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Lymphadenopathy is observed in 55% of children under the age of 10 years and the most often it has a bacterial or viral etiology, but it also can manifest as lymphoproliferative diseases or lymphomas. Lymphoproliferative diseases are characterized by uncontrolled growth of lymphocytes with the development of monoclonal lymphocytosis, lymphadenopathy and bone marrow infiltration. Since the Epstein-Barr virus (EBV) has oncogenic potential, it is essential for doctors to be vigilant about generalized persistent lymphadenopathy on the background of chronic persistent Epstein-Barr infection. The purpose of the article is to increase the awareness of doctors of various specialties about the risk of developing EBV-associated lymphoproliferative diseases in children with generalized persistent lymphadenopathy using the example of a clinical case discussion. The article describes a clinical case of a 14-year-old patient with persistent lymphadenopathy on the background of chronic Epstein-Barr infection. Immunohistochemical study of the lymph node biopsy revealed reactive hyperplasia with expressed immune blast transformation, the presence of CD30-positive cells while excluding Hodgkin lymphoma. It is recommended to involve a multidisciplinary team to prescribe appropriate antiviral therapy, regularly monitor the clinical course, dynamics of laboratory and immunological indicators. The result of the study is the recommendation to repeat biopsy in the absence of positive dynamics in patients with persistent Epstein-Barr infection and lymphadenopathy.

Matteo Bellia, Mariangela Greco, Monia Lunghi, Riccardo Moia, Gianluca Gaidano, Andrea Patriarca Department of Translational Medicine, Division of Hematology, Universita’ del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, 28100, ItalyCorrespondence: Matteo Bellia, Department of Translational Medicine, Division of Hematology, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, Via Solaroli 17, Novara, 28100, Italy, Tel +39-346-5988355, Email matteo.bellia@uniupo.itBackground: Jaundice and hyperbilirubinemia are common clinical problems characterized by the presence of bile pigments in the blood and their deposition in body tissues. This clinical condition can be associated with a broad spectrum of potential benign and malignant causes, including hepatic inflammation, biliary obstruction, impaired bilirubin conjugation and bilirubin overproduction Therefore, the hyperbilirubinemia diagnostic work-up sometimes can be highly challenging and its therapeutic management can require a multidisciplinary approach.Case Report: We report on a unique case of life-threatening jaundice and hepatic failure in a 20-year-old female who presented to the emergency room with complaints of fever, constant left abdominal pain and generalized profuse fatigue. A complete and detailed medical history, multiple tests for various infection, radiologic investigations and histological tests were performed in order to clarify the etiology of that rapidly progressive clinical condition. Based on the results, the patient jaundice was caused by an Epstein-Barr virus (EBV) infection and secondary cold agglutinin syndrome. Given the rare and complex diagnosis, multiple clinical specialists were asked to carry out the best patient management.Conclusion: This rare case highlights how challenging the differential diagnosis and treatment of hyperbilirubinemia can be, presenting a unique case of life-threatening multifactorial hepatic failure treated successfully with rituximab.Keywords: jaundice, Epstein-Barr virus infection, secondary cold agglutinin syndrome, rituximab

Sergiy Kramarov,1 Vitalii Yevtushenko,1 Iryna Seriakova,1 Oleksandr Voronov,1 Nataliia Kyrytsia,1 Liudmyla Vladislavivna Zakordonets,1 Valerii Shadrin,1 Claudia Shatrova,2 Nataliia Savostikova,3 Volodymyr Zhezhera3 1Department of Pediatric Infectious Diseases, Bogomolets National Medical University, Kyiv, Ukraine; 2Department of Morphology, Clinical Pathology and Forensic Medicine, Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine; 3Сhildren’s Pathology Department, National Specialized Children’s Hospital Ministry of Health of Ukraine, Kyiv, UkraineCorrespondence: Iryna Seriakova, Assistant of the Department of Pediatric Infectious Diseases, Bogomolets National Medical University, Degtyarivska Street, 23, Kyiv, 04119, Ukraine, Email ikovaliukh@ukr.netBackground: Fulminant hepatitis is a rare and severe form of acute liver failure (ALF) characterized by rapid and massive destruction of liver cells and associated with a high mortality rate. Infectious factors, in particular viral hepatitis, take a prominent place in the etiology of ALF, however, the presence of chronic liver pathology can play a significant role in the disease progression and development of ALF.Case Presentation: A 2-year-old child was hospitalized on the 4th day of the disease with manifestations of jaundice and general intoxication. The examination revealed markers of active hepatitis A virus infection and Epstein-Barr virus infection. From the seventh day of the disease, the child’s condition began to progressively deteriorate due to manifestations of ALF. Despite the use of immunomodulatory and replacement therapy, the disease ended fatally on the 9th day. Pathohistological examination revealed manifestations of viral necrotic hepatitis on the background of autoimmune sclerosing cholangitis.Conclusion: The case is novel as regards the occurrence of two viral hepatitis with different modes of transmission on a background of unidentified liver disease.Keywords: acute liver failure, fulminant hepatitis, viral hepatitis A, Epstein-Barr virus infection, children

Background and Objectives: Gastric cancer (GC) is the third most common cause of cancer-related mortality. Epstein-Barr virus (EBV) is associated with several human tumors. The present research was performed to investigate the prevalence of EBV-associated gastric cancer (EBVaGC) among Iranian patients. Materials and Methods: Seventy cases of gastric cancer and 30 cases of gastric ulcer, all preserved in formalin-fixed paraffin-embedded (FFPE), were examined in a case-control study conducted between 2011 and 2018. The specimens underwent analysis to detect the presence of the EBV genome using a Nested-PCR method targeting EBNA1. Subsequently, samples testing positive for the EBNA1 underwent further testing for the presence of the EBER gene using PCR. Finally, Positive samples were subjected to sequencing. Results: Five out of 70 cases (7%) were found to be positive for EBV based on EBNA1 testing, while all EBNA1 positive samples were negative for EBER. Notably, EBV was not detected in patients with gastric ulcer. The mean age of EBV-positive gastric carcinomas pateints was 64.5 years. Within this group, 60% were male and 40% were female. A higher prevalence of EBV association was observed in diffuse-type cases, with 60% (3 out of 24) testing positive, compared to intestinal-type cases where 40% (2 out of 46) were EBV-positive. Most cases of EBVaGC belonged to grade I. Conclusion: This research demonstrates a low prevalence of EBVaGC in Iran. Discrepancies in EBVaGC occurrence among countries could be attributed to epidemiological variables and dietary practices. A comprehensive studies will provide significant contributions to understanding of its etiology. [ABSTRACT FROM AUTHOR]

Lymphadenopathy is observed in 55% of children under the age of 10 years and the most often it has a bacterial or viral etiology, but it also can manifest as lymphoproliferative diseases or lymphomas. Lymphoproliferative diseases are characterized by uncontrolled growth of lymphocytes with the development of monoclonal lymphocytosis, lymphadenopathy and bone marrow infiltration. Since the Epstein-Barr virus (EBV) has oncogenic potential, it is essential for doctors to be vigilant about generalized persistent lymphadenopathy on the background of chronic persistent Epstein-Barr infection. The purpose of the article is to increase the awareness of doctors of various specialties about the risk of developing EBV-associated lymphoproliferative diseases in children with generalized persistent lymphadenopathy using the example of a clinical case discussion. The article describes a clinical case of a 14-year-old patient with persistent lymphadenopathy on the background of chronic Epstein-Barr infection. Immunohistochemical study of the lymph node biopsy revealed reactive hyperplasia with expressed immune blast transformation, the presence of CD30-positive cells while excluding Hodgkin lymphoma. It is recommended to involve a multidisciplinary team to prescribe appropriate antiviral therapy, regularly monitor the clinical course, dynamics of laboratory and immunological indicators. The result of the study is the recommendation to repeat biopsy in the absence of positive dynamics in patients with persistent Epstein-Barr infection and lymphadenopathy. [ABSTRACT FROM AUTHOR]

