NK lymphocytosis, and detection of EBV DNA in peripheral blood is commonly observed, and identification of EBV-infected NK cells usually facilitates the diagnosis. However, the effective treatment is limited, and its precise etiology remains unknown. Local CD4+ T cell proliferation triggered by mosquito bites appears to help induce EBV reactivation and EBV-infected NK-cell proliferation. These immunological interactions may explain the transient HMB signs and symptoms and the disease progression toward malignant LPD. Further research to elucidate the mechanism of HMB is warranted for better diagnosis and treatment of HMB and other forms of EBV-associated LPD.

Schmincke described lymphoepithelioma as an undifferentiated carcinoma with abundant lymphoid stroma in the nasopharynx. Tumors with a similar histomorphology in extrapharyngeal areas have been referred to as lymphoepithelioma-like carcinoma (LELC). The association of an Ebstein-Barr virus (EBV) infection with lymphoepithelioma is well established in the nasopharynx but not so well at the extrapharyngeal sites. Only four cases of LELC have been reported in the gall bladder, of which all were negative for the EBV. This paper reports the first case of an EBV-associated mixed gall bladder carcinoma exhibiting a distinct phenotype of LELC and adenocarcinoma with mucinous differentiation. The EBV was confirmed by the strong granular membranous and cytoplasmic expression of LMP-1 (latent membrane protein-1) on immunohistochemistry and nuclear EBER RNA on chromogen in-situ hybridization in the tumor. This is the first case of LELC positive for EBV in the gall bladder. LELC has a more favorable prognosis than conventional adenocarcinoma or squamous cell carcinoma, irrespective of the site. Although a higher T stage and nodal metastasis were exceptional in the present case in contrast to the previous cases, the EBV-associated lymphocytic response might limit the disease spread and confer better overall survival and prognosis in these patients. Nevertheless, more prospective studies with a larger cohort will be needed to understand the pathogenesis, biological behavior, and prognosis of this rare entity.

Elevated Epstein-Barr virus (EBV) DNA load is common in lymphomas. However, it remains unclear whether the disparity in viral load and its prognostic value in lymphomas are correlated with Epstein-Barr encoding region (EBER) status. In this retrospective multicenter study, we collected the data of pretreatment whole blood EBV DNA (pre-EBV DNA) and EBER status and evaluated their disparity and prognostic values in lymphomas. A total of 454 lymphoma patients from December 2014 to August 2020 were retrospectively retrieved. Mann-Whitney U test, Kruskal-Wallis test and Bonferroni's adjustment were used to explore the disparity of EBV DNA and EBER status in lymphomas. Time-dependent receiver operating characteristic analysis and MaxStat analysis were used to determine optimal cutoff points of pre-EBV DNA load. Univariable and multivariable Cox proportional hazards models were established for the estimation of prognostic factors. The positive rate of EBV DNA in natural killer T-cell lymphoma (NKTL) patients was higher than that in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin lymphoma (HL) patients, and the median positive pre-EBV copy number of NKTL was also higher than that of FL and DLBCL. EBV DNA could clearly distinguish the prognosis of DLBCL, NKTL, HL and peripheral T-cell lymphoma, and the integration of EBER status and EBV DNA could differentiate the prognosis of HL patients. Multivariable results revealed that pre-EBV DNA load had an effect on the prognosis of NKTL, FL and DLBCL. The status of pre-EBV DNA and EBER were disparate. Whole blood pre-EBV DNA predicted the prognosis of lymphomas, and the combination of EBV and EBER status could differentiate the prognosis of HL.

Epstein–Barr virus (EBV)+ diffuse large B-cell lymphoma (DLBCL) has specific tumour cell characteristics, and these patients have worse outcomes than EBV-negative DLBCL patients. We compared 38 EBV+ DLBCL patients with 43 methotrexate-associated EBV+ B-cell lymphoproliferative disorders (MTX+/EBV+ BLPDs) and 30 non-germinal centre (GC) subtype DLBCL. Lymphoma cells of the EBV+ DLBCL group were positive for BCL2 in 17 patients (44.7%), CMYC in 23 patients (60.5%), and p53 in 33 patients (86.8%), which was significantly higher than in the MTX+/EBV+ BLPD group (P

