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Non-Hodgkin lymphomas (NHL) commonly occur in immunodeficient patients, both those infected by human immunodeficiency virus (HIV) and those who have been transplanted, and are often driven by Epstein-Barr virus (EBV) with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 immunodeficient (34 post-transplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were large B-cell lymphoma and 25% were primary central nervous system lymphoma, while 40% were EBV+. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden, tumor landscape and tumor microenvironment and prediction of tumor neoepitopes. Both tumor mutational burden (2.2 vs. 3.4/Mb, P=0.001) and numbers of neoepitopes (40 vs. 200, P=0.00019) were lower in EBV+ than in EBV- NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations observed exclusively in EBV+ and immunodeficient NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV- cases but in only half of the EBV+ ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The tumor microenvironment analysis showed higher CD8 T-cell infiltrates in EBV+ versus EBV- NHL, together with a more tolerogenic profile composed of regulatory T cells, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T-cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV- patients, offering potential opportunities for future T-cell-based immune therapies.

Assessing the risk of cancer among people living with HIV (PLHIV) in the current era of antiretroviral therapy (ART) is crucial, given their increased susceptibility to many types of cancer and prolonged survival due to ART exposure. Our study aims to compare the association between HIV infection and specific cancer sites in Rwanda. Population-based cancer registry data were used to identify cancer cases in both PLHIV and HIV-negative persons. A probabilistic record linkage approach between the HIV and cancer registries was used to supplement HIV status ascertainment in the cancer registry. Associations between HIV infection and different cancer types were evaluated using unconditional logistic regression models. We performed several sensitivity analyses to assess the robustness of our findings and to evaluate the potential impact of different assumptions on our results. From 2007 to 2018, the cancer registry recorded 17,679 cases, of which 7% were diagnosed among PLHIV. We found significant associations between HIV infection and Kaposi's Sarcoma (KS) (adjusted odds ratio [OR]: 29.1, 95% CI: 23.2-36.6), non-Hodgkin lymphoma (NHL) (1.6, 1.3-2.0), Hodgkin lymphoma (HL) (1.6, 1.1-2.4), cervical (2.3, 2.0-2.7), vulvar (4.0, 2.5-6.5), penile (3.0, 2.0-4.5), and eye cancers (2.2, 1.6-3.0). Men living with HIV had a higher risk of anal cancer (3.1, 1.0-9.5) than men without HIV, but women living with HIV did not have higher risk than women without HIV (1.0, 0.2-4.3). Our study found that in an era of expanded ART coverage in Rwanda, HIV is associated with a broad range of cancers, particularly those linked to viral infections., (© 2024 World Health Organization; licensed by UICC and The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: Recent studies have found a high prevalence of hepatitis B virus (HBV) infection in patients with non-Hodgkin's lymphoma (NHL), especially B-cell non-Hodgkin's lymphoma (B-NHL). However, most studies did not classify it and analyze the correlation between HBV and its various subtypes., Methods: The authors retrospectively analyzed 1424 patients with lymphoma. Differences in the prevalence of HBV infection in patients with different pathological types of lymphoma were analyzed. The clinical characteristics, progression-free survival (PFS), and overall survival (OS) of HBV-positive and negative B-NHL subtypes were compared according to HBV infection., Results: The HBV infection rate in NHL patients was 7.65%, which was higher than that in HL patients (2.59%, p < 0.05). The HBV infection rate in the B-NHL was higher than that in the T-cell non-Hodgkin's lymphoma (T-NHL) (8.14% vs. 4.95%). The HBV infection rate in the aggressive B-NHL was similar to that of the indolent B-NHL (8.30% vs. 7.88%), and the highest HBV infection rates were found in diffuse large B-cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, but no significant differences in clinical characteristics, PFS, and OS were seen between HBV-positive and negative patients in the two subtypes., Conclusions: There was an association between HBV infection and the development of NHL and HBV infection may play a role in the pathogenesis of B-NHL, but not T-NHL., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Epstein-Barr virus (EBV) is an oncogenic herpes virus associated with several human malignancies. Two main EBV genotypes (type 1 and type 2) distinguished by the differences in EBV nuclear antigens are known. Geographic variability in these genetic differences has been observed in the incidence of some EBV-related tumors. Here, we investigated the genetic variation of EBV in lymphoma specimens collected in Ethiopia. A total of 207 DNA samples were used for EBV detection and typing, and EBNA1 and EBNA3C genes were used to detect and subtype the EBV genome, respectively. EBV genotype 1 was detected in 52.2% of lymphoma patients. EBV genotype 2 was detected in 38.2% of the lymphoma patients, and 9.7% were coinfected by both EBV genotypes. Overall, 52.8% of the Hodgkin's lymphoma (HL) patients and 51.8% of non-Hodgkin's lymphoma (NHL) patients showed the presence of genotype 1. Meanwhile, 42.8% and 2.3% of HL patients and 35.8% and 12.4% of NHL patients showed EBV genotype 2 and both genotypes, respectively. Significant associations between the age groups and EBV genotypes were observed ( p = 0.027). However, no significant association was seen between EBV genotypes and other sociodemographic and clinical characteristics. This study showed that the distribution of EBV genotype 1 was higher in Ethiopian lymphoma patients.

