Exploring atypical manifestations and multisystem involvement of Epstein-Barr virus infection in hospitalized pediatric patients from Mexico: insights from a tertiary hospital (2012-2022).

INTRODUCTION: Epstein-Barr virus (EBV) infection, with a global prevalence exceeding 95%, typically manifests in children as infectious mononucleosis. However, clinical practice frequently encounters diverse atypical presentations characterized by multisystem involvement, often resulting in an unfavorable clinical course. Our objective is to describe the clinical manifestations and results of EBV infection in a tertiary pediatric hospital in Mexico. METHOD: An observational, transversal, retrospective, and descriptive study that included a systematic review of medical records (2012-2022) of patients under 18 years of age with detectable EBV particles in peripheral blood. RESULTS: The study included 26 patients with a median age of 5 years and a male predominance of 53.8%. Predominant symptoms were fever (85%) and lymphadenopathy (35%). Sixty-five percent had severe and atypical manifestations, including pneumonia and hepatic, hematologic-oncologic, and autoimmune diseases. Anemia, thrombocytopenia and leukopenia were common, with lymphocytosis in 19% of cases. The median EBV viral load was 2816 copies/mL (range: 555-355,500 copies/mL). Four deaths related to EBV infection were reported. Viral load in these cases also varied widely from 594 to 121,000 copies/mL. Supportive care was administered to 85% of patients, while others received antiviral treatment, steroids, and rituximab. CONCLUSION: Atypical manifestations were common, especially in children with multisystem involvement. EBV should be considered as a potential contributor to a diverse spectrum of clinical presentations, emphasizing the need for comprehensive evaluation and awareness in clinical diagnosis.

INTRODUCCIÓN: La infección por el virus de Epstein-Barr (VEB) tiene una prevalencia mundial superior al 95%. Se considera que en los niños se manifiesta principalmente como mononucleosis infecciosa; sin embargo, en la práctica clínica, a menudo encontramos numerosas manifestaciones atípicas con compromiso multisistémico que llevan a un curso desfavorable. Nuestro objetivo es describir las manifestaciones clínicas y los resultados de la infección por VEB en un hospital pediátrico de tercer nivel en México. MÉTODO: Estudio observacional, transversal, retrospectivo y descriptivo, en el cual se revisaron sistemáticamente los expedientes médicos de pacientes menores de 18 años con una detección positiva de partículas de VEB en sangre periférica en el periodo 2012-2022. RESULTADOS: Se incluyeron 26 pacientes con una mediana de edad de 5 años y predominio de varones (53.8%). El 65% presentaron manifestaciones graves y atípicas, incluyendo enfermedades respiratorias, hepáticas, hematooncológicas y autoinmunitarias. Los síntomas más frecuentes fueron fiebre (85%) y linfadenopatía (35%). El 54% presentaron manifestaciones atípicas, incluyendo linfohistiocitosis hemofagocítica, neumonía y neoplasia. La anemia, la trombocitopenia y la leucocitopenia fueron comunes, mientras que el 19% presentaron linfocitosis. La media de la carga viral fue de 2816 copias/ml (555-355,500). Se informaron cuatro muertes atribuidas a la infección por VEB, con valores de carga viral de 594 a 121,000 copias/ml. El 85% de los pacientes recibieron solo tratamiento sintomático, mientras que otros recibieron antivirales, esteroides y rituximab. CONCLUSIÓN: Las manifestaciones atípicas se observaron comúnmente, en especial en niños con compromiso multisistémico. El VEB debe considerarse como un potencial factor contribuyente en el diagnóstico de una amplia gama de manifestaciones clínicas.

Epstein-Barr virus-associated post-transplant smooth muscle tumours in a kidney transplant patient.

We report on a 14-year-old girl who developed post-transplantation smooth muscle tumours (PTSMT) located in the spleen, lungs, liver, and central nervous system (CNS), 4 years after kidney transplantation. She was asymptomatic, and the disease was detected during the work-up for a urinary tract infection. Diagnosis was performed by the analysis of a tissue specimen, through the biopsy of a lung tumour, which revealed a proliferation of spindle-shaped cells which were positive for actin and vimentin. In situ hybridization studies were positive for Epstein-Barr virus, and her serologic status was negative prior to transplantation. We reduced immunosuppression by stopping mycophenolate and switching tacrolimus for sirolimus. After 18 months of follow-up, she remains asymptomatic, and the CNS tumour reduced its diameter from 24 × 21 mm to 14 × 13 mm. PTSMT should be considered in the differential diagnosis of transplanted patients who develop neoplastic complications associated with immunosuppression.