ObjectiveEpstein-Barr virus (EBV) is a globally prevalent herpes virus associated with multiple diseases. Oxidative stress is closely related to EBV infection, latency, reactivation, and transformation. Antioxidant diet protects against EBV infection. Composite Dietary Antioxidant Index (CDAI), serving as a key measure of antioxidant intake, is a summary score of six dietary antioxidants, including vitamins A, C, and E, carotenoid, selenium, and zinc. Despite this, the association between CDAI and EBV infection remains uncertain.MethodsThe aim of the study was to evaluate the association between CDAI and EBV infection using cross-sectional data from 3,318 children aged 6–19 years who participated in the American National Health and Nutrition Examination Survey between 2007 and 2010. Data on EBV results, CDAI, and several other essential variables were analyzed.ResultsCompared with that of individuals in Q3 (−1.627–−0.2727) in the multivariate weighted logistic regression model with full adjustment for confounding variables, the adjusted odds ratio (OR) for CDAI and EBV infection in those in Q1 (−6.613 − −2.9157), Q2 (−2.9158–−1.626), Q4 (−0.2728–1.7601), and Q5 (1.7602–21.419) was 1.41 (95% CI: 1.01–1.96, p = 0.043), 1.10 (95% CI: 0.84–1.45, p = 0.447), 1.14 (95% CI: 0.86–1.51, p = 0.343), and 1.41 (95% CI: 1.01–1.98, p = 0.044), respectively. The association between CDAI and EBV infection showed a U-shaped curve (non-linear; p = 0.002). The OR of reducing EBV infection was 0.882 (95% CI: 0.792–0.982, p = 0.025) in participants with a CDAI of ≤ − 0.81. The OR of developing EBV infection was 1.055 (95% CI: 1.000–1.114, p = 0.050) in participants with a CDAI of > − 0.81.ConclusionOur results indicated that the association between CDAI and EBV infection in U.S. adolescents follows a U-shaped curve, with an inflection point around –0.81.This suggests that an antioxidant-rich diet in some amount could help reduce the risk of EBV infection. Future prospective and experimental studies are needed to confirm causality and clarify the exact mechanism concerning antioxidant diets with EBV infection.

Background and Objectives: Gastric cancer (GC) is the third most common cause of cancer-related mortality. Epstein-Barr virus (EBV) is associated with several human tumors. The present research was performed to investigate the prevalence of EBV-associated gastric cancer (EBVaGC) among Iranian patients. Materials and Methods: Seventy cases of gastric cancer and 30 cases of gastric ulcer, all preserved in formalin-fixed paraffin-embedded (FFPE), were examined in a case-control study conducted between 2011 and 2018. The specimens underwent analysis to detect the presence of the EBV genome using a Nested-PCR method targeting EBNA1. Subsequently, samples testing positive for the EBNA1 underwent further testing for the presence of the EBER gene using PCR. Finally, Positive samples were subjected to sequencing. Results: Five out of 70 cases (7%) were found to be positive for EBV based on EBNA1 testing, while all EBNA1 positive samples were negative for EBER. Notably, EBV was not detected in patients with gastric ulcer. The mean age of EBV-positive gastric carcinomas pateints was 64.5 years. Within this group, 60% were male and 40% were female. A higher prevalence of EBV association was observed in diffuse-type cases, with 60% (3 out of 24) testing positive, compared to intestinal-type cases where 40% (2 out of 46) were EBV-positive. Most cases of EBVaGC belonged to grade Ⅰ. Conclusion: This research demonstrates a low prevalence of EBVaGC in Iran. Discrepancies in EBVaGC occurrence among countries could be attributed to epidemiological variables and dietary practices. A comprehensive studies will provide significant contributions to understanding of its etiology.

The goal is to improve the prediction of the immune status state dynamics in children with HIV infection, taking into account the results of clinical and laboratory examination. Materials and methods. Clinical, immunological and molecular genetic examination was carried in 81 children with HIV infection at the age of median Me 22 months (interquartile interval of IQI 13—42 months). The duration of observation of patients was Me 10 months ( IQI 4—12 months). The time interval before the development of severe immunosuppression according to the WHO classification was determined. The criterion for severe immunosuppression was a decrease in the absolute number of CD4-lymphocytes less than 0.5 x 109/l, their relative number — less than 20%. To determine the factors influencing the rate of development of severe immunosuppression, mathematical models of the analysis of the time to the onset of the event (survival) and Cox proportional intensities were used. Results. Severe immunosuppression developed in 92.5% of children aged Me 32 months (IQI 17—54 months). Testing of clinical and laboratory parameters at the beginning of the study in mathematical models showed that statistical significance in the multifactorial model (P = 0.011) was demonstrated by the indicators «HIV blood viral load of 100 000 cop./ml or more» (odds ratio OR 3.1; 95% confidence interval 95% CI 1.9—10.2; P = 0.012), «Active form of cytomegalovirus infection» (OR 2.3; 95% CI 1.2—7.8; P = 0.026), «Active form of Epstein-Barr virus infection» (OR 2.0; 95% CI 1.1—4.6; P = 0.040). Conclusion. The vast majority of children with HIV infection (92.5%) at the age of Me 32 months ( IQI 17—54 months) developed severe immunosuppression. Independent factors that influenced the timing of severe immunosuppression development were the high rate of HIV replication and the presence of active forms of cytomegalovirus infection and Epstein-Barr virus infection. To prevent the progression of immunological disorders in children with HIV infection, it is necessary not only to prescribe antiretroviral therapy earlier, but also timely diagnosis and treatment of active forms of herpesvirus infections.

Abstract A 73‐year‐old woman with a history of rheumatoid arthritis treated with methotrexate (MTX) for the last 10 years was referred to our hospital for a pancreatic tumor examination. Contrast‐enhanced abdominal computed tomography revealed a 20‐mm‐diameter hypovascular tumor in the pancreatic tail. A hypoechoic mass with heterogeneous internal echo was found on an endoscopic ultrasound (EUS). An EUS‐guided fine‐needle biopsy (EUS‐FNB) was performed with a 22‐gauge Franseen‐tip needle. Histologic examination of EUS‐FNB specimens from the pancreatic tumor revealed the proliferation of atypical spindle cells. Immunohistochemical staining for CD20 and Ki‐67 was positive in the atypical cells. Immunohistochemical staining for CD3 was partially positive in the atypical cells. Epstein–Barr virus‐encoded RNA in situ hybridization showed positive staining. MTX‐related lymphoproliferative disorder (MTX‐LPD) with Epstein‐Barr virus infection was diagnosed. MTX treatment was immediately discontinued, and treatment was initiated by a hematologist. However, her condition rapidly deteriorated, and she died of multiple organ failure 4 weeks after diagnosis. MTX‐LPD can complicate gastrointestinal lesions. However, most lesions are localized in the stomach and rarely complicate pancreatic lesions. MTX‐LPD is classified as an “iatrogenic” LPD. Therefore, immediate action, such as MTX discontinuation, is necessary. In conclusion, endoscopists should be aware that MTX‐LPD lesions can occur in the pancreas and gastrointestinal tract. Moreover, EUS‐FNB can be useful in the diagnosis of this rare pancreatic tumor.

