Epstein-Barr Virus In Tumor Cells Research Articles

Ebv-Mir-BART11-3p, Ebv-Mir-BART9 and Ebv-Mir-BART10 Are Present in the Plasma of HIV-Infected Subjects with Lymphoma and Are Potential Lymphoma Biomarkers

Epstein Barr virus (EBV) has been implicated in the lymphomagenesis, particularly of HIV-related lymphomas. EBV-infected cells are able to share miRNAs with other cells via exosomes and certain EBV-miRNAs were found in cells not infected with the virus but from patients with increased levels of EBV copies in plasma such as HIV-infected individuals. Thus, EBV-miRNAs might be detected in the plasma and might be relevant for the diagnosis and follow-up of HIV-related lymphomas.This case-control study included a group of 26 HIV-infected patients with lymphoma that responded to treatment and a control-group of HIV-infected subjetcs without lymphoma matched for age, gender, CD4-lymphocyte counts, plasma HIV viremia and time from HIV infection. We evaluated the presence of 43 EBV-miRNAs in frozen plasma samples from patients with lymphoma at diagnosis (Dx-group, N=26), one year before diagnosis (Pre-group, N=15) and complete response (CR-group, N=26). RNA was extracted from 200µl of plasma using Trizol LS (Ambion, Carlsbad, CA) and cel-miR-39 was used as spike-in. The detection of EBV-miRNAs was assessed by QRT-PCR in a BioMark™ HD System of Fluidigm (San Francisco, CA) using TaqMan® microRNA assays and TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA). The following clinical and biological parameters were collected from records: age, gender, ECOG score, extranodal and bulky disease, B symptoms, Ann-Arbor stage, serum lactate dehydrogenase (LDH) and beta2-microglobulin, International Prognostic Index (IPI), HCV and HBV serology, history of opportunistic infection and of AIDS-defining illnesses, onset of combination antiretroviral therapy, CD4-lymphocyte counts, plasma HIV viremia. McNemar's and Wilcoxon tests were used for paired comparisons between groups. P-values of less than .05 were considered statistically significant.Overall, 30 EBV-miRNAs were detected in the Dx-group whereas only 8 EBV-miRNAs where found in the control-group and 19 in the CR-group. EBV-miRNAs were detected more frequently in the Dx-group (17 out of 26) than in the control-group (7 out of 26) (P =.002) and in the CR-group (11 out of 26) (P=.02). The presence of 6 EBV-miRNAs (ebv-miR-BART11-3p, ebv-miR-BART9, ebv-miR-BART10, ebv-miR-BART15, ebv-miR-BART31, and ebv-miR-BART19) could be associated with the lymphoma condition, since they were detected significantly different in the Dx-group and the control-group (Figure 1). Importantly, 3 of those EBV-miRNAs (ebv-miRBART11-3p, ebv-miR-BART9 and ebv-miRBART10) were found to be significantly less frequent in the CR group, reinforcing the idea that they could be derived from lymphoma cells and be used as biomarkers for diagnosis and follow up of HIV-related lymphoma. EBV-miRNAs cannot be used as early biomarkers of lymphoma in HIV-infected patients because none of the 3 EBV-miRNAs associated with lymphoma was significantly found in samples before diagnosis. The detection in plasma of ebv-miR-BART11-3p, ebv-miR-BART10 or ebv-miR-BART9 was not associated with having tumor cells infected with EBV (Figure 1). Only the detection of ebv-miR-BART9 was associated with detectable EBV loads [7/14 (50%) vs. 1/12 (8.3%), P=.036] (Figure 1). The following were the statistically significant associations between the presence of the 3 potential EBV-miRNA lymphoma biomarkers and the clinical-biological features studied. The presence of ebv-miR-BART10 in plasma was associated with IPI>2 [8/14 (57.1%) vs. 1/9 (11.1%), P=.004] and ECOG>2 [8/14 (57.1%) vs. 1/11 (9.1%), P=.011]. Also, more patients with ebv-miR-BART11-3p expression in plasma had ECOG>2 than patients without it [7/13 (53.8%) vs. 1/12 (8.3%), P=.030].Ebv-miR-BART11-3p, ebv-miR-BART9 and ebv-miR-BART10 can be detected in the plasma of patients with HIV-related lymphoma, independently of the presence of EBV in tumor cells or of EBV plasma viremia. They are potential biomarkers of lymphoma to be used in the diagnosis and follow up of HIV-infected subjects with the advantage of being easily determined by QRT-PCR employing noninvasive procedures.This work was supported in part by 2014 SGR225 (GRE) from CERCA Programme/Generalitat de Catalunya, and by funds from Josep Carreras International Foundation, “la Caixa” Foundation, DKMS, and Celgene Spain. [Display omitted] DisclosuresBaptista:DKMS: Research Funding; la Caixa Foundation: Research Funding; Carreras International Foundation: Research Funding; CERCA Programme/Generalitat de Catalunya: Research Funding; Celgene Spain: Research Funding. Sancho:Roche: Honoraria; Laboratorios Servier: Consultancy; Mundipharma: Honoraria; Kern Pharma: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Ribera:Celgene: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen Inc.: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; Roche: Honoraria. Navarro:Celgene Spain: Research Funding; DKMS: Research Funding; la Caixa Foundation: Research Funding; Josep Carreras International Foundation: Research Funding; CERCA Programme/Generalitat de Catalunya: Research Funding.