Gene profiling of Epstein-Barr Virus and human endogenous retrovirus in peripheral blood mononuclear cells of SLE patients: immune response implications.

Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by the convergence of genetic, immunological, and viral elements resulting in a complex interaction of both internal and external factors. The role of the Epstein-Barr virus (EBV) and human endogenous retroviruses (HERV-E) as triggers and maintenance elements in the pathogenesis of SLE has been widely recognized. Previous studies have independently evaluated the effects of EBV and HERV-E in this disease. In this work, for the first time, these viral factors are jointly investigated in SLE patients. This study aimed at assessing the differential expression of immune regulatory genes and the incidence of specific viral pathogens (EBV and HERV-E), alongside the detailed characterization of surface markers in T- and B-lymphocytes in patients with SLE and control participants. A comparative analysis between patients with SLE and control participants was performed, evaluating the expression of phenotypic markers and genes involved in the immune response (TNF-α, IL-2, IL-6, IL-10, IFNG, TLR3), as well as HERV-E gag and EBV viral genes (LMP1 and BZLF1).A significant association between SLE and EBV was found in this study. A notable increase in EBV LMP1 gene expression was observed in patients with SLE . Also, a significant overexpression of HERV-E was observed, in addition to a considerable increase in the distribution of the cell surface marker CD27 + on T- and B-lymphocytes, observed in individuals with SLE compared to the control group. This study provides evidence regarding the role that EBV virus plays in lymphocytes in the context of SLE, highlighting how both the virus and the host gene expression may influence disease pathogenesis by altering immune regulatory pathways mediated by TNF-α, IFN-γ, and IL-10, as well as parallel overexpression of HERV-E gag. The decrease in TLR3 could indicate a compromised antiviral response, which could facilitate viral reactivation and contribute to disease activity.

[Cold agglutinin syndrome associated with infectious mononucleosis: A case report]. / Síndrome por aglutininas frías secundario a mononucleosis infecciosa: reporte de un caso.

Background: Cold agglutinin syndrome (CAS) is a hemolytic anemia mediated by antibodies, mainly IgM, whose maximum activity occurs at 4 °C. It happens secondary to infectious, autoimmune or neoplastic diseases, due to the formation of antibodies that cross-react against erythrocyte antigens, particularly of the I system. Here, we describe a case of CAS associated to Epstein-Barr virus (EBV) reactivation in a patient with primary human immunodeficiency virus (HIV) infection. Clinical case: 22-year old man with no medical history, hospitalized due to mononucleosis and anemic syndrome. Hemoglobin of 3.7 g/dL and elevation of lactate dehydrogenase were documented. In the peripheral blood smear it was observed spherocytosis, polychromasia and nucleated erythrocytes. EBV infection was confirmed with serology and viral load, as well as seronegative HIV infection with positive viral load. The C3d monospecific direct antiglobulin test was positive and an irregular antibody screening revealed the presence of an anti-I antibody. The patient received transfusion support and conservative treatment, with remission of the symptoms 2 weeks after admission. Conclusions: Cold agglutinin syndrome is a rare, potentially fatal complication of infectious mononucleosis, which should be considered in the face of findings suggestive of hemolysis in order to initiate support measures in a timely manner.

Introducción: el síndrome por aglutininas frías (SAF) es una anemia hemolítica mediada por anticuerpos principalmente de tipo IgM, cuya máxima actividad se da a 4 °C. Se presenta en el contexto de enfermedades infecciosas, autoinmunes o neoplásicas por la formación de anticuerpos que tienen reacción cruzada contra antígenos eritrocitarios, particularmente del sistema I. En este trabajo presentamos un caso de SAF asociado a reactivación del virus de Epstein-Barr (VEB) en un paciente con primoinfección por el virus de la inmunodeficiencia humana (VIH). Caso clínico: hombre de 22 años, sin antecedentes patológicos, hospitalizado por síndrome mononucleósico y anémico. Presentó hemoglobina de 3.7 g/dL y elevación de lactato deshidrogenasa. En el frotis de sangre periférica se observó esferocitosis, policromasia y eritrocitos nucleados. Se confirmó infección por VEB con serología y carga viral, así como infección por VIH seronegativa, con carga viral positiva. La prueba de antiglobulina directa monoespecífica a C3d fue positiva y el rastreo de anticuerpos irregulares demostró un anticuerpo anti-I. El paciente recibió soporte transfusional y tratamiento conservador, con remisión del cuadro a las 2 semanas de su ingreso. Conclusiones: el SAF es una complicación poco frecuente de la mononucleosis infecciosa, potencialmente mortal, la cual debe ser considerada ante hallazgos sugestivos de hemólisis con la finalidad de iniciar medidas de soporte de forma oportuna.

