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.

Analysis of cytokines level in patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis / 白血病·淋巴瘤

Objective:To investigate the level change of cytokines in patients with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH).Methods:A retrospective case control study was conducted. The clinical data of 65 patients with EBV-HLH, 30 patients with infectious mononucleosis (IM) (IM group) and 40 patients with non-EBV infection-associated hemophagocytic lymphohistiocytosis (non-EBV-HLH group) who admitted to Tongji Hospital,Tongji Medical College of Huazhong University of Science and Technology from February 2022 to February 2023 were retrospectively analyzed. The enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of the interleukin (IL)-6, IL-2, IL-10, IL-8, IL-1β, tumor necrosis factor-α (TNF-α) and interferon γ (IFN-γ) in serum samples of patients in the above 3 groups. The cytokines levels in EBV-HLH group were compared with those in IM group and non-EBV-HLH group, respectively.Results:The cytokines levels of IL-6, IL-2, IL-10, IL-8, IL-1β, TNF-α and IFN-γ in EBV-HLH group were higher than those in the non-EBV-HLH group, and the differences were statistically significant (all P < 0.05). The cytokines levels of IL-2, IL-10 and IFN-γ in EBV-HLH group were higher than those in IM group, and the differences were statistically significant (all P < 0.05). Conclusions:The cytokines levels of IL-6, IL-2, IL-10, IL-8, IL-1β, TNF-α, IFN-γ are increased in EBV-HLH patients, which may play an important role in the development and progression of EBV-HLH.

Clinicopathologic characteristics of Epstein-Barr virus-positive inflammatory follicular dendritic cell sarcoma:report of nine cases / 临床与实验病理学杂志

Purpose To explore the clinicopathologic fea-tures of Epstein-Barr virus-positive inflammatory follicular den-dritic cell sarcoma(EBV+IFDCS).Methods The clinico-pathologic features of 9 cases of EBV+IFDCS were retrospective-ly analyzed and followed up.Results The age of 9 patients with EBV+IFDCS ranged from 22 to 78 years(mean 44.7 years).7 cases occurred in the liver and 2 in the spleen.Fi-brinoid degeneration and hyaline degeneration in the vessel walls(6/9),eosinophilic infiltration(3/9),and epithelioid granulo-mas(2/9)were seen in some cases.The tumor cells expressed CD21(7/9),CD23(8/9)and CD35(9/9),partially ex-pressed SMA(6/9)and D2-40(1/9).It was noteworthy that 2 cases from the spleen accompanied by high expression of IgG4 plasma cells(80-135/10 HPF),and in the liver(0-36/10 HPF).All cases were followed up for 3-84 months,with 6 pa-tients disease-free,2 patients underwent metastasis,1 patient lost of follow-up.Conclusion EBV+IFDCS is a rare low-grade malignant tumor.EBER in situ hybridization and immunohisto-chemical detection play important roles in the diagnosis and dif-ferential diagnosis of EBV+IFDCS.Surgical resection is the main therapeutic intervention for EBV+IFDCS,and patients re-quire long-term post-surgical follow-up.

Inflammatory pseudotumor-like follicular dendritic cell sarcoma of the spleen:2 cases report and literature review / 复旦学报（医学版）

Inflammatory pseudotumor-like follicular dendritic cell sarcoma(IPT-like FDCS)is a very rare malignant tumor that is considered to be associated with Epstein-Barr virus.Two patients in this report were generally healthy,and the spleen tumor was found during physical examination.After completing the examination,laparoscopic total splenectomy was performed,and the pathological result showed IPT-like FDCS.Postoperative chemoradiotherapy was not performed in either case.The disease has no characteristic clinical manifestations,and imaging overlaps with sarcoma.Microscopic manifestation showed CD21,CD23 and EBER positive spindle tumor cells in the inflammatory background with matted arrangement.Due to the interwoven distribution of tumor cells and lymphocytes,diagnosis is difficult.In this article,we report this two cases with literature review and summarize their clinical and pathological features to improve diagnostic cognition.