Lymphomatous involvement of the larynx is a rare entity. We present a case of atypical laryngotracheitis as the initial manifestation of non-Hodgkin's lymphoma in a pediatric patient. The diagnosis was aided through the use of microbial cell-free DNA (mcfDNA) testing, which detected the presence of Epstein-Barr virus in the patient's plasma. This enabled the consideration of an Epstein-Barr virus-related lymphoproliferative process, leading to additional workup and the final diagnosis of lymphoma. To our knowledge, this is the first case of mcfDNA testing leading not simply to an infectious organism, but further to a new oncologic diagnosis. Plasma mcfDNA testing has the potential to inform clinical practice beyond classic infectious disease manifestations. In this article, we review both the possible future applications and the areas of further investigation that remain., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Munjal serves as consultant for Spiral Therapeutics for work unrelated to this study; Drs Vukkadala, Hazard, and Meister have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Non-Hodgkin lymphomas (NHL) are underestimated causes of cancer in West Africa where chronic viral hepatitis and HIV are endemic. While the association with HIV infection has already been characterized, limited information is available on the association between chronic viral hepatitis and NHL in sub-Saharan Africa. A case-control study was conducted in referral hospitals of Abidjan (Cote d'Ivoire) and Dakar (Senegal). Cases of NHL were matched with controls on age, gender and participating site. The diagnosis of NHL relied on local pathological examination completed with immunohistochemistry. HIV, HBV and HCV serology tests were systematically performed. A conditional logistic regression model estimated the associations by the Odds Ratio (OR) with their 95% confidence interval (CI). A total of 117 NHL cases (Abidjan n = 97, Dakar n = 20) and their 234 matched controls were enrolled. Cases were predominantly men (68.4%) and had a median age of 50 years (IQR 37-57). While Diffuse Large B-cell lymphoma were the most reported morphological type (n = 35) among mature B-cell NHL, the proportion mature T-cell NHL (30%) was high. The prevalence figures of HBV, HCV and HIV infection were 12.8%, 7.7% and 14.5%, respectively among cases of NHL. In multivariate analysis, HBV, HCV and HIV were independently associated with NHL with OR of 2.23 (CI 1.05-4.75), 4.82 (CI 1.52-15.29) and 3.32 (CI 1.54-7.16), respectively. Chronic viral hepatitis B and C were significantly associated with NHL in West Africa. Timely preventive measures against HBV infection and access to curative anti-HCV treatment might prevent a significant number of NHL., (© 2021 UICC.)