Coinfection Suspicion is Imperative in Immunosuppressed Patients with Suspected Infectious Uveitis and Inadequate Treatment Response: A Case Report.

BACKGROUND: To report a case of coinfection of Toxoplasma gondii (Tg) and Epstein Barr Virus (EBV) in a diabetic patient with rheumatoid arthritis and immunosuppressive biological therapy. CASE PRESENTATION: A 70-year-old female with a history of rheumatoid arthritis on therapy with corticosteroids, methotrexate, and abatacept presented bilateral granulomatous panuveitis associated with retinal necrosis and macular involvement. A diagnostic vitrectomy detected Tg and EBV. Treatment with clindamycin, trimethoprim-sulfamethoxazole, and acyclovir was established, achieving improvement. CONCLUSIONS: Patients undergoing immunosuppressive therapy are at risk of developing opportunistic infections, often presenting with severe and atypical clinical manifestations. In such cases, multiplex polymerase chain reaction is an invaluable diagnostic tool that helps identify the specific pathogens involved. This enables healthcare professionals to make informed treatment decisions and provide targeted therapy for each identified pathogen.

Association between Epstein-Barr virus LMP-1 and Hodgkin lymphoma LMP-1 mechanisms in Hodgkin lymphoma development.

Hodgkin lymphoma is histologically characterised by the presence of Hodgkin (H) and Reed-Sternberg (RS) cells originating from germinal centre B-cells rearranged in the IgV gene. The formation of multinucleated RS cells is a product of telomere organisation in a process initiated by telomere aggregate accumulation in mononuclear H cells and may be mediated by latent membrane protein 1 (LMP-1) expression. LMP-1 is the main oncoprotein of EBV and supports several tumourigenic processes. LMP-1 may rescue proapoptotic B-cells through downregulation of B-cell receptor (BCR) components, mimicking and inducing multiple distinct B-cell signalling pathways to promote proliferation and survival, such as Janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-kappa b (NF-кB), and cellular MYC (c-MYC), and inducing telomere instability mainly through Telomere repeat binding factor 2 (TRF2) downregulation to promote the formation of multinucleated RS cells. This review presents recent discoveries regarding the influence of LMP-1 on the surviving cellular signalling, genomic instability and mecanical formation of HRS cells.

Immune Deficiency/Dysregulation Associated Lymphoid Proliferations, EBV+ In Persons Living With HIV

ABSTRACT Background: The 5th edition of the World Health Organization Classification of Hematolymphoid Tumors recently defined immune deficiency/dysregulation (IDD)-associated-lymphoid-proliferations in HIV settings, where information is scarce, often gone under or misdiagnosed. Objectives: To describe the clinical picture, histopathology, and outcomes of IDD-associated-lymphoid-proliferations Epstein-Barr virus+ (EBV) in people living with HIV without organ transplantation, antiretroviral therapy (ART) treated. Methods: HIV+ patients diagnosed with IDD-associated-lymphoid-proliferations seen at an academic medical center in Mexico from 2016 to 2019 were included. Immunohistochemical studies, in situ hybridization, and polymerase chain reaction analysis for EBV and LMP1 gene deletions were performed and correlated with clinical data. Results: We included 27 patients, all men who have sex with men, median age 36 years (interquartile range [IQR] 22-54). The median baseline CD4+ T cells were 113/mL (IQR 89-243), the CD4+/CD8+ ratio was 0.15 (IQR: 0.09-0.22), and the HIV viral load was 184,280 copies/mL (IQR: 76,000-515,707). Twenty patients (74.07%) had IDD-associated-lymphoid-proliferations hyperplasia plasma cell type EBV+, 3 (11.1%) had hyperplasia mononucleosis-like type (IM-type), 1 patient (3.70%) had florid follicular hyperplasia, 3 (11.1%) IDD-associated-lymphoid-proliferations polymorphic type, and there were 22 cases (81.4%) of synchronic Kaposi Sarcoma. Two patients were diagnosed with Hodgkin lymphoma following a second positron emission tomography-computed tomography scan-guided biopsy. The median follow-up was 228 weeks (IQR 50-269); 6 patients died (22.2%) of causes unrelated to IDD-associated-lymphoid-proliferations related. Conclusion: IDD-associated-lymphoid-proliferations EBV+ occured in severely immunosuppressed HIV+ patients, a high percentage of whom had concomitant Kaposi sarcoma. The prognosis was good in patients treated only with ART.