Purpose: This study aims to investigate the characteristics of Epstein–Barr virus associated-hemophagocytic lymphohistiocytosis (EBV-HLH) and HLH caused by a severe form of infectious mononucleosis (IM-HLH) compared to IM by EBV, and thus also to assist in early diagnosis and providing appropriate treatment.Methods: Data for this analysis were collected from patients at the Department of General Medicine, Nara Medical University, between April 1, 2012, and August 1, 2020. EBV infection was diagnosed using clinical presentation and laboratory tests. HLH diagnosis followed the HLH-2004 protocol, supplemented by plasma EBV DNA detection. A range of clinical and laboratory parameters were collected, including age, sex, clinical outcomes, blood cell counts, hemoglobin, platelets, and various serum values. Plasma EBV DNA levels and flow cytometric analysis (FCM) of bone marrow were performed for HLH cases.Results: Among 1850 hospitalized patients, 14 cases were identified, including 2 HLH cases and 12 IM cases. Comparative analysis revealed distinctive features of HLH, including lower lymphocyte and platelet counts and higher levels of ferritin, soluble interleukin 2 receptor (sIL-2R), and D dimer compared to IM. Notably, one HLH case responded well to corticosteroid monotherapy, while the other case did not, resulting in a fatal outcome. Detection of a cluster of CD5-CD7 lymphocytes in bone marrow is a hallmark of EBV-HLH and useful to distinguish from IM-HLH.Conclusion: This study underscores the importance of early differentiation among EBV-HLH, IM-HLH, and IM in adults to guide appropriate treatment strategies. While specific laboratory markers help distinguish HLH from IM, a more detailed analysis of FCM is crucial for precise diagnosis of HLH cases and tailored therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objective: Primary Epstein‐Barr virus (EBV) infection is observed in 60% of children during the first year after liver transplantation as usage of imm‐unosuppressant. Finding predictive indicators of EBV infection is important to reduce the morbidity and mortality of EBV infection‐related diseases by suggesting a dose reduction of immunosuppressant. Methods: We compared and analysed the gut microbiome of EBV‐infected children with an asymptomatic virus‐carrying status and EBV‐uninfected children after liver transplantation using high‐throughput sequencing. Results: Significant differences in gut microbiome composition in two groups were detected. In detail, Firmicutes and Lactobacillus were increased in EBV‐infected group, while Clostridium was increased in EBV‐uninfected group. Furthermore, CD4 percentage in T cells of blood showed a significant positive correlation with the content of Clostridium sp. CAG: 127 in EBV‐uninfected group. Conclusion: Changes in the gut microbiome could predict and decrease the EBV infection risk of children after liver transplantation. [ABSTRACT FROM AUTHOR]

Resumen: La pancreatitis aguda es una enfermedad inflamatoria con compromiso exocrino del mismo. Los cálculos biliares y el alcohol son sus factores etiológicos más comunes; se menciona que alrededor del 10% de los casos de pancreatitis aguda son causados por otros factores, como infecciones por parásitos, bacterias y virus. Se presenta el caso de una paciente que inicia con cuadro febril de 3 semanas de evolución y que en la última semana se agrega sintomatología abdominal, haciéndose diagnóstico de pancreatitis aguda vírica por criterio clínico y laboratorial; así mismo se hace una revisión de la literatura al respecto. Abstract: Acute pancreatitis is an inflammatory pathology involving the exocrine pancreas. Biliary stones and alcohol are its most common etiological factors; it is mentioned that around 10% of acute pancreatitis cases are caused by other factors, such as infections by parasites, bacteria, and viruses. We present the case of a patient who started with a febrile condition for three weeks and, in the last week, developed abdominal symptoms, leading to a diagnosis of acute viral pancreatitis based on clinical and laboratory criteria. A literature review on this topic is also provided.

Copyright of Die Pathologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Anti-SARS-CoV-2 vaccines were developed in response to the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the BNT162b2 mRNA vaccine is effective, adverse effects have been reported. Here, we report a case of extranodal NK/T-cell lymphoma, nasal type (ENKL), of the left arm following BNT162b2 mRNA vaccination. A 73-year-old male presented with a lump in the left arm, which was the site where he received the BNT162b2 mRNA vaccine 3 months prior. He was treated with topical corticosteroids and debridement, but the tumor progressed. Additionally, fever, night sweats, and general fatigue were observed. Laboratory findings included thrombocytopenia, elevated lactate dehydrogenase, and soluble interleukin-2 receptor levels. Skin biopsy led to a diagnosis of ENKL. The patient was treated with a 50% dose of SMILE therapy and radiotherapy, resulting in regression of the tumor. It seems that latent Epstein–Barr virus (EBV)-infected NK/T cells were reactivated by vaccination and contributed to the onset of ENKL. This is the first report of ENKL after BNT162b2 mRNA vaccination. The present case highlights the possible risk of development of malignant lymphoma, including ENKL at the injection site, after BNT162b2 COVID-19 vaccination. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinical manifestations and gene mutation characteristics of chronic Epstein-Barr virus (EBV) infection caused by a gain-of-function (GOF) mutation of the PIK3CD gene through a case report. Methods The clinical data of a pediatric patient was collected, and whole-exome sequencing was used to detect gene mutations. Related articles were searched and reviewed. Results The pediatric patient experienced recurrent respiratory infection since 2 years of age accompanied by enlargement of liver, spleen, and lymph nodes and recurrent varicella-like rash. There was a significant increase in the serum level of EBV antibody, and lymphoid tissue biopsy showed T lymphocyte proliferative changes and positive EBV-encoded RNA. At the age of 13 years, the pediatric patient experienced a significant increase in the level of immunoglobulins in blood with various positive autoantibodies. Genetic testing revealed a heterozygous mutation in the PIK3CD gene, c.3061G>A(p.E1021K), and literature review showed that this mutation was a GOF mutation. Conclusion The GOF mutation of the PIK3CDgene can lead to susceptibility to EBV and chronic EBV infection, with the clinical manifestations of lymphoid hyperplasia and characteristic rash. Pediatric patients with this disease can also present with significant increases in the levels of immunoglobulins in blood, which may be associated with the formation of massive autoantibodies caused by autoimmune response.

We report a case of an elderly male who presented with enlarged abdominal lymph nodes and was diagnosed as having Epstein-Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS). He was started on chemotherapy which had to be discontinued after three cycles due to the development of life-threatening pneumocystis carinii pneumonia and poor performance status. Within two years, the patient presented with features of relapse. A repeat histopathological examination of the lymph node showed features of peripheral T-cell lymphoma, NOS and the clonality was confirmed by T-cell receptor gamma chain rearrangement assay. More studies are needed to understand the association of EBV+ DLBCL, NOS with other lymphomas. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Pediatric Infection / Çocuk Enfeksiyon Dergisi is the property of Journal of Pediatric Infection / Cocuk Enfeksiyon Dergisi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Methotrexate (MTX) is a well-known agent that can potentially cause lymphoproliferative disorder (LPD), known as MTX-related LPD (MTX-LPD). Only two cases of thyroid MTX-LPD have been reported to date. This study aimed to report 11 cases of MTX-LPDs arising in the thyroid gland and discuss their clinicopathological characteristics. Of the 747 patients with cytologically suspected lymphoma, 11 had received MTX. The mean age of the patients with MTX-LPD was 70.2 years (range: 51–82 years), and all were female. The duration of MTX administration ranged from 5 to 31 years (mean: 19.5 years). Nine patients (81.8 %) tested positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. In three patients, the tumor decreased in size or disappeared without surgery or chemotherapy after withdrawal of MTX therapy. Histologically, all eight nodules examined were B-cell lymphomas, and seven were mucosa-associated lymphoid tissue (MALT) lymphomas. Epstein-Barr virus-encoded small RNA in situ hybridization showed negative results for all six nodules examined. All five patients who were followed-up at our hospital exhibited progression-free survival for >3 years without chemotherapy. Six patients were transferred to other hospitals, and their follow-up details are unknown. MTX-LPDs occurring in the thyroid are characterized by a high female predominance, positivity for anti-thyroid autoantibodies, high prevalence of MALT lymphomas, negativity for Epstein-Barr virus, and good outcomes without chemotherapy. We recommend that patients with thyroid lymphoma should be checked for a history of MTX. • Report of 11 cases of thyroid methotrexate-related lymphoproliferative disorder. • Most of MTX-LPD were MALT lymphomas. • EBER-ISH yielded negative results in all patients assessed. • All patients withdrawn from MTX exhibited tumor reduction or disappearance. • Patients with thyroid lymphoma should be checked for a history of MTX. [ABSTRACT FROM AUTHOR]