Clinical Immunological Characteristic and Influencing Factors Analysis of HIV/AIDS Patients Infected with EBV and HCMV / 现代检验医学杂志

Objective To investigate the basic information of human immunodeficiency virus/acquired immune deficiency syndrome(HIV/AIDS)patients who infected with Epstein-Barr virus(EBV)or human Cytomegalovirus(HCMV),collect the relevant clinical immunological data and analyze the influencing factors.Method A total of 1 093 HIV/AIDS patients treated in the First Hospital of Changsha from January to December 2022 and underwent EBV and HCMV screening were collected.Flow cytometry was used to detect the CD4+T lymphocytes.Fluorescence quantitative PCR was applied for HIV-RNA,EBV-DNA,and HCMV-DNA testing.Statistical analysis was carried out by using SPSS 27.0,and logistic regression was used to analyze the risk factors of HIV/AIDS patients complicated with viral infection.Results Among 1 093 HIV/AIDS patients,the positive rates of EBV-DNA and HCMV-DNA were 48.22%(527/1 093)and 19.03%(208/1 093),respectively.As the number of CD4+T lymphocytes increased,the positive rates of EBV-DNA and HCMV-DNA decreased,and the differences was statistically significant(χ2=39.50,143.0,all P<0.001).As the level of HIV-RNA increased,the positive rates of EBV-DNA and HCMV-DNA increased,and the differences were statistically significant(χ2=46.18,124.3,all P<0.001).The patients receiving antiretroviral therapy(ART)significantly decreased the positive rates of EBV-DNA and HCMV-DNA(χ2=30.60,96.59,all P<0.001).There was a significant negative correlation between the number of CD4+T lymphocytes and the level of HIV-RNA(r=-0.49,P<0.001).Logistic regression analysis showed that the CD4+T lymphocyte count<200/μl(OR=1.46,95%CI:1.02～2.08,P=0.037),HIV-RNA load>200 copies/ml(OR=1.70,95%CI:1.18～2.44,P=0.004)and the age>30 years old(OR=2.15,95%CI:1.44～3.19,P<0.001)were risk factors for HIV/AIDS patients infected with EBV.Without regularly receiving ART(OR=1.83,95%CI:1.10～3.02,P=0.019),HIV-RNA load>200 copies/ml(OR=2.56,95%CI:1.50～4.35,P<0.001)and the CD4+T lymphocyte count<200/μl(OR=4.61,95%CI:2.57～8.28,P<0.001)were risk factors for HCMV infection in HIV/AIDS patients.Conclusion To reduce the possibility of opportunistic infection in HIV/AIDS patients,the surveillance of EBV and HCMV and regular ART should be strengthened,especially when the number of CD4+T lymphocytes decreases(<200/μl),the level of HIV RNA increases(>200 copies/ml)or the age>30 years old.

Circular RNAs Involved in The Development of Nasopharyngeal Carcinoma / 生物化学与生物物理进展

Circular RNAs (circRNAs) are a kind of non-coding RNA (ncRNA) with covalent closed-loop structure. They have attracted more and more attention because of their high stability, evolutionary conservatism, and tissue expression specificity. It has shown that circRNAs are involved in the development of a variety of diseases including malignant tumors recently. Nasopharyngeal carcinoma (NPC) is a malignant tumor that occurs in the nasopharynx and has a unique ethnic and geographical distribution in South China and Southeast Asia. Epstein-Barr virus (EBV) infection is closely related to the development of NPC. Radiotherapy and chemotherapy are the mainstays of treatment for NPC. But tumor recurrence or distant metastasis is the leading cause of death in patients with NPC. Several studies have shown that circRNAs, as gene expression regulators, play an important role in NPC and affect the progression of NPC. This review mainly summarized the research status of abnormally expressed circRNAs in NPC and EBV-encoded circRNAs. We also discussed the possibility of circRNAs as a therapeutic target, diagnostic and prognostic marker for NPC.

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.