Introduction: Several studies have shown an association between infection with Epstein-Barr virus (EBV) and the occurrence of many cancers in humans, including certain gastric carcinomas (GC). Indeed, recent studies have reported that 10% of CGs are associated with EBV. Materials and Methods: Samples of gastric carcinomatous tissues (biopsies and surgical specimens) were analyzed by PCR for the detection of EBV. Samples were collected retrospectively between January 2008 and December 2018. Results: during this period, 52 samples were analyzed. PCR results show the EBV infection rate to be 3.8%. Conclusion: The results obtained during this preliminary study confirm the association of EBV in 3.8% of CG cases, which is consistent with the data in the literature. Key words: EBV, gastric carcinoma, PCR.

Epstein–Barr virus (EBV) and cytomegalovirus (CMV) reactivations are common complications after allogeneic hematopoietic cell transplantation (allo-HCT), but data focusing on non–Hodgkin lymphoma (NHL) are limited. We retrospectively analyzed the prevalence of EBV and CMV reactivation post-allo-HCT and the impacts on transplant outcomes in 160 NHL patients. The 1-year incidences of EBV and CMV reactivation were 22.58% and 25.55%, respectively. Independent impactors for EBV reactivation were more than 6 lines of chemotherapy (P = 0.030), use of rituximab (P = 0.004), and neutrophil recovery within 30 days post-HCT (P = 0.022). For T-cell lymphoblastic lymphoma patients, the International Prognostic Index (IPI) (P = 0.015) and chronic GVHD (P = 0.001) increased the risk of CMV reactivation. CMV reactivation was independently related to a lower risk of relapse (P = 0.027) but higher transplant-related mortality (TRM) (P = 0.038). Although viral reactivation had no significant impact on overall survival (OS) in the whole cohort, it led to an inferior 2-year OS (67.6% versus 92.5%, P = 0.005) and TRM (20.1% versus 4.7%, P = 0.020) in recipients surviving for more than 180 days. We concluded that EBV and CMV reactivation post-allotransplant still deserved concern particularly in NHL patients with high-risk factors, since it is generally related to a deteriorated prognosis. Large-scale studies are warranted to validate our findings.

Primary infection with Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease and severe disease in patients with X-linked lymphoproliferative disease; no therapies are approved to prevent EBV infection in these patients. Hyperimmune globulin has been used to prevent some virus infections in immunocompromised persons. Here, we identified plasma donors with high titers of EBV gp350 and EBV B cell neutralizing antibodies. Pooled IgG isolated from these donors was compared to intravenous immunoglobulin (IVIG) for its ability to reduce viral load in the blood in humanized mice challenged with EBV. Mice that received EBV hyperimmune globulin had significantly reduced EBV DNA copy numbers compared to animals that received saline control; however, while animals that received EBV hyperimmune globulin had lower EBV DNA copies than those that received IVIG, the difference was not significant. Thus, while EBV hyperimmune globulin reduced viral load compared to IVIG, the effect was modest.

Epstein‐Barr virus (EBV)‐associated gastric cancer belongs to 1 of the 4 subtypes of gastric cancer and accounts for 10% of total gastric cancers. However, most cases of gastric cancer have a history of Helicobacter pylori infection. Therefore, we investigated the possibility that H. pylori infection promotes the development of EBV‐associated gastric cancer. H. pylori was exposed to principal EBV receptor, CD21, negative gastric epithelial cells, and then infected with EBV recombinant expressing enhanced green fluorescent protein. Changes in EBV infectivity due to prior H. pylori exposure were analyzed using flow cytometry. The treatment of gastric epithelial cells with H. pylori increased the efficiency of EBV infection. An increase was also observed when CagA‐deficient, VacA‐deficient, and FlaA‐deficient H. pylori strains were used, but not when cag pathogenicity island‐deficient H. pylori was used. The treatment of epithelial cells with H. pylori induced the expression of accessory EBV receptors, EphA2 and NMHC‐IIA, and increased the efficiency of EBV infection depending on their expression levels. When gastric epithelial cells were treated with EPHA2 or NMHC‐IIA siRNA, EBV infection via H. pylori attachment was decreased. The adhesion of H. pylori induced the expression of accessory EBV receptors in gastric epithelial cells and increased the efficiency of EBV infection., We investigated the possibility that H. pylori infection promotes the development of EBV‐associated gastric cancer (EBVaGC). H. pylori adheres to gastric epithelial cells and induces low‐affinity EBV receptor expression in epithelial cells. A continuous increase in the number of EBV‐infected cells is expected during life‐long gastric inflammation caused by H. pylori. Therefore, H. pylori infection is thought to increase the incidence of EBVaGC by increasing the efficiency of EBV infection.