Invadopodia are actin‐rich membrane protrusions that digest the matrix barrier during cancer metastasis. Since the discovery of invadopodia, they have been visualized as localized and dot‐like structures in different types of cancer cells on top of a 2D matrix. In this investigation of Epstein–Barr virus (EBV)‐associated nasopharyngeal carcinoma (NPC), a highly invasive cancer frequently accompanied by neck lymph node and distal organ metastases, we revealed a new form of invadopodium with mobilizing features. Integration of live‐cell imaging and molecular assays revealed the interaction of macrophage‐released TNFα and EBV‐encoded latent membrane protein 1 (LMP1) in co‐activating the EGFR/Src/ERK/cortactin and Cdc42/N‐WASP signaling axes for mobilizing the invadopodia with lateral movements. This phenomenon endows the invadopodia with massive degradative power, visualized as a shift of focal dot‐like digestion patterns on a 2D gelatin to a dendrite‐like digestion pattern. Notably, single stimulation of either LMP1 or TNFα could only enhance the number of ordinary dot‐like invadopodia, suggesting that the EBV infection sensitizes the NPC cells to form mobilizing invadopodia when encountering a TNFα‐rich tumor microenvironment. This study unveils the interplay of EBV and stromal components in driving the invasive potential of NPC via unleashing the propulsion of invadopodia in overcoming matrix hurdles. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

To study a case of a middle-aged male with a non-tumor-associated Epstein–Barr virus (EBV) infection associated with Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE), to explore the role of EBV in the pathogenesis of anti-NMDARE. The patient was diagnosed with "Anti-NMDARE, EBV infection" by using Cerebrospinal fluid (CSF) autoimmune encephalitis profile, and Metagenomics Next-Generation Sequencing (mNGS) pathogenic microbial assays, we discuss the relationship between EBV and NMDARE by reviewed literature. EBV infection may trigger and enhance anti-NMDARE, and the higher the titer of NMDAR antibody, the more severe the clinical presentation. [ABSTRACT FROM AUTHOR]

Backgrounds & aimsEpstein-Barr virus (EBV) infection occurs commonly in children and may cause acute infectious mononucleosis (AIM) and various malignant diseases. Host immune responses are key players in the resistance to EBV infection. We here assessed the immunological events and laboratory indicators of EBV infection, as well as determined the clinical usefulness of evaluating the severity and efficacy of antiviral therapy in AIM patients.MethodsWe enrolled 88 children with EBV infection. The immune environment was defined by immunological events such as frequencies of lymphocyte subsets, phenotypes of T cells, and their ability to secrete cytokines, and so on. This environment was analyzed in EBV-infected children with different viral loads and in children in different phases of infectious mononucleosis (IM) from disease onset to convalescence.ResultsChildren with AIM had higher frequencies of CD3+ T and CD8+ T cells, but lower frequencies of CD4+ T cells and CD19+ B cells. In these children, the expression of CD62L was lower and that of CTLA-4 and PD-1 was higher on T cells. EBV exposure induced granzyme B expression, but reduced IFN-γ secretion, by CD8+ T cells, whereas NK cells exhibited reduced granzyme B expression and increased IFN-γ secretion. The frequency of CD8+ T cells was positively correlated with the EBV DNA load, whereas the frequencies of CD4+ T cells and B cells were negatively correlated. During the convalescent phase of IM, CD8+ T cell frequency and CD62L expression on T cells were restored. Moreover, patient serum levels of IL-4, IL-6, IL-10, and IFN-γ were considerably lower throughout the convalescent phase than throughout the acute phase.ConclusionRobust expansion of CD8+ T cells, accompanied by CD62L downregulation, PD-1 and CTLA-4 upregulation on T cells, enhanced granzyme B production, and impaired IFN-γ secretion, is a typical characteristic of immunological events in children with AIM. Noncytolytic and cytolytic effector functions of CD8+ T cells are regulated in an oscillatory manner. Furthermore, the AST level, number of CD8+ T cells, and CD62L expression on T cells may act as markers related to IM severity and the effectiveness of antiviral treatment.

Post-transplant lymphoproliferative disease (PTLD) is the most common malignancy complicating solid organ transplantation (SOT) in adults and children. PTLD encompasses a spectrum of histopathologic features and organ involvement, ranging from benign lymphoproliferation and infectious-mononucleosis like presentation to invasive neoplastic processes such as classical Hodgkin lymphoma. The predominant risk factors for PTLD are Epstein-Barr virus (EBV) serostatus at the time of transplant and the intensity of immunosuppression following transplantation; with EBV-negative recipients of EBV-positive donor organs at the highest risk. In children, PTLD commonly presents in the first two years after transplant, with 80% of cases in the first year, and over 90% of cases associated with EBV-positive B-cell proliferation. Though pediatric kidney transplant recipients are at lower risk (1–3%) for PTLD compared to their other SOT counterparts, there is still a significant risk of morbidity, allograft failure, and an estimated 5-year mortality rate of up to 50%. In spite of this, there is no consensus for monitoring of at-risk patients or optimal management strategies for pediatric patients with PTLD. Here we review pathogenesis and risk factors for the development of PTLD, with current practices for prevention, diagnosis, and management of PTLD in pediatric kidney transplant recipients. We also highlight emerging concepts, current research gaps and potential future developments to improve clinical outcomes and longevity in these patients.

Objective To observe the changes of T lymphocyte subsets and cytokines in peripheral blood of children with Epstein-Barr virus associated hemophagocytic lymphohistiocytosis(EBV-HLH). Methods Twenty-three children with EBV-HLH(EBV-HLH group) and 29 children with EBV-infection-associated infectious mononucleosis(EBV-IM) (EBV-IM group) were selected. Venous blood samples were collected from the two groups. The proportions of PD1+ cells, CD57+ cells and CD69+ activated cells in T lymphocyte subsets of CD3+(total T lymphocytes), CD4+CD3+(regulatory T lymphocytes) and CD8+CD3+(killer T lymphocytes) were detected by flow cytometry. The expression levels of cytokines IL- 2，IL-4，IL-6，IL-10，TNF- α and IFN- γ were detected by fluorescence microbeads combined with flow cytometry. Results The proportion of activated CD69+CD3+ T lymphocytes in the EBV-HLH group was higher than that in the EBV-IM group(P<0. 05) . The proportion of PD1+CD3+ T cells in the EBV-HLH group was lower than that in the EBV-IM group, especially the proportion of PD1+CD8+CD3+ T cells with killer function was much more obvious(P<0. 05) . There was no significant difference in the proportion of senescent CD57+CD3+ T cells between the two groups(P>0. 05). The levels of IL- 2，IFN-γ and IL-10 in the EBV-HLH group were significantly higher than those in the EBV-IM group(all P<0. 05). Conclusion The killer function of T lymphocytes in peripheral blood of children with EBV-HLH decreased，not the increase of senescent cells, which was partly reflected in the exhaustion of T lymphocytes function in EBV-HLH. [ABSTRACT FROM AUTHOR]