Hydroa vacciniforme-like lymphoproliferative disorder in Ecuadorian children: A case series

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

Carcinoma tipo-linfoepitelioma pulmonar con expresión de virus de Epstein-Barr y PD-L1 / Pulmonary lymphoepithelioma-like carcinoma with ex pression of Epstein-Barr virus and PD-L1

Resumen El carcinoma tipo-linfoepitelioma pulmonar es una variante rara de carcinoma de células no pequeñas de pulmón, representa aproximadamente 0.7% de todos los casos. Está usualmente asociado con la infección por el virus de Epstein-Barr y es más prevalente en el Sureste de Asia; sin embargo, es extremadamente raro en Améri ca Latina. Informamos el caso de un hombre de 65 años de edad con un carcinoma tipo-linfoepitelioma pulmo nar, que se presentó con tos, disnea y pérdida de peso. La TAC de tórax mostró nódulo mal definido localizado en el pulmón derecho. Se realizó biopsia transtorácica de la lesión, y el estudio microscópico reveló células gran des poligonales dispuestas en mantos, infiltrados por abundantes linfocitos y células plasmáticas, alrededor del intersticio. Las células neoplásicas fueron positivas para citoqueratina 5/6 y p63, y negativas para Napsina A y el factor de transcripción tiroideo 1 (TTF-1). La expre sión de PD-L1 fue positivo (aproximadamente 100%) por inmunohistoquímica; así como el núcleo de las células neoplásicas mediante hibridación in situ para el RNA codificado por el virus de Epstein-Barr (EBER-ISH). El paciente recibió seis ciclos de un esquema combinado de quimioterapia basado en platino (gencitabina/cisplatino) más durvalumab. Presentó progresión de la enfermedad y finalmente murió 9 meses después del diagnóstico.

Abstract Pulmonary lymphoepithelioma-like carcinoma is a rare type of non-small cell lung cancer, it accounts for approximately 0.7% of all cases. It is usually associated with Epstein-Barr virus infection and is more prevalent in Southeast Asia; however, it is extremely rare in Latin America. We present a 65-year-old man with a primary pulmonary lymphoepithelioma-like carcinoma, who presented with cough, dyspnoea and weight loss. Com puter tomographic scan of the thorax showed a nodule localized in the right lung. A transthoracic biopsy of the lung lesion was made and the microscopic obser vation revealed large polygonal cells that proliferated in a nest pattern with infiltration by lymphocytes and plasma cells around the interstitium. The tumour cells were positive for citokeratin 5/6 and p63, and negative for Napsin A and thyroid transcription factor 1 (TTF-1). PD-L1 expression was positive (approximately 100%) in the immunohistochemical study, and the nuclei of the tumour cells were positive for EBV-encoded small RNA in-situ hybridization (EBER-ISH). The patient underwent six cycles of platinum-based combination (gencitabine/ carboplatin) chemotherapy plus durvalumab. He pre sented progression of the disease and finally he died 9 months after diagnosis.

Vírus Epstein-Barr associado ao Linfoma de Hodgkin clássico: um estudo de casos / Epstein-Barr virus associated with classical Hodgkin lymphoma: a case study

Introdução: A expressão da positividade do vírus Epstein-Barr nas células de Reed-Sternberg/Hodgkin e o impacto dessa relação na sobrevida do Linfoma de Hodgkin clássico (LHc) permanecem controversos. Objetivo: Avaliar a presença de Epstein Baar Vírus (EBV) em pacientes com LHc, associando com características anatomopatológicas e clínicas. Materiais e Métodos: Para determinar a presença de EBV, a partir de um material de biópsia de tecidual foi realizada analise por hibridização para RNA codificado para EBV (EBER) e imuno-histoquímica para proteína de membrana latente viral (LMP-1) de uma amostra de demanda de pacientes com diagnóstico entre janeiro de 2009 e janeiro de 2015. As características clínicas avaliadas foram as que compõem o Escore Prognóstico Internacional para estadiamento avançado e os fatores de risco desfavoráveis instituídos pelo Grupo Alemão de Estudos em Hodgkin para estadiamento limitado. Posteriormente, tais características foram relacionadas com a situação do vírus nas células tumorais. Resultados: Foram avaliadas as lâminas de biópsia de 29 pacientes com diagnóstico de Linfoma de Hodgkin. Em relação as características histológicas, o subtipo histológico de celularidade mista apresentou associação estatística com EBV positivo (p= 0,02). Além disso, a presença de EBV foi mais comum em pacientes com 45 anos ou mais (p= 0,07). Embora sem significância estatística, houve uma tendência de melhor sobrevida livre de eventos (p= 0,07), para os pacientes EBV positivo. Conclusão: O subtipo histológico de celularidade mista, apresentou uma relação estatisticamente significativa com a presença de EBV nas células tumorais, em conformidade com a literatura. São necessários estudo com maior número de casos para que se possa entender melhor a relação entre a presença de EBV e o prognóstico do LHc em nosso meio.