Summary Chronic active Epstein–Barr virus (CAEBV) disease is a rare condition characterised by persistent EBV infection in previously healthy individuals. Defective EBV genomes were found in East Asian patients with CAEBV. In the present study, we sequenced 14 blood EBV samples from three UK patients with CAEBV, comparing the results with saliva CAEBV samples and other conditions. We observed EBV deletions in blood, some of which may disrupt viral replication, but not saliva in CAEBV. Deletions were lost overtime after successful treatment. These findings are compatible with CAEBV being associated with the evolution and persistence of EBV+ haematological clones that are lost on successful treatment.

Epstein–Barr virus (EBV) is a type IV herpesvirus that widely infects the vast majority of adults, and establishes a latent infection pattern in host cells to escape the clearance of immune system. The virus is intimately associated with the occurrence and progression of lymphomas and epithelial cell cancers. EBV latent membrane proteins (LMPs) can assist its immune escape by downregulating host immune response. Besides EBV, LMPs have important effects on the functions of exosomes and autophagy, which also help EBV to escape immune surveillance. These escape mechanisms may provide conditions for further development of EBV-associated tumors. In this article, we discussed the potential functions of EBV-encoded LMPs in promoting immune escape.

Objective: Epstein-Barr virus (EBV) can cause different clinical pictures from infectious mononucleosis (IM) to malignancies such as B-cell lymphomas, Burkitt’s lymphoma, nasopharyngeal carcinoma, and Hodgkin lymphoma. VCA-IgM, VCA-IgG, EBNA-1 IgG antibodies are the most commonly used antibodies in revealing the serological profile. This study aimed to examine the serological profiles of patients with suspected EBV infection and to interpret the atypical profiles encountered. Methods: The results of VCA-IgM, VCA-IgG, and EBNA-1 IgG antibodies studied in the Microbiology Laboratory between 2017-2019 were evaluated retrospectively. EBV serological tests (VCA-IgM, VCA-IgG, and EBNA-1 IgG) were performed according to the manufacturer’s recommendations using the chemiluminescent microparticle immunoassay (CMIA) method (Architect, Abbott, Wiesbaden, Germany). Results: Of the 2486 patients evaluated, 1341 (53.9%) were male, 1145 (46.1%) were female, and the average age was determined as 16.93 ± 19.5. EBV past infection was detected in 56.65% of the cases, the acute infection was detected in 17.25%, and 21.09% did not encounter EBV. Atypical serological profile was detected in 5.01%. As an atypical profile, the most common positivity of three antibodies together (3.90%), then isolated VCA-IgG positivity (0.91%), and isolated EBNA-1 IgG positivity (0.20%) were determined. It was determined that 24.24% of the cases with an atypical profile were immunosuppressive patient. Conclusions: The rate of encountering EBV in our study is 78.91%. The atypical EBV serological profile rate was found to be 5.01%. Approximately one-fourth of the cases with an atypical profile was found to be in the patient group with immune disorders. It is thought that antibody tests are not sufficient to determine the stage of infection, especially in these patient groups, and further tests should be performed. It has been demonstrated that serological monitoring is required for the interpretation of atypical profiles. Keywords: Epstein-Barr virüs, serological tests, chemiluminescent microparticle immunoassay (CMIA), atypical serological profile