Epstein–Barr Virus (EBV) Viral Load in Tumor Cells Did Not Predict Tumor Extensiveness in Nasopharyngeal Cancer

Background: Nasopharyngeal cancer is commonly associated with Epstein–Barr virus (EBV) infection, especially undifferentiated non-keratinized histology. EBV DNA quantification through nasopharyngeal brushing was previously reported to be not related to disease stage. This study aimed to reinvestigate the relationship of EBV viral load in tumor tissue with tumor extensiveness by more accurate EBV DNA quantification through microscopically confirmed tumor cells from nasopharyngeal biopsy. Method: The specimens for EBV DNA quantification were derived from histopathology slides which were pre-treated following the QIAsymphony® SP protocol for tissue DNA extraction. Then, the extracted DNA underwent real-time polymerase chain reaction (RT-PCR) using the artus® EBV RG PCR Kit for EBV DNA quantification. The tumor volume was determined by delineating the gross tumor based on 3D imaging of the patient’s nasopharynx. Result: Twenty-four subjects were included in this study. All subjects were stage III and above, with more males (75%) than females. EBV viral load in tumor cells was found to have no correlation to tumor volume both in local and nodal regions. The median local tumor volume was 81.3 cm3 ± 80 cm3. The median EBV viral load in tumor cells was 95,644.8 ± 224,758.4 copies/100 ng of DNA. The median nodal or regional tumor volume was 35.7 ± 73.63 cm3. Conclusion: EBV viral load from tumor cells from nasopharyngeal biopsy has no relationship with tumor extensiveness in nasopharyngeal cancer. The presence and amount of EBV in tumor cells did not translate into larger or smaller tumors. The EBV viral proteins and RNAs were perhaps more likely to confer some prognostic information due to the fact that those molecules were related to carcinogenesis.

Latent Epstein–Barr virus infection status and prognosis in patients with newly diagnosed Hodgkin lymphoma in Southeast China: a single-center retrospective study