Background: Post‐transplant lymphoproliferative disorder (PTLD) are the most common de novo malignancies after liver transplantation (LT) in children. The aim of our study was to assess the role of pre‐LT EBV status and post‐LT EBV viral load as risk factors for developing PTLD in a cohort of pediatric LT recipients. Methods: Data of all children who underwent LT between January 2002 and December 2019 were collected. Two cohorts were built EBV pre‐LT primary infected cohort and EBV post‐LT primary infected cohort. Moreover, using the maximal EBV viral load, a ROC curve was constructed to find a cutoff point for the diagnosis of PTLD. Results: Among the 251 patients included in the study, fifteen PTLD episodes in 14 LT recipients were detected (2 plasmacytic hyperplasia, 10 polymorphic PTLD, 2 monomorphic PTLD, and 1 Classical‐Hodgkin's lymphoma). Patients of the EBV post‐LT primary infected cohort were 17.1 times more likely to develop a PTLD than patients of the EBV pre‐LT primary infected cohort (2.2–133.5). The EBV viral load value to predict PTLD was set at 211 000 UI/mL (93.3% sensitivity and 77.1% specificity; AUC 93.8%; IC 0.89–0.98). In EBV post‐LT primary infected cohort, patients with a viral load above 211 000 were 30 times more likely to develop PTLD than patients with a viral load below this value (OR 29.8; 3.7–241.1; p < 0.001). Conclusions: The combination of pretransplant EBV serological status with EBV post‐transplant viral load could be a powerful tool to stratify the risk of PTLD in pediatric LT patients. [ABSTRACT FROM AUTHOR]

Lymphoepithelial carcinoma is rare in the salivary glands, with an incidence of 0.4%. The most commonly affected site is the parotid gland, followed by the submandibular gland. Lymphoepithelial carcinoma in the sublingual gland has been reported only four times in the existing English-language literature. Such tumours are characterized by the presence of a poorly differentiated carcinoma that is surrounded and infiltrated by lymphocytes, and they are strongly associated with Epstein–Barr virus infection, patient ethnicity, and prominent radiosensitivity. Wide surgical excision combined with adjuvant therapy has been suggested as the first-choice therapeutic regimen. This report describes the case of a 34-year-old Indonesian woman who was evaluated and treated in Taipei Medical University Hospital. She had a tumour that presented as a painless swelling on the floor of the mouth. The diagnosis was confirmed by conducting an incisional biopsy, and a wide surgical excision with bilateral supraomohyoid neck dissection and free flap reconstruction was performed. The patient also underwent adjuvant chemoradiotherapy. No evidence of local recurrence or distant metastasis was detected during the 6 months of follow-up. Subsequently, the patient returned to her home country, and further follow-ups were not conducted. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) plays the most important role in various types of human cancers. Patients receiving chemotherapy have low white blood cell (WBC) counts that elevate the risk of infection and is the first public health priority in Iraq. WBCs are capable of tumor destruction and aid in combatting infection; they also promote tumor growth, metastasis and chemotherapy resistance. Low WBC count makes the body more predisposed to infection. Our study sought to investigate the relationship between low WBC count and EBV infection in cancer patients. A cross-sectional study was performed using 120 samples obtained from cancer patients, who had a low WBC count and were receiving chemotherapy. The study included samples from 60 males and 60 females aged between 7 and 80 years from Najaf / Iraq. Among the different cancer types, breast cancer cases were high (24 patients; 20%); additionally, a high number of cancer patients (52; 43.3%) also had a low WBC count (≤2 to ≥4 in 109 / L of cells). There were no significant differences in the serological detection of positive cases for viral capsid protein IgM and EBNA-1 and EBNA-2 nuclear genes (P˃0.05) between the cancer patients of different age groups and genders. EBV infection is associated with a low WBC count in cancer patients receiving chemotherapy. No significant differences for patients was observed with respect to age and gender.

Abstract Myocardial infection by Epstein–Barr virus (EBV) may manifest with inflammatory cardiomyopathy, coronary syndrome X, and rarely with infarct‐like myocarditis. The aim of the report is to describe a case of myocardial EBV infection causing acute myocarditis with heart failure, necrotizing coronary vasculitis, and multiple left ventricular (LV) aneurysms. A 67‐year‐old woman presented with fever, chest pain, and heart failure. She underwent non‐invasive cardiac studies including electrocardiography, 2D‐echocardiography, cardiac magnetic resonance, hematochemical exams with Troponin T determination, and invasive studies including cardiac catheterization, coronary angiography, and LV endomyocardial biopsy. Five endomyocardial samples were processed for histology and immunohistochemistry for inflammatory cells characterization and detection of viral antigens. Two additional frozen samples were evaluated by real‐time polymerase chain reaction for the presence of cardiotropic viral genomes. Routine laboratory tests revealed the presence of elevated white blood cells (17 000 103/μL) and increased Troponin T. Electrocardiogram showed sinus tachycardia with ST elevation in V2–V5. Two‐dimensional echocardiography showed normal LV dimension with reduced LV contractility (LVEF = 40%) with mild pericardial effusion. Cardiac magnetic resonance revealed the presence of a micro‐aneurism in the inferior LV wall, a diffuse oedematous imbibition of LV myocardium suggested by hyper‐intensity of T2 mapping, and increased fibrosis as suggested by areas of late gadolinium enhancement signals. Coronary arteries were normal while several micro‐aneurysms were observed at LV angiography. At histology, a lymphocytic myocarditis with necrotizing coronary vasculitis sustained by a positive real‐time polymerase chain reaction for EBV, detectable in cardiomyocytes and inflamed intramural vessels by positive immunohistochemistry for EBV latent membrane protein 1 antigen, was observed. Myocardial EBV infection is an unusual cause of acute heart failure and cardiac aneurysms, increasing the risk of electrical instability, cardiac perforation, and sudden death.