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening clinical syndrome. HLH can be classified into 2 major forms: primary and secondary. Viral infections are frequently implicated in the onset of active HLH episodes. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for primary HLH and refractory/relapsed HLH after proper chemoimmunotherapy, although following immunosuppressive therapy may lead to infectious complications, including viral infections. Case Presentation We report a case of a 6-year-old boy with Epstein-Barr virus (EBV)–induced hemophagocytic lymphohistiocytosis. The patient underwent an allo-HSCT from a 10/10 HLA-matched unrelated donor. Because he received myeloablative and immunosuppressive treatment, another EBV reactivation occurred, as well as cytomegalovirus (CMV) reactivation. After antiviral therapy, on day +27, elimination of EBV and CMV was achieved. Repeated chimerism tests evaluated decreasing donor chimerism; graft-versus-host disease prophylaxis was reduced from day +32 and eventually withdrawn. Later on, the patient developed acute graft-versus-host disease (skin rush, gastrointestinal dysfunction). Immunosuppressive agents (methylprednisolone, cyclosporine) were applied once again, which led to an increase of CMV viremia and polyomavirus (BK virus) primary infection. Conclusions Virus infection can induct a severe disorder, such as HLH, and recur after its treatment. We believe our case represents dynamic changes in immunologic reaction to viral infection, which depend on modifications in treatment after allo-HSCT. These observations underscore the importance and difficulty of balancing immunosuppressive therapy and infection control.

Epstein Barr virus (EBV) related lymphoproliferative diseases may occur in immunocompromised patients or patients with a history of drug use causing immunodeficiency. EBV positive mucocutaneous ulceration in the new classification of lymphoproliferative diseases in 2016 is very rare in children. Involvement occurs in the skin, oral mucosa, and gastrointestinal system. Gastric involvement is very rare in the literature. There is no case of gastric involvement in children. There are no specified modalities in the treatment of EBV positive mucocutaneous ulceration. We presented our pediatric patient with ataxia telangiectasia who presented with abdominal pain and difficulty swallowing and diagnosed with EBV positive mucocutaneous ulceration in the stomach. We started brentuximab vedotin during the treatment process, and complete remission was achieved after 6 cures of treatment. Our patient is the first case of EBV positive mucocutaneous ulceration in the pediatric case series.

Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus with >90% of the adult population worldwide harboring latent infection. A small subset of those infected develop EBV-associated neoplasms including a range of lymphoproliferative disorders (LPD). The diagnostic distinction of these entities appears increasingly relevant as our understanding of EBV-host interactions and mechanisms of EBV-driven lymphomagenesis improves. EBV may lower the mutational threshold for malignant transformation, create potential vulnerabilities related to viral alteration of cell metabolism and allow for improved immune targeting. However, these tumors may escape immune surveillance by affecting their immune microenvironment, limiting viral gene expression or potential loss of the viral episome. Methods to manipulate the latency state of the virus to enhance immunogenicity are emerging as well as the potential to detect so-called "hit and run" cases where EBV has been lost. Finally, measurement of EBV DNA remains an important biomarker for screening and monitoring of LPD. Methods to distinguish EBV DNA derived from virions during lytic activation from latent, methylated EBV DNA present in EBV-associated neoplasms may broaden the utility of this testing, particularly in patients with compromised immune function. We will highlight some of these emerging areas relevant to the diagnosis and treatment of EBV-associated LPD with potential applicability to other EBV-associated neoplasms.

Epstein‐Barr virus (EBV) is associated with approximately 10% of gastric cancers (GCs). We previously showed that EBV infection of gastric epithelial cells induces aberrant DNA methylation in promoter regions, which causes silencing of critical tumor suppressor genes. Here, we analyzed gene expressions and active histone modifications (H3K4me3, H3K4me1, and H3K27ac) genome‐widely in EBV‐positive GC cell lines and in vitro EBV‐infected GC cell lines to elucidate the transcription factors contributing to tumorigenesis through enhancer activation. Genes associated with “signaling of WNT in cancer” were significantly enriched in EBV‐positive GC, showing increased active β‐catenin staining. Genes neighboring activated enhancers were significantly upregulated, and EHF motif was significantly enriched in these active enhancers. Higher expression of EHF in clinical EBV‐positive GC compared with normal tissue and EBV‐negative GC was confirmed by RNA‐seq using The Cancer Genome Atlas cohort, and by immunostaining using our cohort. EHF knockdown markedly inhibited cell proliferation. Moreover, there was significant enrichment of critical cancer pathway–related genes (eg, FZD5) in the downstream of EHF. EBV protein LMP2A caused upregulation of EHF via phosphorylation of STAT3. STAT3 knockdown was shown to inhibit cellular growth of EBV‐positive GC cells, and the inhibition was rescued by EHF overexpression. Our data highlighted the important role of EBV infection in gastric tumorigenesis via enhancer activation., We here analyzed the global alteration of gene expressions and active histone modifications to identify activated enhancer regions after EBV infection and to predict the master transcription factors in EBV‐positive GC. We identified that EHF was a critical transcription factor at active enhancers, which promoted cell proliferation in EBV‐positive GC. In addition, we identified its downstream target gene, FZD5, which is a potential oncogene that regulates cell growth after EBV infection.