ABSTRACT Purpose This study aimed to investigate the latent Epstein–Barr virus (EBV) infection status of patients with newly diagnosed Hodgkin lymphoma (HL) and to discuss the relationship between tumor cell EBV status and the prognosis of HL patients. Patients and methods A total of 134 previously untreated HL patients were analyzed in the study. Epstein–Barr virus encoded RNAs (EBERs) in situ hybridization was performed to detect the EBV status of tumor cells. Results EBV positive status correlated with sex (p=0.046) and the proportion of extranodal lesions(p=0.037). There was no obvious correlation between EBV status and overall survival (OS) or failure-free survival (FFS) in all cases, but in cases over 50 years old, EBV positive group had an inferior 5-year FFS compared with EBV negative group (38.5%±13.5% vs 90.9%±8.7%, p=0.012). In FFS multivariate analysis of this age subgroup, EBV positive status was associated with significantly inferior survival (HR, 10.10; 95% CI, 1.26–81.08; p=0.030). Conclusion This study demonstrates positive tumor cell EBV status is an unfavorable prognostic factor in elder HL patients.

Lytic Induction Therapy against Epstein-Barr Virus-Associated Malignancies: Past, Present, and Future.

Epstein–Barr virus (EBV) lytic induction therapy is an emerging virus-targeted therapeutic approach that exploits the presence of EBV in tumor cells to confer specific killing effects against EBV-associated malignancies. Efforts have been made in the past years to uncover the mechanisms of EBV latent-lytic switch and discover different classes of chemical compounds that can reactivate the EBV lytic cycle. Despite the growing list of compounds showing potential to be used in the lytic induction therapy, only a few are being tested in clinical trials, with varying degrees of success. This review will summarize the current knowledge on EBV lytic reactivation, the major hurdles of translating the lytic induction therapy into clinical settings, and highlight some potential strategies in the future development of this therapy for EBV-related lymphoid and epithelial malignancies.

Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes

The success of immunotherapy using immune checkpoint blockade in solid tumors and in relapsed/refractory classical Hodgkin lymphoma and chronic lymphocytic leukemia holds promise for targeted therapy in hematologic malignancies. Because efficacy of immunomodulatory therapy is correlated with numbers of cells that express programmed death (PD-1) ligands, we evaluated the expression of PD-L1 and PD-L2 proteins using immunohistochemistry in more than 702 diagnostic lymphoma biopsies. In classical Hodgkin lymphoma, PD-L1 and PD-L2 were expressed in 82% and 41% of cases, respectively, and PD-L1 but not PD-L2 expression correlated with Epstein-Barr virus in tumor cells. PD-L1 staining was detected in 80% of anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, and follicular dendritic cell sarcoma; 75% of nodular lymphocyte-predominant Hodgkin lymphoma; 53% of primary mediastinal large B-cell lymphoma; 39% of extranodal NK/T cell lymphoma; 26% of peripheral T-cell lymphoma; 10% of diffuse large B-cell lymphoma; and very rare examples of mantle, marginal zone, and small lymphocytic lymphomas. PD-L2 staining was present in 78% of primary mediastinal large B-cell lymphoma but in fewer cases in all other categories including 40% of follicular dendritic cell sarcoma and 7% of anaplastic large cell lymphoma. Our results confirm and extend prior studies of PD-L1 and provide new data of PD-L2 expression in lymphomas. The differential expression patterns in some tumor types and the expression of PD-L2 in the absence of PD-L1 raise the possibility of targeted therapy for additional subsets of patients with lymphoma.

Epstein–Barr virus latency type and spontaneous reactivation predict lytic induction levels

The human Epstein–Barr virus (EBV) evades the immune system by entering a transcriptionally latent phase in B cells. EBV in tumor cells expresses distinct patterns of genes referred to as latency types. Viruses in tumor cells also display varying levels of lytic transcription resulting from spontaneous reactivation out of latency. We measured this dynamic range of lytic transcription with RNA deep sequencing and observed no correlation with EBV latency types among genetically different viruses, but type I cell lines reveal more spontaneous reactivation than isogenic type III cultures. We further determined that latency type and spontaneous reactivation levels predict the relative amount of induced reactivation generated by cytotoxic chemotherapy drugs. Our work has potential implications for personalizing medicine against EBV-transformed malignancies. Identifying latency type or measuring spontaneous reactivation may provide predictive power in treatment contexts where viral production should be either avoided or coerced.