Treatment of chronic viral infections accompanied by permanent virus persistence in the target epitopes of the oral cavity, skin, urogenital tract is complicated by virtual lack of available drugs exerting combined systemic virulicidal and immunomodulatory effects. Here we demonstrate clinical and immunological efficacy of combined therapy in treatment of Epstein–Barr virus (EBV)-associated chronic infections. The aim of the study was to evaluate the clinical and immunological efficacy of combined etiopathogenetic therapy using the Acegram cosmetic product in patients with EBV-associated chronic infections. Materials and methods. There were enrolled 40 patients monitored before treatment as well as 20 patients followed up after combination therapy (cycle therapy consisted of oral valaciclovir (Valtrex) applied at dose of 500 μg twice a day for 10 days, glucosaminylmuramyldipeptide (Licopid) — 10 mg 2 twice a day for 10 days, topical irrigation for mucous membranes with granulocyte-macrophage colony-stimulating factor active center-derived peptide (Acegram-spray) 3 times a day for 10 days. If necessary, treatment courses were repeated 20 days after the onset. All patients were examined for the presence of EBV genomes in the oral fluid and blood using the qualitative and quantitative polymerase chain reaction (PCR) using the DNA technology test system (Russia) on a DT-Lite device prior treatment and 30, 60 days post-therapy time points. In addition, serum samples were analyzed for level of class G immunoglobulins specific to the EBV nuclear and capsid antigens by using enzyme immunoassay (test systems manufactured by CJSC Vector Best, Russia) as well as immune status (clinical methods, enu flow cytometry evaluation of the phagocytic activity of neutrophils, ELISA method). Results. Use of single or two course combination therapy in subjects with fully eradicated EBV carriage associated with reversed clinical symptoms was accompanied by recovered immune system status (T and B cells, T-helper cells, CD3+ CD25+ cells, phagocytosis parameters). A non-invasive approach proposed for controlling virus elimination in the oral fluid by using polymerase chain reaction method may serve as to objectively monitor therapeutic efficacy.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by excessive production of inflammatory cytokines and multiple organs injury. Ruxolitinib, an oral selective JAK1/2 inhibitor, has recently shown efficacy and safety in the treatment of secondary HLH, which may be an alternative to intensive chemotherapy. Case report: We report a case of a 2-year-old boy who presented to our institution with recurrent fever and acute renal failure. We made the diagnosis of Epstein-Barr virus related HLH based on the HLH-2004 protocol, and gave the treatment of ruxolitinib instead of etoposide. Management and outcome: The patient received dexamethasone and continuous renal replacement therapy due to renal failure, but he still had fever and anuria. Given that the use of etoposide may deteriorate renal function, ruxolitinib was administered instead of etoposide. After 5 days of ruxolitinib treatment, the patient's fever was resolved and renal function also gradually recovered 14 days later. Discussion: Currently, dexamethasone, etoposide and cyclosporine A are the main drugs in HLH treatment. However, cytotoxic chemotherapy can temporally deteriorate organ damage and induce serious myelosuppression, which makes clinicians hesitate to implement these regimens. Ruxolitinib has shown efficacy in treating HLH without much toxicity in clinical trials. Thus, we suggest that ruxolitinib constitutes a treatment option for secondary HLH complicated by severe renal damage which may reduce toxic effects compared with intense chemotherapy. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infection is prevalent and associated with distinct diseases including infectious mononucleosis (IM), chronic active EBV infection (CAEBV) and NK/T-cell lymphoma (NKTL). However, the specific roles of EBV in these diseases remain unclear. Here, the whole miRNA expression datasets derived from 7 IM, 6 CAEBV, and 3 NKTL biopsies were obtained. Homo sapiens microRNA-372-5p (Hsa-miR-372-5p) was upregulated in both CAEBV and NKTL patients. Overexpression of hsa-miR-372-5p altered the expression of over 100 proteins. In addition, hsa-miR-372-5p may target NIMA related kinase 7 to regulate NLRP3 inflammasome activation in host cell. Taken together, we reported different miRNA expression profiles in distinct EBV associated diseases, which provided novel insights to understand how host miRNAs contribute to the mechanism of EBV associated diseases. Hsa-miR-372-5p, as well as other differential expressed miRNA, might serve as potential targets in the therapy of various EBV associated diseases. [ABSTRACT FROM AUTHOR]

We report a rare case of localized NK/T-cell lymphoma following a mosquito bite after achieving complete response of extranodal NK/T-cell lymphoma, nasal type (ENKL). T cells and NK cells infected by Epstein-Barr virus (EBV) lead to NK/T-cell lymphoma, including ENKL. Lymphoma related to mosquito bites usually requires a prolonged treatment course, and the disease onset of hypersensitivity begins in early childhood. In the current case, the patient had no history of hypersensitivity to mosquito bites. We speculate that the latently EBV-infected NK/T cells in the blood were reactivated by mosquito gland antigens, expanded abnormally, and accumulated at the site of the mosquito bite.

Background and Objective: Primary adrenal lymphoma is a rare, progressive, easily misdiagnosed adrenal tumor with a poor prognosis. There are limited data on its clinical characteristics, and these have been derived from small sample studies. This study aimed to identify the clinical characteristics and prognosis of primary adrenal lymphoma.Methods: This single-center study retrospectively analyzed data of 50 primary adrenal lymphoma patients treated between January 2008 and January 2018. Demographic information, biochemical indexes, computed tomography images, pathological findings, treatment regimens, and prognostic factors were analyzed.Results: The median age of onset was 60.3 years, and 30 (60.0%) of 50 patients were male. Abdominal pain was the most common symptom, followed by incidentaloma and B symptoms. On average, patients presented with elevated lactate dehydrogenase (348 IU/L, normal range 110–220 IU/L) and hydroxybutyrate dehydrogenase levels (287 IU/L, normal range 72–182 IU/L) and decreased high-density lipoprotein cholesterol levels (0.88 mmol/L, normal range > 0.9 mmol/L). Bilateral lesions in the adrenal glands were observed in 30 (60.0%) patients. Computed tomography showed that 42 (84%) patients had signs of infiltration. Diffuse large B-cell lymphoma was present in 44 (88%) patients. Immunohistochemistry revealed that 70.6% (12/17), 89.5% (17/19), 92.0% (23/25), and 68.8% (11/16) of patients were positive for MYC, p53, BCL2, and both MYC and BCL2, respectively. Combined chemotherapy was associated with a good prognosis.Conclusions: Early diagnosis of primary adrenal lymphoma depends on a combination of biochemical examination, imaging studies, and pathological biopsy, and combined chemotherapy may lead to a better prognosis.

A 57-year-old male who had a successful live-related renal transplantation 14 years ago with stable graft function, on minimal triple immunosupression, presented with Burkholderia cepecia septicemia and graft dysfunction. He was successfully treated with parenteral imepenam. He was found to be Epstein–Barr virus Immunoglobulin G seropositive. Positron-emission tomography scan done showed metabolically active multiple cervical, mediastinal, axillary retroperitoneal, mesenteric, iliac, and inguinal lymphadenopathy. Further investigations revealed polymorphic posttransplant lymphoproliferative disease. His immunosuppressive therapy was tailored to lower cyclosporine dosage and discontinuation of azathioprine. His renal function improved. He was diagnosed to have a T-cell non-Hodgkin's lymphoma and subsequently succumbed to sepsis.

Background. Today, there is a tendency to increase in Epstein-Barr virus infection (EBVI) morbidity. The purpose of the study was to identify the incidence and features of atypical forms of acute EBVI in children. Material and methods. We have examined 28 children aged 6 months to 18 years with EBVI who were monitored in pediatric polyclinic. The activity of alanine aminotransferase and aspartate aminotransferase, levels of bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, markers of viral hepatitis were evaluated. Enzyme-linked immunosorbent assay was performed with determination of blood markers of EBV (immunoglobulin (Ig) M viral capsid antigen (VCA), IgG early antigen, IgG VCA, avidity) and cytomegalovirus (CMV) (IgM, IgG, avidity), EBV deoxyribonucleic acid (DNA), CMV DNA; polymerase chain reaction was used for serological diagnosis. The data were processed by statistical analysis using Statistica 6 program. Results. In 71.4 % of cases, EBVI had usual course and moderate severity. The atypical forms of acute EBVI were observed in 28.5 % of cases. Clinically atypical forms began mainly from signs of acute respiratory infections followed by lesions of the internal organs (liver and heart), in particular, in children under 1 year of age, and changes in liver functional tests. Conclusions. The incidence of atypical forms of EBVI is 28.5 %. Atypical forms of EBVI are more common in infants and adolescents and associated with the damage to the internal organs (liver and heart).