Immune Deficiency/Dysregulation Associated Lymphoid Proliferations, EBV+ In Persons Living With HIV.

Background: The 5th edition of the World Health Organization Classification of Hematolymphoid Tumors recently defined immune deficiency/dysregulation (IDD)-associated-lymphoid-proliferations in HIV settings, where information is scarce, often gone under or misdiagnosed. Objectives: To describe the clinical picture, histopathology, and outcomes of IDD-associated-lymphoidproliferations Epstein-Barr virus+ (EBV) in people living with HIV without organ transplantation, antiretroviral therapy (ART) treated. Materials and Methods: HIV+ patients diagnosed with IDD-associated-lymphoid-proliferations seen at an academic medical center in Mexico from 2016 to 2019 were included. Immunohistochemical studies, in situ hybridization, and polymerase chain reaction analysis for EBV and LMP1 gene deletions were performed and correlated with clinical data. Results: We included 27 patients, all men who have sex with men, median age 36 years (interquartile range [IQR] 22-54). The median baseline CD4+ T cells were 113/mL (IQR 89-243), the CD4+/CD8+ ratio was 0.15 (IQR: 0.09-0.22), and the HIV viral load was 184,280 copies/mL (IQR: 76,000-515,707). Twenty patients (74.07%) had IDD-associated-lymphoid-proliferations hyperplasia plasma cell type EBV+, 3 (11.1%) had hyperplasia mononucleosis-like type (IM-type), 1 patient (3.70%) had florid follicular hyperplasia, 3 (11.1%) IDD-associated-lymphoid-proliferations polymorphic type, and there were 22 cases (81.4%) of synchronic Kaposi Sarcoma. Two patients were diagnosed with Hodgkin lymphoma following a second positron emission tomography-computed tomography scan-guided biopsy. The median follow-up was 228 weeks (IQR 50-269); 6 patients died (22.2%) of causes unrelated to IDD-associated-lymphoid-proliferations related. Conclusion: IDD-associated-lymphoid-proliferations EBV+ occured in severely immunosuppressed HIV+ patients, a high percentage of whom had concomitant Kaposi sarcoma. The prognosis was good in patients treated only with ART.

Lytic and Latent Genetic Diversity of the Epstein-Barr Virus Reveals Raji-Related Variants from Southeastern Brazil Associated with Recombination Markers.

Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus etiologically associated with benign and malignant diseases. Since the pathogenic mechanisms of EBV are not fully understood, understanding EBV genetic diversity is an ongoing goal. Therefore, the present work describes the genetic diversity of the lytic gene BZLF1 in a sampling of 70 EBV-positive cases from southeastern Brazil. Additionally, together with the genetic regions previously characterized, the aim of the present study was to determine the impact of viral genetic factors that may influence EBV genetic diversity. Accordingly, the phylogenetic analysis of the BZLF1 indicated two main clades with high support, BZ-A and BZ-B (PP > 0.85). Thus, the BZ-A clade was the most diverse clade associated with the main polymorphisms investigated, including the haplotype Type 1 + V3 (p < 0.001). Furthermore, the multigene phylogenetic analysis (MLA) between BZLF1 and the oncogene LMP1 showed specific clusters, revealing haplotypic segregation that previous single-gene phylogenies from both genes failed to demonstrate. Surprisingly, the LMP1 Raji-related variant clusters were shown to be more diverse, associated with BZ-A/B and the Type 2/1 + V3 haplotypes. Finally, due to the high haplotypic diversity of the Raji-related variants, the number of DNA recombination-inducing motifs (DRIMs) was evaluated within the different clusters defined by the MLA. Similarly, the haplotype BZ-A + Raji was shown to harbor a greater number of DRIMs (p < 0.001). These results call attention to the high haplotype diversity of EBV in southeast Brazil and strengthen the hypothesis of the recombinant potential of South American Raji-related variants via the LMP1 oncogene.