Recent studies have shown that persistent SARS-CoV-2 infections in immunocompromised patients can trigger the accumulation of an unusual high number of mutations with potential relevance at both biological and epidemiological levels. Here, we report a case of an immunocompromised patient (non-Hodgkin lymphoma patient under immunosuppressive therapy) with a persistent SARS-CoV-2 infection (marked by intermittent positivity) over at least 6 months. Viral genome sequencing was performed at days 1, 164, and 171 to evaluate SARS-CoV-2 evolution. Among the 15 single-nucleotide polymorphisms (SNPs) (11 leading to amino acid alterations) and 3 deletions accumulated during this long-term infection, four amino acid changes (V3G, S50L, N87S, and A222V) and two deletions (18-30del and 141-144del) occurred in the virus Spike protein. Although no convalescent plasma therapy was administered, some of the detected mutations have been independently reported in other chronically infected individuals, which supports a scenario of convergent adaptive evolution. This study shows that it is of the utmost relevance to monitor the SARS-CoV-2 evolution in immunocompromised individuals, not only to identify novel potentially adaptive mutations, but also to mitigate the risk of introducing "hyper-evolved" variants in the community. IMPORTANCE Tracking the within-patient evolution of SARS-CoV-2 is key to understanding how this pandemic virus shapes its genome toward immune evasion and survival. In the present study, by monitoring a long-term COVID-19 immunocompromised patient, we observed the concurrent emergence of mutations potentially associated with immune evasion and/or enhanced transmission, mostly targeting the SARS-CoV-2 key host-interacting protein and antigen. These findings show that the frequent oscillation in the immune status in immunocompromised individuals can trigger an accelerated virus evolution, thus consolidating this study model as an accelerated pathway to better understand SARS-CoV-2 adaptive traits and anticipate the emergence of variants of concern.

Background: Non-Hodgkin's lymphoma (NHL) is currently the most common malignancy among people living with HIV (PLWH) in the USA. NHL in PLWH is more frequently associated with oncogenic viruses than NHL in immunocompetent individuals and is generally associated with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less immunosuppressive than chemotherapy may decrease infection risk, improve immune control of oncogenic viruses, and ultimately allow for better lymphoma control., Methods: We conducted a retrospective study of patients with HIV-associated lymphomas treated with pembrolizumab±pomalidomide in the HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute., Results: We identified 10 patients with stage IV relapsed and/or primary refractory HIV-associated NHL who were treated with pembrolizumab, an immune checkpoint inihibitor, with or without pomalidomide. Five patients had primary effusion lymphoma (PEL): one had germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL); two had non-GCB DLBCL; one had aggressive B cell lymphoma, not otherwise specified; and one had plasmablastic lymphoma. Six patients received pembrolizumab alone at 200 mg intravenously every 3 weeks, three received pembrolizumab 200 mg intravenously every 4 weeks plus pomalidomide 4 mg orally every day for days 1-21 of a 28-day cycle; and one sequentially received pembrolizumab alone and then pomalidomide alone. The response rate was 50% with particular benefit in gammaherpesvirus-associated tumors. The progression-free survival was 4.1 months (95% CI: 1.3 to 12.4) and overall survival was 14.7 months (95% CI: 2.96 to not reached). Three patients with PEL had leptomeningeal disease: one had a complete response and the other two had long-term disease control. There were four immune-related adverse events (irAEs), all CTCAEv5 grade 2-3; three of the four patients were able to continue receiving pembrolizumab. No irAEs occurred in patients receiving the combination of pembrolizumab and pomalidomide., Conclusions: Treatment of HIV-associated NHL with pembrolizumab with or without pomalidomide elicited responses in several subtypes of HIV-associated NHL. This approach is worth further study in PLWH and NHL., Competing Interests: Competing interests: Pembrolizumab for NCT02595866 was provided to the NCI by Merck and Co. KL, RR, TSU and RY report research funding through Cooperative Research and Development Agreements (CRADAs) between Celgene Corporation (now Bristol Myers Squibb, Co) and the National Cancer Institute as well as a CRADA between EMD-Serrono and the National Cancer Institute. RY has also used drugs for his clinical or laboratory research provided to the NCI by Genentech Corp, EMD-Serono, Janssen Research, and CTI Biopharma. RY and TSU are co-inventors on US Patent 10,001,483 entitled 'Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers'. The patent application for this was filed in part based on the results of NCI protocol 12-C-0047, entitled 'A Phase I/II Study of the Safety, Pharmacokinetics and Efficacy of Pomalidomide (CC-4047) in the Treatment of Kaposi Sarcoma in Individuals with or without HIV'. It is their understanding that foreign patents have also been filed for this invention. This invention was made as full-time employees of the US government under 45 Code of Federal Regulations Part 7. RY’s spouse, who is also a US Government employee, has a patent on KSHV viral IL-6. All rights, title, and interest to these patents have been or should by law be assigned to the US Department of Health and Human Services. The government conveys a portion of the royalties it receives to its employee-inventors under the Federal Technology Transfer Act of 1986 (PL 99-502). TSU reports research funding to Fred Hutchinson Cancer Center from Roche and consulting fees (