Epstein-Barr virus (EBV) infection is associated with some autoimmune diseases. We report here a 32 months old girl with fever, isthmitis, lymphadenectasis, and excessive atypical lymphocytes, who developed seizures, personality and behavior changes, with positive anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody and EBV-early antigen (EA)-IgG antibody in cerebrospinal fluid (CSF), which suggested the possibility that the acute EBV infection have triggered the anti-NMDAR encephalitis, which has not been reported previously. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus-associated gastric cancer [EBV-associated GC, EBV(+) GC] is a distinct molecular subtype of gastrointestinal (GI) cancers. It accounts for up to 10% of all molecular subtypes of gastric cancer (GC). It has unique genetic and epigenetic features, which determine its definitive phenotype with male and younger age predominance, proximal stomach localization, and diffuse adenocarcinoma histology. EBV(+) GC also has a unique epigenetic profile and mutational status with frequent mutations of PIK3CA, ARID1A and BCOR, and PD-L1 and PD-L2 amplifications, as well. The aim of this review is to highlight clinical significance of EBV(+) GC and prognostic role of EBV infection, and to determine potentially appropriate drug therapy for this disease. [ABSTRACT FROM AUTHOR]

Background and Objective: Primary adrenal lymphoma is a rare, progressive, easily misdiagnosed adrenal tumor with a poor prognosis. There are limited data on its clinical characteristics, and these have been derived from small sample studies. This study aimed to identify the clinical characteristics and prognosis of primary adrenal lymphoma. Methods: This single-center study retrospectively analyzed data of 50 primary adrenal lymphoma patients treated between January 2008 and January 2018. Demographic information, biochemical indexes, computed tomography images, pathological findings, treatment regimens, and prognostic factors were analyzed. Results: The median age of onset was 60.3 years, and 30 (60.0%) of 50 patients were male. Abdominal pain was the most common symptom, followed by incidentaloma and B symptoms. On average, patients presented with elevated lactate dehydrogenase (348 IU/L, normal range 110–220 IU/L) and hydroxybutyrate dehydrogenase levels (287 IU/L, normal range 72–182 IU/L) and decreased high-density lipoprotein cholesterol levels (0.88 mmol/L, normal range > 0.9 mmol/L). Bilateral lesions in the adrenal glands were observed in 30 (60.0%) patients. Computed tomography showed that 42 (84%) patients had signs of infiltration. Diffuse large B-cell lymphoma was present in 44 (88%) patients. Immunohistochemistry revealed that 70.6% (12/17), 89.5% (17/19), 92.0% (23/25), and 68.8% (11/16) of patients were positive for MYC, p53, BCL2 , and both MYC and BCL2 , respectively. Combined chemotherapy was associated with a good prognosis. Conclusions: Early diagnosis of primary adrenal lymphoma depends on a combination of biochemical examination, imaging studies, and pathological biopsy, and combined chemotherapy may lead to a better prognosis. [ABSTRACT FROM AUTHOR]

Background: Epstein‐Barr virus (EBV)‐positive gastric cancers (GCs) have been recently identified as a molecular subgroup showing excellent outcomes after surgery for early‐stage disease and responsiveness to immune checkpoint inhibitors (ICIs) for metastatic stage. No data are available on the prevalence, clinical characteristics, and prognosis of this subgroup of GCs in the metastatic setting. Materials and Methods: In this cohort study, we assessed the impact of EBV status in patients with metastatic GC treated with chemotherapy at two Italian institutions. Results: Among the 175 cases analyzed, only 7 (4%) were EBV positive and all showed long‐lasting and even complete responses to first‐line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV‐negative patients (3‐year overall survival: 80% vs. 20.1%; hazard ratio: 0.12). Conclusion: If confirmed in larger data sets, our results may give a strong rationale for investigating the addition of ICIs to chemotherapy, in order to maximize the chance of achieving durable and complete responses in this uncommon subtype of GC. Implications for Practice: To date, no data are available on the prevalence and clinical characteristics of patients with Epstein‐Barr virus (EBV)‐positive metastatic gastric cancer (GC), a specific subtype of GC showing excellent outcomes after radical surgery in early‐stage disease and responsiveness to immune checkpoint inhibitors (ICIs). This cohort study showed that patients with EBV‐positive GC who did not receive ICIs had exceptional, long‐lasting, and even complete responses to first‐line chemotherapy with fluorouracil and platinum and a significantly better survival compared with EBV‐negative patients. If confirmed in larger series, these results may give a strong rationale for investigating the combination of chemotherapy and ICIs to achieve durable and potentially complete response in this uncommon subtype of GC. This article assesses the effect of Epstein‐Barr virus status in patients with metastatic gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Opportunistic Epstein–Barr virus (EBV) infection in patients with ulcerative colitis (UC) has attracted increasing attention. This study aimed to evaluate the clinicopathological characteristics and clinical outcomes of UC with intestinal EBV infection and to explore the predictive value of blood EBV DNA for the presence of EBV in the intestine. Methods: Both peripheral blood and intestinal biopsies from 92 consecutive UC inpatients were included in this study. Normal colonic mucosal tissues from 20 colon cancer patients were used as controls. EBV testing and assessment were performed by EBV-DNA polymerase chain reaction (PCR), EBV-encoded small RNA in situ hybridization (EBER-ISH) and immunohistochemistry. Results: A total of 36 patients (39.1%) had UC with superimposed EBV colitis [EBER greater than 2/high-power field (HPF)]. EBER counts and disease activity were significantly correlated (p < 0.05). The major endoscopic findings revealed more irregular and longitudinal ulcers in patients with superimposed EBV colitis (p = 0.016, p = 0.021, respectively). Age, steroid dependence, and irregular ulcerations were identified as possible risk factors. The best EBER cut-off point for outcome prediction was 2.5/HPF. At a cut-off value of 2035 copies/ml, the sensitivity and specificity of the blood EBV-DNA PCR analysis for predicting EBV presence in the intestine were 76.5% and 68.5%, respectively. EBV-infected cells in UC with high EBV concentrations mainly included B lymphocytes by clinicopathology, and the infection might have progressed from the latent to the lytic phase of the EBV life cycle. Conclusion: The EBER count is positively correlated with disease activity. The best cut-off point for outcome prediction is 2.5/HPF. A high EBV viremia load may effectively predict EBV presence in the colonic mucosa. [ABSTRACT FROM AUTHOR]

Purpose: Nasopharyngeal cancer is a type of malignancy originating from the epithelial cells lining the nasopharynx. In genetic and environmental factors, infection with Epstein–Barr virus is one of the particular factors held accountable for the etiopathogenesis. Human papillomavirus has been associated with cervical, anogenital, and oropharyngeal cancers. The aim of the present study is to demonstrate the presence and incidence of Epstein–Barr virus and human papillomavirus in patients with nasopharyngeal cancer. Methods: The information collected for these patients included age at the time of biopsy, gender, alcohol consumption and smoking, and histopathological type of nasopharyngeal cancer. Only patients for whom nasopharyngeal biopsy was performed as punch biopsy were included in the study. In situ hybridization was performed with formalin-fixed, paraffin-embedded tissue sections for Human Papillomavirus and Epstein–Barr virus nucleic acids obtained by means of automated Ventana BenchMark Medical system Results: Utilizing in situ hybridization with samples obtained from 56 patients diagnosed with nasopharyngeal cancer. Epstein–Barr virus was positive in 41 out of the 56 (73.2%) patients, while human papillomavirus was positive in 3 (5.4%), and 1 patient (1.8%) had co-infection. Thirty seven (90.2%) of the 41 patients positive for Epstein–Barr virus were Type-2 according to WHO, while 4 (9.8%) were Type-1. All three patients (100%) with Human Papillomavirus positivity were Type-2 according to WHO. Conclusions: This study shows the close association between nasopharyngeal cancer and Epstein–Barr virus whereas such an association is not shown for Human Papillomavirus. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) play a decisive role in the development and progression of cancer. To investigate CSCs in Epstein‐Barr virus (EBV)‐associated carcinoma (EBVaGC), we screened previously reported stem cell markers of gastric cancer in EBV‐infected gastric cancer cell lines (TMK1 and NUGC3) and identified CD44v6v9 double positive cells as candidate CSCs. CD44v6/v9+/+ cells were sorted from EBVaGC cell line (SNU719) cells and EBV‐infected TMK1 cells and these cell populations showed high spheroid‐forming ability and tumor formation in SCID mice compared with the respective CD44v6/v9−/− cells. Sphere‐forming ability was dependent on the nuclear factor‐κB (NF‐κB) signaling pathway, which was confirmed by decrease of sphere formation ability under BAY 11‐7082. Small interfering RNA knockdown of latent membrane protein 2A (LMP2A), one of the latent gene products of EBV infection, decreased spheroid formation in SNU719 cells. Transfection of the LMP2A gene increased the sphere‐forming ability of TMK1 cells, which was mediated through NF‐κB signaling. Together, these results indicate that CD44v6v9+/+ cells are CSCs in EBVaGC that are maintained through the LMP2A/NF‐κB pathway. Future studies should investigate CD44v6/v9+/+ cells in normal and neoplastic gastric epithelium to prevent and treat this specific subtype of gastric cancer infected with EBV. [ABSTRACT FROM AUTHOR]