Introduction: The expression of Epstein-Barr virus positivity in Reed-Sternberg/Hodgkin cells and the impact of this relationship on survival in classical Hodgkin Lymphoma (cHL) remain controversial. Objective: To evaluate the presence of Epstein Baar Virus (EBV) in patients with cHL, associating it with anatomopathological and clinical characteristics.Materials and Methods: To determine the presence of EBV, analysis was carried out using a tissue biopsy material by hybridization for EBV-encoded RNA (EBER) and immunohistochemistry for viral latent membrane protein (LMP-1) from a demand sample of patients diagnosed between January 2009 and January 2015. The clinical characteristics evaluated were those that make up the International Prognostic Score for advanced stage and the unfavorable risk factors established by the German Hodgkin Study Group for limited stage. Subsequently, these characteristics were related to the status of the virus in tumor cells. Results: Biopsy slides from 29 patients diagnosed with Hodgkin's Lymphoma were evaluated. Regarding histological characteristics, the histological subtype of mixed cellularity showed a statistical association with positive EBV (p= 0.02). Furthermore, the presence of EBV was more common in patients aged 45 years or older (p= 0.07). Although not statistically significant, there was a trend towards better event-free survival (p= 0.07) for EBV positive patients. Conclusion: The histological subtype of mixed cellularity showed a statistically significant relationship with the presence of EBV in tumor cells, in accordance with the literature. Studies with a larger number of cases are needed to better understand the relationship between the presence of EBV and the prognosis of cHL in our country.

Linfoma de células T/NK primario de testículo. Caso clínico y revisión de la literatura / Primary testicular NK/T cell lymphoma. Case report and review of literature

Natural killer/T cell lymphomas chiefly involving the midline facial structures including the nasal cavity or nasopharyns are a relatively rare type of non-Hodgkin's lymphoma. Apart from the upper respiratory tract, the disease occasionally presents in certain extranodal sites, such as the central nervous system, skin, gastrointestinal tract, or testes. We report a case of natural killer NK/T cell lymphoma as a testicular tumor in a 36-year-old man with a history of progressive swelling of his right testicle. Histologically, the testicular mass showed a diffuse infiltrate of medium-sized and atypical large lymphoid cells with angiocentric infiltration and areas of coagulative necrosis. Immunohistochemical studies demonstrated tumor cells staining positively with CD3, TIA-1, and Granzyme B. The Epstein-Barr virus genoma was detected by in situ hybridization. There were no abnormal findings in the nasal and nasopharyngeal regions. Classified as stage IEA, the patient received involved-field irradiation to contralateral testis (45 Gy), followed by systemic chemotherapy with a combination regimen ofL-asparaginase, methotrexate and dexamethasone. Relevant literature is reviewed, and the clinicopathologic features, natural history, and treatment options for primary testicular NK/T cell lymphoma are discussed.

The role of mammalian target of rapamycin inhibitor in virus infection of organ transplant recipients / 器官移植

At present, mammalian target of rapamycin (mTOR) inhibitors are commonly-used immunosuppressive drugs after organ transplantation, including sirolimus (rapamycin) and everolimus. mTOR inhibitors not only exert an immunosuppressive effect by inhibiting T cell proliferation, but also possess multiple potential functions, such as antiaging, anti-tumor and anti-virus infection, etc. Virus infection is one of the most common complications after organ transplantation. Current anti-viral treatments are limited and yield poor efficacy. In this article, the role of mTOR pathway in virus infection, the mechanism of common mTOR inhibitors and the role of mTOR inhibitors in different types of virus infections were reviewed, aiming to provide reference for clinical application and subsequent research of mTOR inhibitors in organ transplant recipients.