Background: Improved hepatitis C virus (HCV) clearance due to directly acting antiviral agents has led to remarkably improved outcomes of indolent HCV-associated non-Hodgkin lymphoma (NHL). The impact of directly acting antivirals on the outcomes of aggressive NHL is still under investigation. Characteristics of HCV-associated NHL in black patients are not well characterized. We report outcomes of HCV-associated NHL compared to their HCV-negative counterparts in a predominantly black population., Patients and Methods: Patients with lymphoma between January 2007 and December 2017 were retrospectively studied. Depending on presence or absence of HCV RNA, patients were grouped into HCV positive (HCV + ) and HCV negative (HCV - ) cohorts. Depending on virologic clearance (VC), HCV + were classified into HCV + with VC and HCV + without VC. Overall response rate (ORR), complete response, overall survival (OS), and progression-free survival (PFS) of HCV + patients with and without VC were compared to HCV -  patients., Results: Of 397 patients with lymphoma, 40 had HCV. Black comprised 90% of HCV + patients. Diffuse large B-cell lymphoma was most frequent (47%) in the HCV + group. HCV + patients without VC had significantly worse OS and PFS compared to HCV - patients. There were no differences in ORR, complete response, PFS, and OS of HCV + patients with VC and HCV - patients. These results were consistent in subgroups of diffuse large B-cell lymphoma and aggressive lymphoma., Conclusion: HCV clearance is positively associated with lymphoma outcomes in black patients. Patients who clear HCV have noninferior outcomes to HCV - patients, while those who fail to clear HCV have significantly worse outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The Epstein-Barr virus (EBV) is linked to various B-cell lymphomas, including Burkitt lymphoma (BL), classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) at frequencies ranging, by routine techniques, from 5 to 10% of cases in DLBCL to >95% in endemic BL. Using higher-sensitivity methods, we recently detected EBV traces in a few EBV-negative BL cases, possibly suggesting a "hit-and-run" mechanism. Here, we used routine and higher-sensitivity methods (qPCR and ddPCR for conserved EBV genomic regions and miRNAs on microdissected tumor cells; EBNA1 mRNA In situ detection by RNAscope) to assess EBV infection in a larger lymphoma cohort [19 BL, 34 DLBCL, 44 cHL, 50 follicular lymphomas (FL), 10 T-lymphoblastic lymphomas (T-LL), 20 hairy cell leukemias (HCL), 10 mantle cell lymphomas (MCL)], as well as in several lymphoma cell lines (9 cHL and 6 BL). qPCR, ddPCR, and RNAscope consistently documented the presence of multiple EBV nucleic acids in rare tumor cells of several cases EBV-negative by conventional methods that all belonged to lymphoma entities clearly related to EBV (BL, 6/9 cases; cHL, 16/32 cases; DLBCL, 11/30 cases), in contrast to fewer cases (3/47 cases) of FL (where the role of EBV is more elusive) and no cases (0/40) of control lymphomas unrelated to EBV (HCL, T-LL, MCL). Similarly, we revealed traces of EBV infection in 4/5 BL and 6/7 HL cell lines otherwise conventionally classified as EBV negative. Interestingly, additional EBV-positive cases (1 DLBCL, 2 cHL) relapsed as EBV-negative by routine methods while showing EBNA1 expression in rare tumor cells by RNAscope. The relapse specimens were clonally identical to their onset biopsies, indicating that the lymphoma clone can largely loose the EBV genome over time but traces of EBV infection are still detectable by high-sensitivity methods. We suggest EBV may contribute to lymphoma pathogenesis more widely than currently acknowledged.