[Anything that can go wrong: cytotoxic cells and their control of Epstein-Barr virus]. / Si algo puede fallar: las células citotóxicas en la contención del virus Epstein-Barr.

Epstein-Barr virus (EBV) is an gamma of herpes virus affecting exclusively humans, was the first oncogenic virus described and is associated with over seven different cancers. Curiously, the exchange of genes during viral infections has enabled the evolution of other cellular organisms, favoring new functions and the survival of the host. EBV has been co-evolving with mammals for hundreds of millions of years, and more than 95% of adults have been infected in one moment of their life. The infection is acquired primarily during childhood, in most cases as an asymptomatic infection. However, during adolescence or young adulthood, around 10 to 30% develop infectious mononucleosis. The NK and CD8+ T cells are the cytotoxic cells of the immune system that focus on antiviral responses. Importantly, an essential role of NK and CD8+ T cells has been demonstrated during the control and elimination of EBV-infected cells. Nonetheless, when the cytotoxic function of these cells is compromised, the infection increases the risk of developing lymphoproliferative diseases and cancer, often fatal. In this review, we delineate EBV infection and the importance of cytotoxic responses by NK and CD8+ T cells during the control and elimination of EBV-infected cells. Furthermore, we briefly discuss the main inborn errors of immunity that compromise cytotoxic responses by NK and CD8+ T cells, and how this scenario affects the antiviral response during EBV infection. Finally, we conclude the review by underlying the need for an effective EBV vaccine capable of preventing infection and the consequent development of malignancies and autoimmune diseases.

El virus Epstein-Barr es una variante del herpes virus que afecta exclusivamente a humanos; fue el primer virus oncogénico descrito y se ha relacionado con más de siete diferentes tipos de cáncer. Curiosamente, el intercambio de genes debido a infecciones virales ha permitido la evolución de los organismos celulares, favoreciendo el desarrollo de nuevas funciones y supervivencia del hospedero. El virus Epstein-Barr comparte cientos de millones de años de coevolución con la especie humana y más del 95% de la población adulta mundial se ha infectado en algún momento de su vida. La infección se adquiere principalmente durante la infancia, y en la mayoría de los casos aparece sin ninguna manifestación grave aparente. Sin embargo, en los adolescentes y la población joven-adulta, alrededor de un 10 a 30% evolucionan a mononucleosis infecciosa. Las células NK y T CD8+ son células citotóxicas cruciales durante las respuestas antivirales y se ha demostrado que que controlan y eliminan la infección por el virus Epstein-Barr. No obstante, cuando se afecta su función efectora, el desenlace puede ser fatal. El objetivo de esta revisión es describir la infección por el virus Epstein-Barr y el papel decisivo de las células NK y T CD8+ durante el control y eliminación de la infección. Además, se discuten brevemente los principales defectos genéticos que afectan a estas células y conllevan a la incapacidad para eliminar el virus. Finalmente, se resalta la necesidad de elaborar una vacuna efectiva contra el virus Epstein-Barr y cómo podrían evitarse los procesos neoplásicos y enfermedades autoinmunes.

The role and impact of viruses on cancer development.

This review focuses on three major aspects of oncoviruses' role in cancer development. To begin, we discuss their geographic distribution, revealing that seven oncoviruses cause 20% of all human cancers worldwide. Second, we investigate the primary carcinogenic mechanisms, looking at how these oncogenic viruses can induce cellular transformation, angiogenesis, and local and systemic inflammation. Finally, we investigate the possibility of SARS-CoV-2 infection reactivating latent oncoviruses, which could increase the risk of further disease. The development of oncovirus vaccines holds great promise for reducing cancer burden. Many unanswered questions about the host and environmental cofactors that contribute to cancer development and prevention remain, which ongoing research is attempting to address.

Mononucleosis infecciosa en paciente con fiebre prolongada

La mononucleosis infecciosa es una enfermedad infectocontagiosa causada por el virus de Epstein-Barr, que afecta principalmente a personas jóvenes, se caracteriza por presencia de fiebre, faringitis y linfadenopatía, generalmente autolimitada, de 1-2 semanas de evolución. Se presenta el caso de un paciente masculino de 22 años con historia de 1 mes de evolución de fiebre y cefalea al que posteriormente se añade odinofagia, adenopatía cervical posterior y exantema generalizado. En analítica laboratorial se constata leucocitosis con neutrofilia. Entre sus estudios complementarios retorna IgM para virus de Epstein-Barr positivo.