Pathological Types,Expression of Mismatch Repair Protein,Human Epidermal Growth Factor Receptor 2,and Pan-TRK,and Eostein-Barr Virus Infection in Patients With Colorectal Cancer Resected in Tibet / 中国医学科学院学报

Objective To study the pathological types,expression of mismatch repair protein,human epidermal growth factor receptor 2(HER2),and Pan-TRK,and Epstein-Barr virus(EBV)infection in patients with colorectal cancer resected in Tibet. Methods A total of 79 patients with colorectal cancer resected in Tibet Autonomous Region People's Hospital from December 2013 to July 2021 were enrolled in this study.The clinical and pathological data of the patients were collected.The expression of mismatch repair protein,HER2,and Pan-TRK was detected by immunohistochemical(IHC)staining,and detection of HER2 gene by fluorescence in situ hybridization(FISH)in the patients with HER2 IHC results of 2+ or above.EBV was detected by in situ hybridization with EBV-encoded small RNA. Results A total of 79 colorectal cancer patients were included in this study,with the male-to-female ratio of 1.26:1 and the mean age of(57.06±12.74)years(24-83 years).Among them,4 patients received preoperative neoadjuvant therapy.Colonic cancer and rectal cancer occurred in 57(57/79,72.15%,including 31 and 26 in the right colon and left colon,respectively)and 22(22/79,27.85%)patients,respectively.The maximum diameter of tumor varied within the range of 1-20 cm,with the mean of(6.61±3.33)cm.Among the 79 colorectal cancer patients,75(75/79,94.94%)patients showed adenocarcinoma.Lymph node metastasis occurred in 12(12/21,57.14%)out of the 21 patients with severe tumor budding,13(13/23,56.52%)out of the 23 patients with moderate tumor budding,and 2(2/31,6.45%)out of the 31 patients with mild tumor budding,respectively.The lymph node metastasis rate showed differences between the patients with severe/moderate tumor budding and the patients with mild tumor budding(all P<0.001).The IHC staining showed that mismatch repair protein was negative in 10(10/65,15.38%)patients,including 5 patients with both MSH2 and MSH6 negative,4 patients with both MLH1 and PMS2 negative,and 1 patient with MSH6 negative.Pan-TRK was negative in 65 patients.The IHC results of HER2 showed 0 or 1+ in 60 patients and 2+ in 5 patients.FISH showed no positive signal in the 5 patients with HER2 IHC results of 2+.The detection with EBV-encoded small RNA showed positive result in 1(1/65,1.54%)patient. Conclusions Non-specific adenocarcinoma of the right colon is the most common in the patients with colorectal cancer resected in Tibet,and 15% of the patients showed mismatch repair protein defects.EBV-associated colorectal carcer is rare,Pan-TRK expression and HER2 gene amplification are seldom.The colorectal cancer patients with moderate and severe tumor budding are more likely to have lymph node metastasis.

Advances in the role of innate immunity in Epstein-Barr virus infection / 国际儿科学杂志

Epstein-Barr virus(EBV)is a double-stranded DNA herpes virus that is universally susceptible to human populations worldwide.It mainly infects B cells and epithelial cells and has the characteristics of incubation and transformation.The innate immune response is the first line of defense against EBV.In particular, the immune response of type Ⅰ interferons and the direct cell-killing effects of innate cytotoxic lymphocyte are essential for initial control of viral infection and subsequent activation of adaptive immune responses.There is a delicate balance between innate immune response and immune escape of EBV, and the breakdown of the balance is related to the occurrence and prognosis of EBV-related diseases.A better understanding of this balance mechanism will guide the prevention and targeted therapy of EBV-related diseases.This article reviews the role of innate immune cells(epithelial cells, mononuclear/dendritic cells, NK cells, γδT cells, NKT cells)and type Ⅰ interferon in EBV infection and the immune escape mechanism of EBV.

Analysis of the efficacy of allogeneic hematopoietic stem cell transplantation on 9 children with Epstein-Barr virus-positive lymphoproliferative diseases / 中华实用儿科临床杂志