Double-hit lymphoma (DHL) is a unique subtype of non-Hodgkin lymphoma characterized by atleast two rearrangements involving MYC, BLC2, and/or BCL6. These lymphomas are uncommon and aggressive, responding poorly to typical chemotherapy regimens. Lymphomas rarely arise from the oral cavity or tonsils, and those presenting as a neck mass are predominantly diffuse large B-cell lymphoma. To date, primary DHL of the tonsils has yet to be described in the literature. Here, we report a case of a 44 year-old male patient with well-controlled human immunodeficiency virus (HIV) who presented with a sore throat. He subsequently developed acute respiratory compromise due to a rapidly enlarging tonsillar mass. Pathologic and genetic analysis confirmed the presence of BCL6 and MYC rearrangements suggestive of DHL of the tonsils. In a young patient with HIV and a neck mass, it is essential that lymphoma remains on the list of differential diagnoses as prompt diagnosis and treatment may prevent complications from its rapid expansion.

Hepatitis B virus (HBV) infection has been reported to be associated with non-Hodgkin lymphoma (NHL). However, the evidence is limited to the seroepidemiological study. There is a lack of evidence showing the HBV infection and integration in NHL cells. Here, we reported that in the Shanghai area, the positive rates of serum HBsAg (OR: 3.11; 95% CI: 2.20-4.41) and HBeAg (OR: 3.99; 95% CI: 1.73-9.91) were significantly higher in patients with NHL. HBsAg, HBcAg and HBV DNA were detected in 34.4%, 45.2% and 47.0% of the NHL tissues, respectively. Furthermore, by using a high-throughput viral integration detection approach (HIVID), integrated HBV DNA was identified from 50% (6/12) HBV-related NHL tissues. There were a total of 313 HBV integration sites isolated from the NHL tissues, among which four protein-coding genes (FAT2, SETX, ITGA10 and CD63) were interrupted by HBV DNA in their exons. Seven HBV preferential target genes (ANKS1B, HDAC4, EGFLAM, MAN1C1, XKR6, ZBTB38 and CCDC91) showed significantly altered expression levels in NHL, suggesting a potential role of these genes in NHL development. Taken together, HBV integration is a common phenomenon in NHL. This finding opens up a new direction of research into the mechanistic link between HBV infection and NHL., (© 2020 UICC.)

Germinotropic lymphoproliferative disorder is a rare and rather enigmatic novel entity with distinctive clinicopathological features, one of which is the typical co-infection by Human herpesvirus 8 and Epstein-Barr virus. Human herpesvirus 8 is a lymphotropic virus detected in Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, Human herpesvirus 8-positive diffuse large B cell lymphoma not otherwise specified, and germinotropic lymphoproliferative disorder. Co-infection by Human herpesvirus 8 and Epstein-Barr virus is identified only in two lymphoproliferative diseases: germinotropic lymphoproliferative disorder and primary effusion lymphoma, which are otherwise diseases with totally different clinical presentations and outcomes. Unlike primary effusion lymphoma mostly occurring in immunocompromised individuals and following an aggressive course, germinotropic lymphoproliferative disorder usually presents with single or multiple lymphadenopathy affecting mainly immunocompetent individuals and mostly follows an indolent course. Based on the PRISMA guidelines, we carried out a systematic search on PubMed/MEDLINE, Web of Science, Scopus, EMBASE, and Cochrane Library using the search terms "germinotropic" and "lymphoproliferative disorder." Current scientific literature reports just 19 cases of germinotropic lymphoproliferative disorder. The purpose of our systematic review is to improve our understanding of the disease, focusing on epidemiology, clinical presentation, pathological features, treatment, and outcome. In addition, we discuss the differential diagnosis with the other Human herpesvirus 8-related lymphoproliferative diseases as currently recognized in the World Health Organization classification, adding a focus on lymphoproliferative disorders showing overlapping features.

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384., (© 2020 by The American Society of Hematology.)

Noncanonical transcriptions include transcriptions that systematically exchange nucleotides, also called bijective transformations or swinger transformations. Swinger transformation A↔T+C↔G recovers identities of 8 among 9 unknown RNAs differentially expressed in centroblastic lymphoma, a human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma. The identified RNAs align with human genes with known anti-HIV1 or oncogenic activities. Function disruption through swinger-transformed transcription potentially enables avoiding antiviral responses and contributes to cancer induction.