Genetic associations in classical hodgkin lymphoma: a systematic review and insights into susceptibility mechanisms.

Both targeted and genome-wide studies have revealed genetic associations for susceptibility, prognosis, and treatment-induced secondary malignancies and toxicities in classical Hodgkin lymphoma (cHL). This review gives a systematic and comprehensive overview of significant associations and places them into a biologic context. The strongest susceptibility polymorphisms have been found for the human leukocyte antigen (HLA) genes. These associations are specific for cHL overall or for subgroups based on tumor cell Epstein-Barr virus (EBV) status. These findings strongly suggest that EBV-specific immune responses influence cHL susceptibility in EBV(+) cHL and that immune responses targeting other tumor-associated antigens are important in EBV(-) cHL. Accordingly, most of the numerous other susceptibility loci map to genes that affect functionality of the immune system, underscoring the crucial role of the immune system in cHL development. The number of association studies on cHL prognosis is limited with one consistent association for the drug-metabolizing UGT1A1 gene. PRDM1 is associated with radiation-induced secondary malignancies and a small number of genes are associated with treatment-related toxicities. In conclusion, most loci showing genetic associations in cHL harbor genes with a potential functional relevance for cHL susceptibility.

Hodgkin lymphoma incidence in California Hispanics: influence of nativity and tumor Epstein-Barr virus.

For classical Hodgkin lymphoma (HL), migrant studies could elucidate contributions of environmental factors (including Epstein-Barr virus (EBV)) to the lower rates in non-whites. Given the well-described etiologic complexity of HL, this research requires a large, immigrant population, such as California Hispanics. With 1988-2004 California Cancer Registry data (2,595 Hispanic, 8,637 white HL cases) and tumor cell EBV status on a subset (218 Hispanics, 656 whites), we calculated ethnicity- and nativity-specific HL incidence rates simultaneously by age, sex, and histologic subtype, and tumor cell EBV prevalence. Compared with white rates, Hispanic HL rates were lower overall (70 %) and for nodular sclerosis HL, particularly among young adults (60-65 % for females). However, they were higher among children (200 %) and older adults, and for mixed cellularity HL. Compared with rates in foreign-born Hispanics, rates in US-born Hispanics were higher among young adults (>threefold in females), lower for children and adults over age 70, and consistently intermediate compared with rates in whites. EBV tumor prevalence was 67, 32, and 23 % among foreign-born Hispanics, US-born Hispanics, and whites, respectively, although with variation by age, sex, and histology. Findings strongly implicate environmental influences, such as nativity-related sociodemographic differences, on HL occurrence. In addition, lower young adult rates and higher EBV prevalence in US-born Hispanics than in whites raise questions about the duration/extent of environmental change for affecting HL rates and also point to ethnic differences in genetic susceptibility. Lesser variation in mixed cellularity HL rates and greater variation in rates for females across groups suggest less modifiable factors interacting with environmental influences.

Epstein–Barr virus and Hodgkin lymphoma in Jordan

This study aims to examine the possible association of Epstein-Barr virus (EBV) in Classical Hodgkin lymphoma (cHL) and to shed light on the epidemiology of Hodgkin lymphoma (HL) in Jordan. We examined 100 consecutive cases of HL for the presence of EBV in tumor cells by immunohistochemistry for latent membrane protein-1 (LMP-1). We collected patient data on age, sex and histologic subtype. We reviewed the pathological findings in each case and confirmed diagnosis. Nodular lymphocyte predominant HL was diagnosed in 6% of the cases and these were negative for EBV LMP-1. Of the 94 cases of cHL, 65% were males, the most common subtype was nodular sclerosis (NS), representing 70% of the cases, and 45.7% of cHL (43% of all HL) cases were positive for EBV LMP-1. The positive cases were significantly related to age: ⩽15 years and >51 years (p: 0.009 and 0.014 respectively), male gender (p: 0.03) and mixed cellularity (MC) subtype (p: <0.0001). In line with other developing countries, there also appears to be a trend towards a decreasing association of EBV with cHL and a subtype switch from MC to NS in Jordan. The epidemiology of HL in Jordan and some developing countries is approaching that of developed countries.