SummaryEpstein-Barr virus (EBV) T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells, including chronic active EBV infection of T/NK-cell type (CAEBV+T/NK), EBV-associated hemophagocytic lymphohistiocytosis (EBV+HLH), extranodal NK/T-cell lymphoma of nasal type (ENKTL), and aggressive NK-cell leukemia (ANKL). However, the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown. A total of 171 nonimmunosuppressed patients with EBV+T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed. The 94 gene variants, mostly located in UNC13D, LYST, ITK, and PRF1 genes were detected, and mutations covered 28/50 (56.00%) of CAEBV-T/NK, 31/51 (60.78%) of EBV+HLH, 13/28 (46.42%) of ENKTL, and 13/48 (27.09%) of ANKL. Most mutations represented monoallelic and missense. Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations (P=0.0284, P=0.0137). Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV+T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication of both allogeneic solid organ (SOT) and hematopoietic cell transplantation (HCT). The histology of PTLD ranges from benign polyclonal lymphoproliferation to a lesion indistinguishable from classic monoclonal lymphoma. Most commonly, PTLDs are Epstein-Barr virus (EBV) positive and result from loss of immune surveillance over EBV. Treatment for PTLD differs from the treatment for typical non-Hodgkin lymphoma because prognostic factors are different, resistance to treatment is unique, and there are specific concerns for organ toxicity. While recipients of HCT have a limited time during which they are at risk for this complication, recipients of SOT have a lifelong requirement for immunosuppression, so approaches that limit compromising or help restore immune surveillance are of high interest. Furthermore, while EBV-positive and EBV-negative PTLDs are not intrinsically resistant to chemotherapy, the poor tolerance of chemotherapy in the post-transplant setting makes it essential to minimize potential treatment-related toxicities and explore alternative treatment algorithms. Therefore, reduced-toxicity approaches such as single-agent CD20 monoclonal antibodies or bortezomib, reduced dosing of standard chemotherapeutic agents, and non-chemotherapy-based approaches such as cytotoxic T cells have all been explored. Here, we review the chemotherapy and non-chemotherapy treatment landscape for PTLD.

We report a rare case of primary central nervous system (CNS) lymphoma as methotrexate-associated lymphoproliferative disorders (MTX-LPD). A 75-year-old woman who had been treated for rheumatoid arthritis (RA) with MTX for 3 years was admitted to our hospital complaining of unsteady gait, nausea, and vomiting. T2-weighted image of magnetic resonance imaging (MRI) showed multiple high intensity mass-like lesions including right lateral, frontal and temporal lobes, and right cerebellar hemisphere. We performed surgical biopsy, and the pathological and immunohistochemical examinations identified T-cell lymphoma. The tumor regressed and the symptoms were resolved soon after MTX withdrawal. Primary CNS lymphoma due to MTX-LPD is a rare disease and only eight cases including ours are reported.