Objective:To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the childhood Epstein-Barr virus(EBV)-positive lymphoproliferative diseases(EBV + LPD). Methods:The clinical features, treatment course, and prognosis of 9 children with EBV + LPD who underwent allo-HSCT in Children′s Hospital Affiliated to Zhengzhou University from July 2019 to July 2022 were analyzed retrospectively. Results:All the 9 children underwent histopathological examination, including 6 patients with EBV-positive T-cell lymphoproliferative disease (EBV + T-LPD), 1 with pulmonary lymphomatoid granuloma, and 2 with systemic EBV-positive T-cell lymphoma.There were 6 males and 3 females, with the median age of 5.8 (1.5-13.0) years.At the initial diagnosis, plasma and peripheral EBV-DNA copy at the initial diagnosis was (5.67-865.00)×10 2/mL, and (5.13-1 250.00)×10 2/mL, respectively.The EBV-DNA load of cerebrospinal fluid increased to (5.18-291.00)×10 2/mL in 3 cases.The whole exon sequencing data showed no abnormality in 3 cases, pulmonary lymphomatoid granuloma with the IL2RG mutation in 1 case and EBV + T-LPD with a hemizygous mutation in the SH2D1A gene as the pathogenic mutation in 1 case.Pathogenic mutations were not detected in the remaining 4 cases.The course of disease before transplantation was 5.4(3.0-10.0) months.Disease status before transplantation was as follows: all 3 cases of lymphomas had partial regression; 2 cases of EBV + T-LPD had active disease; and 4 cases had no active disease.Among the donors, there were 5 cases of half-matched relatives, 2 cases of full-matched siblings and 2 cases of unrelated full-matched donors.The median number of mononuclear cells in peripheral blood and/or bone marrow hematopoietic stem cell was 6.60(3.64-12.18)×10 8/kg, while the median implantation time of neutrophils was 18(9-23) days.One month after the transfusion of hematopoietic stem cells, plasma EBV-DNA copy was negative in all cases, and peripheral EBV-DNA copy was negative in 7 cases.The copy number in the other 2 cases was 10 2/mL.At the 3-month evaluation, plasma and peripheral EBV-DNA copy were negative in all cases.In addition, 3 cases of lymphomas achieved radiographic complete remission, and 6 cases of EBV + T-LPD were inactive.All transplant-related complications were effectively controlled after medication.Following the median follow-up of 24 (11-42) months, all patients had disease-free survival.Serious impact on the quality of life due to graft versus host disease was not reported. Conclusions:allo-HSCT is an effective treatment of childhood EBV + LPD, which is able to control transplant-related complications.Children with EBV + LPD can achieve long-term disease-free survival through transplantation.

Establishment of mouse models of lymphoma with dual-labeled EBV-immortalized lymphoblastoid cell lines by intravenous versus subcutaneous injection / 中国肿瘤临床

Objective:To establish a green fluorescent protein(GFP)and firefly luciferase(Luc)double-labeled Epstein-Barr virus(EBV)infec-ted B lymphoblastoid cell lines(B-LCL)and apply them to mouse models,then compare the advantages and disadvantages of models inocu-lated by intravenous(IV)or subcutaneous(SC).Methods:B lymphoblastoid cell lines double-tagged with GFP/Luc(B-LCL-GL)were con-structed through lentivirus transduction,puromycin intervention.Subcutaneous xenograft and hematogenous metastasis models were re-spectively established by subcutaneous or intravenous injection of B-LCL-GL cells at three concentrations in(NOD)/Prkdcscid/IL-2Rγnull(NPG)mice for in vivo bioluminescence imaging.Results:In the B-LCL-GL group,the ratio of the GFP-positive cell population was 92.5%,and the average luminescence intensity was as high as 4.80E+08 Photons/s,which was considerably higher than that of untreated B-LCLs.In the hematogenous metastasis models,tumor bioluminescence was initially located in the peritoneal area and then spread throughout the en-tire body between 7 and 28 days.In the subcutaneous xenograft models,strong central and weak peripheral tumor-related biolumines-cence signal was detected on day 7 in the three groups,which then spread throughout the body on day 28 in the high-dose group.Taken to-gether,there was no significant difference in tumor progression between the two routes of administration when using the same dose of B-LCL-GL cells.However,the survival analysis indicated that the IV injection group,in which all the mice ultimately died,had a shorter time frame for testing than that of the SC injection group,in which the mice survived until day 100 in the low-dose and medium-dose groups,thus allowing for long-term testing.Conclusions:GFP and Luc dual-positive B-LCLs were successfully established to generate hematogenous metastasis and subcutaneous xenograft models,which allow the monitoring of the location and size of lymphomas in vivo.It provide plat-form for the study of tumor characteristics and selecting anti-tumor drugs.