Exposure to UV radiation and risk of Hodgkin lymphoma: a pooled analysis

AbstractUltraviolet radiation (UVR) exposure has been inversely associated with Hodgkin lymphoma (HL) risk, but only inconsistently, only in a few studies, and without attention to HL heterogeneity. We conducted a pooled analysis of HL risk focusing on type and timing of UVR exposure and on disease subtypes by age, histology, and tumor-cell Epstein-Barr virus (EBV) status. Four case-control studies contributed 1320 HL cases and 6381 controls. We estimated lifetime, adulthood, and childhood UVR exposure and history of sunburn and sunlamp use. We used 2-stage estimation with mixed-effects models and weighted pooled effect estimates by inverse marginal variances. We observed statistically significant inverse associations with HL risk for UVR exposures during childhood and adulthood, sunburn history, and sunlamp use, but we found no significant dose-response relationships. Risks were significant only for EBV-positive HL (pooled odds ratio, 0.56; 95% confidence interval, 0.35 to 0.91 for the highest overall UVR exposure category), with a significant linear trend for overall exposure (P = .03). Pooled relative risk estimates were not heterogeneous across studies. Increased UVR exposure may protect against HL, particularly EBV-positive HL. Plausible mechanisms involving UVR induction of regulatory T cells or the cellular DNA damage response suggest opportunities for new prevention targets.

Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma

AbstractAn altered anti–Epstein-Barr virus (EBV) serologic profile preceding diagnosis is associated with an increased risk of Hodgkin lymphoma. It is unknown whether this atypical pattern predicts Hodgkin lymphoma risk further subdivided by determination of EBV in tumor cells. A nested case-control study of 128 incident Hodgkin lymphoma cases and 368 matched controls from active-duty military personnel with archived serum in the US Department of Defense Serum Repository was conducted to determine whether a panel of anti-EBV antibody titers differed in EBV+ and EBV− Hodgkin lymphoma. Among 40 EBV+ Hodgkin lymphoma cases and matched controls, statistically significant increased risks were associated with elevated anti-EBV VCA IgG antibody titers (relative risk = 3.1; 95% confidence interval [CI], 1.1-8.7), and an anti–EBNA-1/anti–EBNA-2 antibody ratio ≤ 1.0 versus > 1.0 (relative risk = 4.7; 95% CI, 1.6-13.8). In contrast, no significant associations were found among 88 EBV− Hodgkin lymphoma cases relative to their matched controls. In case-case analysis, EBV+ disease was significantly associated with a low anti–EBNA-1/anti–EBNA-2 antibody ratio. This distinc-tive serologic response to EBV latent antigens, indicative of immune dysfunction in other clinical settings, is associated with an increased risk of developing EBV+ but not EBV− Hodgkin lymphoma.

Impact of the Epstein–Barr virus positivity on Hodgkin's lymphoma in a large cohort from a single institute in Korea

Epstein-Barr virus (EBV) is considered a prognostic marker in Hodgkin lymphoma (HL) patients, but previous studies have yielded mixed findings because of the confounding effects of factors including age. We examined the prognostic impact of EBV status on 159 patients with HL. The median age at diagnosis was 32 years (range, 4-77 years). The median follow-up time was 5.83 years (range, 0.33-19.69 years). Tumor cell EBV status was positive in 34.5 %. EBV-positive HL was associated with age of ≥ 25 years, male gender, B symptoms, advanced stage, high-risk IPS, nonnodular sclerosis subtype, and treatment with chemotherapy only (P < 0.05). The 5-year disease-specific survival (DSS) rates were 94.1 and 76.4 % for the EBV-negative and EBV-positive HL, respectively, (P < 0.001). On univariate analysis, event-free survival, DSS, and overall survival (OS) were significantly associated with age 40 years or older, B symptoms, and high-risk international prognostic score (≥ 4). On multivariate analysis, EBV positivity was found to be a significant prognostic factor for DSS, particularly in adults 25 years or older. Subgroup analysis showed significant association of EBV-positive HL with poorer DSS and OS in adults 25 years or older with advanced stage disease. In the present series of HL patients, the presence of EBV in tumor cells is associated with adverse prognostic factors. EBV-positive HL is significantly associated with poorer DSS in all age groups.