Background We analyzed cell-free serum Epstein-Barr virus (EBV) DNA to identify its prognostic role in patients with newly diagnosed lymphoma. Patients and methods We retrospectively reviewed patients diagnosed with lymphoma between January 2014 and July 2020. Patients were enrolled according to the following criteria: i) pathologically confirmed lymphomas according to the World Health Organization criteria, ii) age over 18 years, iii) serum EBV DNA measurement using polymerase chain reaction prior to first-line therapy, and iv) receipt of curative standard chemotherapy. In total, 263 patients met these criteria and were included in this study. Results Serum EBV DNA was detected in 79 patients (30.0%). Patients with positive serum EBV tended to be older (P=0.090), and the proportion of T-cell lineage lymphomas was higher than that of B-cell lymphomas (P=0.003). EBV positivity was significantly associated with more advanced disease based on the Ann Arbor staging system (P=0.008) and the International Prognostic Index (P=0.009). EBV positivity was also associated with higher disease relapse (P=0.038) and death rates (P=0.005). EBV-positive lymphomas further showed inferior long-term survival outcomes in terms of progression-free survival (PFS) (P=0.053) and overall survival (OS) (P=0.014). In the subgroup analyses, serum EBV positivity was a significant prognostic factor for patients with B-cell lineage lymphomas in terms of PFS (P=0.003) and OS (P=0.033). Conclusion We demonstrated that cell-free serum EBV DNA status at the time of diagnosis has potential as a prognostic biomarker for patients with newly diagnosed malignant lymphomas.

Background Epstein–Barr virus (EBV)-associated NK/T-cell lymphoproliferative disorder (LPD) involving the gastrointestinal tract is rarely observed in individuals with normal immunity. The atypical clinical, colonoscopic manifestations often confuse clinicians, leading to misdiagnosis and delays in the treatment. Case presentation Herein, we reported on a single case of a patient with gastrointestinal symptoms. Several colonoscopies showed multiple irregular ulcerations, while biopsies showed colitis with infiltration of neutrophils or lymphocytes. After 2 months follow-up, the patient was diagnosed with the extranodal NK/T-cell lymphoma, nasal type, and was treated with thalidomide. Later on, a second check was performed on his first pathological sample. Immunohistochemistry revealed EBV associated NK/T-cell LPD. Conclusions Multiple, multiform, and segmental gastrointestinal ulcers should be an indication for EBV infection, regardless of the presence of fever, lymphadenopathy, and hepatosplenomegaly. If EBV-associated NK/T-cell LPD is considered, serum EBV-DNA should be measured, and the tissue obtained by biopsy should be carefully analyzed for a positive expression of the EBER marker.

Epstein Barr virus (EBV) is associated with a wide range of human lymphoproliferative disorders (LPD) of B, T, and natural killer (NK)-cell lineage. In children, abnormal immune response to primary EBV infection can cause peculiar forms of T/NK- cell LPD of childhood, such as the systemic form of chronic active EBV infection, hydroa vacciniforme-like LPD, severe mosquito bite allergy and systemic T cell lymphoma of childhood. In adults, dysregulation of the immune response to EBV infection, immunosenescence caused by aging, chronic inflammation in a closed space, and iatrogenic immune suppression can lead to EBV-positive LPD of diverse types involving B, T, and NK cells with unique clinical and pathological presentations. This review describes the clinical, pathological, and genetic findings of EBV-positive LPD listed in the revised 2016 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue.

BACKGROUND AND AIMS. Epstein-Barr Virus (EBV)-associated Gastric Carcinoma (EBVaGC) is the most common EBV-associated cancer and accounts for ~10% of all gastric cancers (GC). Epstein-Barr virus Nuclear Antigen 1 (EBNA1), which is critical for the replication and maintenance of the EBV latent genome, is consistently expressed in all EBVaGC tumors. We previously developed small molecule inhibitors of EBNA1. In this study, we investigated the efficacy and selectivity of an EBNA1 inhibitor in cell-based and animal xenograft models of EBV-positive and EBV-negative gastric carcinoma. METHODS. We tested the potency of an EBNA1 inhibitor, VK-1727, in vitro and in xenograft studies, using EBV-positive (SNU-719 and YCCEL1) and EBV-negative (AGS and MKN74) GC cell lines. After treatment, we analyzed cell viability, proliferation, and RNA expression of EBV genes by RT-qPCR. RESULTS. Treatment with VK-1727 selectively inhibits cell cycle progression and proliferation in vitro. In animal studies, treatment with an EBNA1 inhibitor resulted in a significant dose-dependent decrease in tumor growth in EBVaGC xenograft models, but not in EBV-negative GC xenograft studies. Gene expression analysis revealed that short term treatment in cell culture tended towards viral gene activation, while long-term treatment in animal xenografts showed a significant decrease in viral gene expression. CONCLUSIONS. EBNA1 inhibitors are potent and selective inhibitors of cell growth in tissue culture and animal models of EBV-positive GC. Long-term treatment with EBNA1 inhibitors may lead to loss of EBV in mouse xenografts. These results suggest that pharmacological targeting of EBNA1 may be an effective strategy to treat patients with EBVaGC.