Two anti-thymocyte globulin (ATG) forms are used in graft-versus-host disease (GVHD) prophylaxis during haploidentical hematopoietic stem cell transplantations (haplo-HSCTs): ATG-thymoglobulin (ATG-T) and ATG-fresenious (ATG-F). However, comparable dosages for haplo-HSCT remain unclear. We compared and evaluated the effects of ATG-T (7.5 mg/kg) or ATG-F (20 mg/kg) dosages in a relatively homogenous population in haplotype HSCT settings. Patients administered ATG-T 7.5 mg/kg (n = 81) or ATG-F 20 mg/kg (n = 35) as part of GVHD prophylaxis during haplo-HSCT were enrolled. Incidence and severity of GVHD, Epstein-Barr virus (EBV) infection, and immune cell recovery were compared using the Mann-Whitney U rank test and chi-square test. Cumulative incidences of GVHD, EBV infection and its subgroups, and relapse mortality were computed; overall survival (OS) was analyzed using the Kaplan-Meier method, with the log-rank test used for univariate comparison. Risk factors for OS were analyzed by the Cox proportional hazards model. Incidence and cumulative incidence of all grades of acute GVHD and subgroups were comparable in both groups (all p > 0.05); however, cumulative incidence of any grade and limited chronic GVHD was significantly higher in the ATG-T group (p = 0.002, p = 0.007, respectively). Cumulative incidences of EBV infections, EBV-DNAemia, and EBV-related diseases were similar; relapse mortality and OS rates were comparable between both groups (all p > 0.05). ATG-T dosage (7.5 mg/kg) appeared comparable to ATG-F dosage (20 mg/kg) for haplo-HSCT. Currently approved ATG-T and ATG-F doses appear efficient to balance the risk-benefit ratio of GVHD, OS, relapse mortality, and EBV infection in haplo-HSCT. [ABSTRACT FROM AUTHOR]

Myocardial infection by Epstein–Barr virus (EBV) may manifest with inflammatory cardiomyopathy, coronary syndrome X, and rarely with infarct‐like myocarditis. The aim of the report is to describe a case of myocardial EBV infection causing acute myocarditis with heart failure, necrotizing coronary vasculitis, and multiple left ventricular (LV) aneurysms. A 67‐year‐old woman presented with fever, chest pain, and heart failure. She underwent non‐invasive cardiac studies including electrocardiography, 2D‐echocardiography, cardiac magnetic resonance, hematochemical exams with Troponin T determination, and invasive studies including cardiac catheterization, coronary angiography, and LV endomyocardial biopsy. Five endomyocardial samples were processed for histology and immunohistochemistry for inflammatory cells characterization and detection of viral antigens. Two additional frozen samples were evaluated by real‐time polymerase chain reaction for the presence of cardiotropic viral genomes. Routine laboratory tests revealed the presence of elevated white blood cells (17 000 103/μL) and increased Troponin T. Electrocardiogram showed sinus tachycardia with ST elevation in V2–V5. Two‐dimensional echocardiography showed normal LV dimension with reduced LV contractility (LVEF = 40%) with mild pericardial effusion. Cardiac magnetic resonance revealed the presence of a micro‐aneurism in the inferior LV wall, a diffuse oedematous imbibition of LV myocardium suggested by hyper‐intensity of T2 mapping, and increased fibrosis as suggested by areas of late gadolinium enhancement signals. Coronary arteries were normal while several micro‐aneurysms were observed at LV angiography. At histology, a lymphocytic myocarditis with necrotizing coronary vasculitis sustained by a positive real‐time polymerase chain reaction for EBV, detectable in cardiomyocytes and inflamed intramural vessels by positive immunohistochemistry for EBV latent membrane protein 1 antigen, was observed. Myocardial EBV infection is an unusual cause of acute heart failure and cardiac aneurysms, increasing the risk of electrical instability, cardiac perforation, and sudden death. [ABSTRACT FROM AUTHOR]

The presence of mutations in PRF1, UNC13D, STX11 and STXBP2 genes in homozygosis or compound heterozygosis results in immune deregulation. Most such cases lead to clinical manifestations of haemophagocytic lymphohistiocytosis (HLH). In the present study, we analyzed degranulation and cytotoxicity in a pediatric patient with a late presentation of HLH associated with Epstein-Barr virus infection. Remarkably, the results of the degranulation assay showed reduction of CD107a median fluorescence intensity (MFI) and absent cytotoxicity. Genetic analysis identified compound heterozygous mutations in STXBP2 gene: a previously reported splicing defect in exon 15 (c.1247-1G>C, p.V417LfsX126) and a novel missense mutation in exon 9 (c.728T>G, p.L243R). Transfection experiments of STXBP2-L243R or STXBP2-WT constructs showed an undetectable protein expression of the STXBP2-L243R mutation. The residue L243 is highly preserved evolutionarily; moreover, computational analysis of its structure revealed its participation in the rich network of interactions that stabilizes domains 2 and 3 of the protein. Altogether, we demonstrated by molecular and in silico analysis that the new L243R mutation in STXBP2 plays a pathogenic role that, together with the p.Val417Leufsc mutation, shows the synergistic negative effect of these two mutations on STXBP2 function, leading to a decrease of degranulatory activity in vivo. [ABSTRACT FROM AUTHOR]

ObjectivesFew studies of pediatric Epstein-Barr virus (EBV)-associated infectious mononucleosis (IM) have been conducted in Korea. We evaluated the clinical features of children with IM to define differences according to age. MethodsWe conducted retrospective chart reviews of 68 children aged 0 to 15 years who were diagnosed by EBV-associated IM with EBV-Viral Capsid Antigen(VCA) IgM at laboratory test and were admitted between 2010 and 2014. The children were classified into four age groups: aged 0–3, 4–6, 7–9, and 10–15 years. ResultsThe age distribution of patients was as follows: 19 (27.9%) 0–3, 25 (36.8%) 4–6, 13 (19.1%) 7–9, and 11 (16.2%) 10–15. Fever was the most common presentation regardless of age. It was more common in the 0–3 group than the 4–6 group (P = 0.018). Pharyngitis was more common in the 7–9 group than the 0–3 group (P = 0.048), and myalgia was more common in the 10–15 group than the 0–3 group (P = 0.007). Pharyngitis was accompanied by lymphadenopathy, protracted fever, and rash. In the 0–3 age group, the prevalence of rash was higher while the percentage of atypical lymphocytes was lower, but there was no statistical support for this tendency. There were no differences in the frequency of hepatosplenomegaly or laboratory findings between age groups. ConclusionsIM is not uncommon in young children and its clinical presentation varies with age. Therefore, IM should be suspected in young febrile children with pharyngitis and rash despite low percentages of atypical lymphocytes.