Latent Epstein-Barr Virus Infection of Tumor Cells in Classical Hodgkin's Lymphoma Predicts Adverse Outcome in Older Adult Patients

In classical Hodgkin's lymphoma (cHL), the impact of tumor cell Epstein-Barr virus (EBV) status on clinical outcome is controversial. We assessed failure-free survival (FFS) and relative survival (RS) in 412 patients with cHL and age-defined subgroups in a population-based study in the northern Netherlands. Tumor cell EBV status was positive in 34%, and the median follow-up time was 7.1 years. Patients' median age at diagnosis was 35 years (range, 7 to 91 years), and 63% had Ann Arbor stage I or II, 24% had stage III, and 12% had stage IV disease. EBV status influenced 5-year FFS and RS only in patients from the age group 50 to 74 years. Five-year FFS was 60% in patients with EBV-positive versus 85% in EBV-negative tumors (P = .01). Five-year RS was 69% in patients with EBV-positive versus 82% in EBV-negative tumors (P = .03). After adjusting for histology, HLA class II expression by tumor cells, stage, presence of extranodal localizations and treatment, and the effect of positive EBV tumor status remained significant in FFS multivariate analysis (hazard ratio, 3.11; 95% CI, 1.28 to 7.53; P = .01). This study indicates that treatment failure in older adult patients with cHL is associated with positive tumor cell EBV status.

Epstein-Barr Virus: Main Pathogenic Agent in Hodgkin Lymphoma Associated Hemophagocytic Syndrome?.

Hemophagocytic syndrome (HPS) is characterized by an uncontrolled proliferation of macrophages displaying extensive phagocytosis of hematopoietic cells that can be associated with non Hodgkin lymphomas. However, Hodgkin lymphoma associated with hemophagocytic syndrome (HL-HPS) has rarely been published. We report here a large series of 34 patients presenting HL-HPS. Histological analysis and Epstein-Barr Virus (EBV) studies were performed. The 34 patients were enrolled from 1992 to 2006. HPS diagnosis was based on usual clinico-biological criteria. Bone marrow aspiration or biopsy were performed in all cases and confirmed HPS, showing hemophagocytic features in scattered macrophages. HL was documented on histological material in all 34 patients. The biopsies were performed on different localizations: lymph nodes (n=18), bone marrow (n=27), liver (n=2) and tonsil (n=1). All histological slides were reviewed and classified according to the World Health Organization (WHO) Lymphoma classification. The presence of EBV in the tumour cells was detected using EBER RNA in situ hybridization and the expression of viral proteins LMP-1, EBNA-2 by immunoperoxidase. Patients were 26 men and 8 women (sex ratio M/F = 3.3). The median age was 45 years (range 19–84). HIV status was negative in 26 patients and positive in 8 patients. All patients were in clinical stage IVB. HL subtypes (18 lymph nodes) were Mixed Cellularity (n=12, 67%), Nodular Sclerosis (n=2, 11%) and Lymphocyte Depleted (n=4, 22%). Extra nodal tissues were highly infiltrated by tumour cells in all cases. The presence of EBV in tumour cells was detected in 32 out of the 34 patients (94%). In all EBV positive cases, high levels of LMP-1 without EBNA2 expression were detected, defining a latency II. This study reports the largest series to date of HL-HPS. The features of HL-HPS are particular by the high proportion of mixed cellularity subtypes (67%) in contrast to the frequency of nodular sclerosis subtypes observed in the general population of non overt immunosuppressed patients, and by the striking high proportion of EBV associated HL (32 out of the 34 patients, 94%). Our findings suggest not only a pathogenic role of EBV, but also a defective immune system in the control of EBV infection in HL-HPS patients.The high predominance of male in our population of HPS-HL (sex ratio M/F = 4.3 after exclusion of HIV positive patients) and the strong association with EBV could suggest X-linked immune defect in these patients.