Infectious mononucleosis is an infectious disease caused by the Epstein-Barr virus, which mainly affects young people. It is characterized by the presence of fever, pharyngitis and lymphadenopathy, generally self-limited, lasting 1-2 weeks. The case of a 22-year-old male patient with a 1-month history of fever and headache is presented to which odynophagia, posterior cervical lymphadenopathy, and generalized rash are later added. Laboratory analysis revealed leukocytosis with neutrophilia. Among his complementary studies, IgM for Epstein-Barr virus was positive.

Disseminated Nasal subtype Extranodal NK/T-cell lymphoma and its diagnostic difficulties in antemortem biopsies.

Extranodal NK/T- cell lymphoma (ENKTCL) is an aggressive lymphoma driven by Epstein-Barr virus (EBV) infection in genetically susceptible individuals. It was historically called a lethal midline granuloma. Due to the angio-destructive nature of ENKTCL, lymphoma cells are often accompanied and masked by necrosis and dense inflammation in the biopsy. Further, the biopsy may show vasculitis, which can mimic granulomatosis with polyangiitis. Due to these masquerades, ENKTCL is often misdiagnosed in the biopsy. Several biopsies may be required to establish the diagnosis. We describe the clinical course and autopsy findings of a young female who presented with a hard-palate ulcer. Antemortem biopsies failed to establish the diagnosis. The autopsy revealed an advanced nasal subtype of Extranodal NK/T-cell lymphoma with dissemination to the kidneys, adrenals, liver, spleen, and small intestine.

Extranodal NK-/T-cell lymphoma, nasal type: what advances have been made in the last decade?

Extranodal NK-/T-cell lymphoma (ENKTCL) is a rare and highly aggressive malignancy with significant racial and geographic variations worldwide. In addition to the formerly "nasal-type" initial description, these lymphomas are predominantly extranodal in origin and typically cause vascular damage and tissue destruction, and although not fully understood, Epstein-Barr virus (EBV) has an important role in its pathogenesis. Initial assessment must include a hematopathology review of representative and viable tumor areas without necrosis for adequate immunohistochemistry studies, including EBV-encoded small RNA (EBER) in situ hybridization (ISH). Positron emission tomography with 18-fluorodeoxyglucose (18F-FDG-PET/CT) for accurate staging is essential, and most patients will have localized disease (IE/IIE) at diagnosis. Apart from other T-cell malignancies, the best treatment even for localized cases is combined modality therapy (chemotherapy plus radiotherapy) with non-anthracycline-based regimens. For advanced-stage disease, l-asparaginase-containing regimens have shown improved survival, but relapsed and refractory cases have very poor outcomes. Nowadays, even with a better understanding of pathogenic pathways, up-front therapy is completely based on chemotherapy and radiotherapy, and treatment-related mortality is not low. Future strategies targeting signaling pathways and immunotherapy are evolving, but we need to better identify those patients with dismal outcomes in a pre-emptive way. Given the rarity of the disease, international collaborations are urgently needed, and clinical trials are the way to change the future.

p16INK4a and pRb expression in laryngeal squamous cell carcinoma with and without infection by EBV or different genotypes of HPV: a retrospective study.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) represents one of the principal tumors of the head and neck. Human papillomavirus (HPV) and Epstein-Barr virus (EBV) are considered risk factors for the development and the clinical prognosis of LSCC. High levels of p16INK4a are suggested as a surrogate marker of HPV or EBV infection in some head and neck tumors but in LSCC is still controversial. Furthermore, pRb expression may be considered an additional biomarker but it has not been clearly defined. This work aimed to compare the expression of pRb and p16INK4a as possible biomarkers in tumor tissues with and without infection by EBV or different genotypes of HPV from patients with LSCC. METHODS: Tumor samples from 103 patients with LSCC were previously investigated for the presence and genotypes of HPV using the INNO-LiPA line probe assay and for the infection of EBV by qPCR. p16 INK4a and pRb expression was assessed by immunohistochemistry. RESULTS: Of the 103 tumor samples, expression of p16INK4a was positive in 55 (53.4%) and of this, 32 (56.1%) were positive for HPV whereas 11 (39.3%) were EBV positive but both without a significantly difference (p > 0.05). pRb expression was positive in 78 (75.7%) and a higher frequency of this expression was observed in HPV negative samples (87.0%) (p = 0.021) and in high-risk HPV negative samples (85.2%) (p = 0.010). No difference was observed when comparing pRb expression and EBV infection status (p > 0.05). CONCLUSION: Our results support the suggestion that p16INK4a is not a reliable surrogate marker for identifying HPV or EBV infection in LSCC. On the other hand, most of our samples had pRb expression, which was more frequent in tumors without HPV, suggesting that pRb could indicate HPV negativity. However, more studies with a larger number of cases are required, including controls without LSCC and evaluating other molecular markers to determine the real role of p16INK4a and pRb in LSCC.