Introduction Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood. Methods We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years. Clinical data were reviewed. Pathologic data including histologic types and EBV status were analyzed. Additional immunohistochemical stains, FISH studies, and TP53 gene mutational status were performed. Results 4 of 18 cases were EBV-negative. All 4 EBV-negative cases were strikingly confined to the gastrointestinal (GI) tract or abdominal lymph nodes, while tumors in EBV-positive cases were found at various anatomic sites; 2 of 4 EBV-negative cases carried mutations in TP53 gene. Our cohort also included 2 rare types of PTLD, one plasmablastic lymphoma and one high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). Conclusion We report that monomorphic B-cell PTLDs in children have distinctive clinical and pathological features. More studies are needed to clarify whether and how much these pediatric PTLDs differ from their adult counterparts.

Objective To molecularly characterise the relationship between Epstein-Barr virus (EBV) genotypes and Pashtun ethnicity. Methods The cross-sectional study was conducted from November 2018 to December 2019 after approval from the Gomal University, Dera Ismail Khan, Pakistan, and comprised blood samples from transgender sex workers who were seropositive for human immunodeficiency virus-1 and seronegative for human immunodeficiency virus residing in two cities of Khyber Pakhtunkhwa province and Islamabad, the federal capital. Formalin-fixed paraffin-embedded (FFPE). Samples were collected from the partner institute along with the patients data, but without any follow-up from the study subjects which was purely on the basis of physical availability. β-globin gene and EBER-1(EBV encoded small RNA-1) were amplified for qualitative assessment and existence of Epstein-Barr virus. Characterisation of EBNA-2 (EBV Nuclear Antigen-2 was done through nested polymerase chain reaction. Results Of the 80 subjects, 40(50%) each were seropositive and seronegative individuals. The overall mean age was 28±6.917 years. Among the seropositive group, 38(95%) were homosexual and 2(5%) were heterosexual. Among the seropositive group, 16(40%) had Epstein-Barr virus genotype 1 and 6(15%) had genotype 2, while co-infections were found in 2(5%) subjects. In the seronegative group, 36(90%) subjects had Epstein-Barr virus genotype 1, while there was no case of genotype 2 or co-infection. EBV-2 genotypes with HIV seropositivity showed strong association (p=0.005). Amplification for the EBER-1 gene was done in all the 80(100%) samples. Conclusions Epstein-Barr virus EBV genotype 1 was found to be the most frequent type, while genotype 2 and co-infections were detected in only seropositive samples.

We report the clinical and histopathological features of hydroa vacciniforme-like lymphoproliferative disorder in five indigenous and Mestizo children. All the children resided at higher altitudes, experiencing maximal solar exposure. All cases presented with prurigo along with Epstein-Barr virus infection. Histopathologic examination showed an atypical, CD30 + lymphocytic infiltrate with angiocentricity in all, while three cases demonstrated panniculitis-like infiltrate.

Primary immunodeficiencies in the costimulatory molecule CD27 and its ligand, CD70, predispose for pathologies of uncontrolled Epstein-Barr virus (EBV) infection in nearly all affected patients. We demonstrate that both depletion of CD27+ cells and antibody blocking of CD27 interaction with CD70 cause uncontrolled EBV infection in mice with reconstituted human immune system components. While overall CD8+ T-cell expansion and composition are unaltered after antibody blocking of CD27, only some EBV-specific CD8+ T-cell responses, exemplified by early lytic EBV antigen BMLF1-specific CD8+ T cells, are inhibited in their proliferation and killing of EBV-transformed B cells. This suggests that CD27 is not required for all CD8+ T-cell expansions and cytotoxicity but is required for a subset of CD8+ T-cell responses that protect us from EBV pathology.