Role of Chemotherapy and Rituximab for Treatment of Posttransplant Lymphoproliferative Disorder in Solid Organ Transplantation

To evaluate the role of chemotherapy and/or rituximab for treatment of posttransplant lymphoproliferative disorder (PTLD) in solid organ transplantation. A MEDLINE search (1966-May 2007) was conducted using the key words posttransplant lymphoproliferative disorder, solid organ transplantation, chemotherapy, and rituximab. References of relevant articles and abstracts from recent hematology, oncology, and transplantation scientific meetings (2004-May 2007) were also reviewed. Prospective and retrospective studies identified from the data sources were evaluated, and all information deemed relevant was included for this review. Overall response rates ranged from 53% to 68%, 25% to 83%, and 74% to 100% for rituximab monotherapy, chemotherapy, and chemotherapy plus rituximab, respectively. Positive response to treatment was influenced by prognostic factors, including presence of Epstein-Barr virus in tumor cells, normal lactate dehydrogenase levels, good performance status, early disease onset after transplantation, and early disease stages. These factors in study patients likely contribute to the variability in response rates seen between treatment options. Severe adverse effects, ranging from grade 3 neutropenia to infection resulting in death, occurred more frequently in patients receiving chemotherapy than in patients receiving only rituximab. Although reduction in immunosuppressive medications remains the first-line therapy for PTLD treatment, many cases do not respond to this treatment alone, especially monomorphic or more aggressive cases of lymphoma. Therefore, it is reasonable to begin active treatment including rituximab and/or chemotherapy initially, along with reduction in immunosuppression in many cases. Further prospective, comparative studies are urgently needed to confirm the efficacy of these treatment strategies as well as to clarify which subset of patients may benefit most from them.

Cyclosporine A effectively inhibits graft-versus-host disease during development of Epstein-Barr virus-infected human B cell lymphoma in SCID mouse.

We previously constructed human peripheral blood lymphocyte (hu-PBL)/severe combined immunodeficiency mouse (SCID) chimeras and induced human B-cell lymphomas associated with Epstein-Barr virus (EBV) in SCID mice. However, a number of SCID mice died of graft-versus-host disease (GVHD) during the early experimental course. The aim of this study was to test the efficacy of cyclosporine A (CSA) for prevention of GVHD and to define how CSA inhibits the occurrence of GVHD and the production of soluble interleukin (IL) 2 receptor (sIL-2R) in hu-PBL/SCID mice. No mouse died in the active EBV infection group with CSA administration, while 17 mice in three groups without CSA administration died of GVHD. Mortalities in these three groups were 55.56% (5/9), 30.43% (7/23), and 27.78% (5/18), and the medium life span was 17 days. Over the first 33 days after hu-PBL transplantation, serum level of human sIL-2R in hu-PBL/SCID chimeras was stable in the active EBV infection plus CSA group, while sIL-2R concentration gradually increased in the sera of mice with active EBV infection without CSA administration and peaked at 22 days. Thirty-two mice developed tumors among the 43 surviving SCID mice. There was no significant difference of tumor incidence between the active EBV infection groups with CSA and without CSA administration (P > 0.05). From their morphological and immunohistochemical features, as well as detection of human Alu-sequence and EBV in tumor cells, these EBV-induced tumors were identified as human B-cell lymphomas. Thus, CSA can strikingly inhibit GVHD in hu-PBL/SCID chimeras, and should therefore be effective to establish a stable SCID mouse model of human lymphoma associated with EBV. Treatment with CSA had no effect on the tumor incidence in hu-PBL/SCID chimeras after active EBV infection. Accordingly, serum level of sIL-2R is a valuable indicator of GVHD occurrence in hu-PBL/SCID chimeras.