Epstein­Barr virus as a promoter of tumorigenesis in the tumor microenvironment of breast cancer (Review).

Epstein­Barr virus (EBV) is an oncovirus associated with various neoplasms, including breast cancer (BC). EBV­associated oncogenesis requires the action of several viral molecules, such as EBV nuclear antigen 3C, latent membrane protein 1, microRNAs and long non­coding RNAs, which are able of manipulating the cellular machinery, inducing an evasion of the immune system, blocking apoptosis processes, promoting cell survival and metastasis. The risk of developing cancer is associated with epigenetic alterations and alterations in various signaling pathways. The activation of all these molecules can modify the expression of EBV proteins with oncogenic activity, influencing the oncogenic process. It is clear that BC, being multifactorial, presents a greater complexity; in numerous cases, the infection associated with EBV may be crucial for this neoplasia, if particular conditions for both the virus and host are present. In the present review, all these variables are analyzed in an aim to improve the understanding of the participation of EBV in BC.

Exploring the Genetic Diversity of Epstein-Barr Virus among Patients with Gastric Cancer in Southern Chile.

The Epstein-Barr virus (EBV) has been associated with gastric cancer (GC), one of the deadliest malignancies in Chile and the world. Little is known about Chilean EBV strains. This study aims to investigate the frequency and genetic diversity of EBV in GC in patients in southern Chile. To evaluate the prevalence of EBV in GC patients from the Chilean population, we studied 54 GC samples using the gold standard detection method of EBV-encoded small RNA (EBER). The EBV-positive samples were subjected to amplification and sequencing of the Epstein-Barr virus nuclear protein 3A (EBNA3A) gene to evaluate the genetic diversity of EBV strains circulating in southern Chile. In total, 22.2% of the GC samples were EBV-positive and significantly associated with diffuse-type histology (p = 0.003). Phylogenetic analyses identified EBV-1 and EBV-2 in the GC samples, showing genetic diversity among Chilean isolates. This work provides important information for an epidemiological follow-up of the different EBV subtypes that may cause GC in southern Chile.

Single-center "Argentine" analysis of post-transplant lymphoproliferative disorders: incidence, histopathological characteristics and EBV status

ABSTRACT Introduction: Post-transplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations occurring after solid organ or bone marrow transplantation. The primary aims of our study were to characterize cumulative incidence of PTLDs, clinical and pathological features according to the Epstein-Barr virus (EBV) status and survival. Methods: This was a retrospective cohort study on adult and pediatric patients, from January 2001 to December 2017. The cumulative incidence of PTLD was calculated by analyzing all the patients transplanted at our hospital, based on the database of the Organ Donation and Ablation Authority of Argentina (INCUCAI). The Kaplan-Meier method was used to plot the survival. Results: Fifty-eight cases of biopsy-confirmed PTLD were identified and 12 cases of clinical data were incomplete and these patients were excluded. The median age at the time of the PTLD diagnosis was 17.5 years (interquartile range [IQR] 9 - 57). The median interval between transplant and PTLD diagnosis was 39 months (IQR 9 - 113). The most commonly transplanted organ was the liver (24 cases, 52.2%), followed by kidney (20 cases, 43.5%). The Epstein-Barr encoding region in situ hybridization (EBER ISH) was positive in 29 (69.8%) of the 43 evaluable biopsies. The PTLD cumulative incidence was 1.84% (95%CI 1.77 - 1.91) for solid organ and 0.84% (95%CI 0.48 - 1.2) for bone marrow transplant patients. The overall survival rate at 5 years was 0.77 (95%CI 0.61 - 0.87). Subgroups by the EBV EBER status, transplant type, PTLD subtype and age group (adult vs. pediatric) showed no statistically significant association with the overall survival. Conclusion: The PTLD incidence was similar to that of previous series and the EBER did not appear as a relevant factor in our patient survival.