Expression of hsa_circ_0001459 in peripheral blood mononuclear cells of patients with Epstein-Barr virus infection and its clinical significance / 中华微生物学和免疫学杂志

Objective:To detect the expression of has_circ_0001459 in peripheral blood mononuclear cells (PBMCs) of Epstein-Barr virus (EBV)-infected individuals and evaluate its diagnostic value for EBV infection.Methods:The expression profiles of circRNAs in PBMCs of patients with EBV infection were obtained by whole-transcriptome sequencing. Differentially expressed circRNAs with statistical significance were selected based on the criteria of ∣log 2Fold Change∣≥1 and P<0.05. Based on the composition, length and primer specificity, hsa_circ_0001459 with high expression was selected for further research. The relative expression of hsa_circ_0001459 in PBMCs of 60 patients with EBV infection and 45 healthy people was detected by real-time fluorescent quantitative PCR. Receiver operating characteristic (ROC) curve and Kappa analysis were used to analyze the diagnostic value of hsa_circ_0001459 expression for EBV infection. Results:The expression of hsa_circ_0001459 showed an up-regulation trend in patients with EBV infection as compared with that in the healthy people, and the results were consistent with the sequencing results. The area under the ROC curve for screening EBV-infected individuals was 0.83(95%CI: 0.75-0.91) with the sensitivity of 0.80(95%CI: 0.66-0.89) and the specificity of 0.77(95%CI: 0.65-0.86). Kappa analysis indicated that hsa_circ_0001459 was moderately consistent with EBV DNA in the diagnosis of EBV infection (κ=0.51).Conclusions:Hsa_circ_0001459 tended to be highly expressed in PBMCs of EBV-infected individuals, which might be uses as a diagnostic marker for EBV infection.

Dynamic monitoring of plasma Epstein-Barr Virus DNA load can predict the occurrence of lymphoproliferative disorders after haploidentical hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To determine the optimal cutoff value of Epstein-Barr virus (EBV) DNA load that can assist in the diagnosis of post-transplant lymphoproliferative disease (PTLD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) . Methods: The data of patients with EBV infection after haplo-HSCT from January to December 2016 were retrospectively analyzed. Through constructing the receiver operating characteristic (ROC) curve and calculating the Youden index to determine the cutoff value of EBV-DNA load and its duration of diagnostic significance for PTLD. Results: A total of 94 patients were included, of whom 20 (21.3% ) developed PTLD, with a median onset time of 56 (40-309) d after transplantation. The median EBV value at the time of diagnosis of PTLD was 70,400 (1,710-1,370,000) copies/ml, and the median duration of EBV viremia was 23.5 (4-490) d. Binary logistic regression was used to analyze the peak EBV-DNA load (the EBV-DNA load at the time of diagnosis in the PTLD group) and duration of EBV viremia between the PTLD and non-PTLD groups. The results showed that the difference between the two groups was statistically significant (P=0.018 and P=0.001) . The ROC curve was constructed to calculate the Youden index, and it was concluded that the EBV-DNA load ≥ 41 850 copies/ml after allogeneic hematopoietic stem cell transplantation had diagnostic significance for PTLD (AUC=0.847) , and the sensitivity and specificity were 0.611 and 0.932, respectively. The duration of EBV viremia of ≥20.5 d had diagnostic significance for PTLD (AUC=0.833) , with a sensitivity and specificity of 0.778 and 0.795, respectively. Conclusion: Dynamic monitoring of EBV load in high-risk patients with PTLD after haplo-HSCT and attention to its duration have important clinical significance, which can help clinically predict the occurrence of PTLD in advance and take early intervention measures.

Advances in diagnosis and treatment of non-neoplastic Epstein-Barr virus infection-related diseases in children / 国际儿科学杂志

The infection rate of Epstein-Barr virus(EBV)in the population is as high as 95%.It is the first carcinogenic virus found by human beings.Children infected with EBV often cause non-neoplastic diseases, including infectious mononucleosis, chronic active EBV infection and hemophagocytic lymphohistiocytosis.Most of the diseases related to non-neoplastic EBV infection in children are self-limited diseases, and a few of them are complicated with serious complications or develop into neoplastic diseases.The pathogenesis of this kind of disease is complex, the condition is varied, and some children with gene defects have a poor prognosis.Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is an effective treatment for refractory children.At the same time, the condition of some critically ill children is progressing rapidly, so it is very important to create the opportunity of allo-HSCT for such children.