Population-based patterns of human immunodeficiency virus-related Hodgkin lymphoma in the Greater San Francisco Bay Area, 1988-1998.

Epidemiologic characteristics of human immunodeficiency virus (HIV)-related Hodgkin lymphoma (HL) have not been examined in the Greater San Francisco Bay Area, a center of the HIV/acquired immunodeficiency syndrome (AIDS) epidemic, for a decade, despite changes in AIDS-associated diseases after the availability of highly active antiretroviral therapies (HAART). With population-based cancer registry data for 1988-1998, the authors examined risk factors, Epstein-Barr virus (EBV) association, incidence rates, and survival probabilities for 1752 patients with HL who were classified as HIV-positive or HIV-negative by a cancer registry-based method. One hundred twenty-eight patients with HL (7%) were classified with HIV/AIDS; 95% were male. Among males, multivariate analysis (n=514 patients) found that HIV-related HL was associated strongly at diagnosis with ages 30-49 years, San Francisco residence, late-stage disease, lymphocyte depletion and unspecified histologic subtypes, and tumor cell EBV but not with other clinical features or mixed cellularity histology. Survival among patients with HIV-related HL, although it was poor, did not differ by race/ethnicity but was worse for patients with the nonnodular sclerosis histologic subtypes. Patients who were HIV-positive with HAART era (1996-1998) diagnoses were slightly older, were less likely to live in San Francisco, and were much more likely to be Hispanic compared with HIV-positive patients who were diagnosed before the HAART era; they had somewhat less aggressive disease and better survival. Incidence rates were higher for patients with HL overall compared with patients who had HIV-unrelated HL by 11% for white patients, 22% for black patients, and by 14% for Hispanic patients; excesses were greater in young adults. Among males in the San Francisco Bay Area, HIV-related HL had distinctive demographic features, more aggressive clinical characteristics, stronger EBV association, and poorer survival and contributed to elevated regional HL incidence rates, particularly in young adults. Patients with HIV-related HL who were diagnosed after HAART was introduced appeared to have less aggressive disease and better survival.

In situ hybridization of Epstein-Barr virus in tumor cells and tumor-infiltrating lymphocytes of the gastrointestinal tract

Unlike gastric carcinoma, associations of the Epstein-Barr virus (EBV) with carcinomas of other sites in the gastrointestinal tract have not yet been clarified. To elucidate these associations, we investigated the presence of EBV in 142 cases of esophageal carcinoma, 107 cases of ampulla of Vater carcinoma, and 274 cases of colorectal carcinoma in Korean patients using EBV-encoded small RNAs (EBER)—in situ hybridization (ISH). In all cases, none of the tumor cells showed a positive signal, indicating that EBV is not generally related to the carcinogenesis of these cancers. Some EBV-positive tumor-infiltrating lymphocytes (TILs) were found in 8 of 142 cases (5.6%) of esophageal carcinoma, 8 of 107 cases (7.5%) of ampulla of Vater cancer, and 35 of 274 cases (12.8%) of colorectal carcinoma. For comparison, EBER-ISH was performed in consecutive gastric carcinomas; the EBER signal on tumor cells was observed in 17 of 306 cases (5.6%), and EBV-positive TILs were seen in 31 of the 289 cases (10.7%). There was no statistically significant difference in the frequencies of cases with EBV-positive TILs among the gastrointestinal tract cancers. We suggest that the reservoir lymphocytes carrying EBV, like other inflammatory cells, are able to reach anywhere, and that the chance for an epithelial cell to be exposed to EBV is similar at different sites of the gastrointestinal tract, regardless of its carcinogenic effect on the epithelial cell. HUM PATHOL 32:297-301. Copyright © 2001 by W.B. Saunders Company