Background: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are suspected of being associated with non-Hodgkin lymphoma (NHL); however, persuasive data are lacking. Hence, a nested large-population case-control study was performed to investigate such associations in Koreans., Methods: Data were collected from 929 patients with NHL and 3716 healthy subjects, who were matched 1:4 for age, sex, income, and region of residence, from the Korean Health Insurance Review and Assessment Service-National Sample Cohort. The diagnoses of NHL and HBV/HCV infection were based on the International Classification of Diseases (version 10) codes. Conditional logistic regression models were used to assess odds ratios (ORs) for NHL with respect to HBV or HCV with adjustment for the Charlson comorbidity index., Results: HBV and HCV rates were higher in the NHL group (3.3% and 1.3%, respectively) than in the control group (0.9% and 0.3%, respectively; P < .001 for each). The adjusted OR of hepatitis infection in patients with NHL were 3.25 (95% confidence interval [CI] = 1.99-5.31) for HBV and 3.36 (95% CI = 1.51-7.46) for HCV (P < .001 for each). Subgroups categorized by age (<55 vs ≥55 years) or sex showed significantly higher adjusted ORs of HBV for NHL. Moreover, patients with NHL ≥ 55 years of age or those who were female showed significantly higher adjusted ORs of HCV; those <55 years or who were male also tended to have higher ORs of HCV., Conclusion: Infection with either HBV or HCV is associated with NHL in Koreans., (© 2019 Wiley Periodicals, Inc.)

Objective: Chronic Hepatitis C virus (HCV) infection can cause severe extrahepatic manifestations, such as mixed cryoglobulins (MC), up to the development of B cell nonHodgkin's lymphoma (B-NHL). Mechanisms transforming of HCV infection into lymphoproliferative and/or autoimmune disorders are still poorly understood. In course of HCV infection, the sustained virus-driven antigenic stimulation may probably induce a B-cell clonal expansion. Measurements of serum free light chains (FLCs) levels, considered as a direct marker of B cell activity, are analyzed with increasing interest in clinical practice, for diagnosis, monitoring and follow-up of plasma cell dyscrasia. Syndecan-1 (CD138) is a transmembrane heparan sulfate proteoglycan expressed and actively shed by most myeloma cells. Membrane CD138 represents the major receptor protein for HCV attachment to the hepatocyte surface and high levels of circulating sCD138 levels are detected in patients at early stage of B-cell chronic lymphocytic leukemia. This study is aimed to evaluate sCD138 and FLC levels as diagnostic biomarkers of HCV-related MC with B-NHL., Patients and Methods: We enrolled 35 HCV-MC-NHL patients, characterized for the specific type of cryoglobulins, and 25 healthy blood donors (HBD) as negative control. Serum sCD138 levels were determined using ELISA kits specific for human sCD138. Serum FLCs were assessed by means of the turbidimetric assay., Results: We found that serum levels of sCD138, as well as FLCs, were significantly higher in patients than in HBD (p<0.001)., Conclusions: In agreement with the definition of HCV-driven lymphoproliferative disorders as the consequence of a multifactorial and multistep pathogenetic process, we suggest that sCD138 and FLCs could be considered putative independent markers of worsening progression of the disease.

Objectives: Non-Hodgkin's lymphoma (NHL) primarily derived from the base of the tongue, is rare. Human papillomavirus (HPV) and Epstein-Barr virus (EBV) are important aetiological risk factors for tumours of the head and neck. This study describes the clinicopathological features of NHL in the tongue base and the status of HPV and EBV in these cases., Methods: Seven cases were identified from the Pathological Registry Database at Peking Union Medical College Hospital (PUMCH). The study utilized immunochemistry, in situ hybridization (ISH), and gene rearrangement to confirm the disease and and performed a clinical follow up for each case., Results: All 7 lymphomas were localized at the base of the tongue. Six of the cases exhibited tongue base masses with smooth surface membranes. One case presented as multiple deep ulcers. The most common histologic subtype was diffuse large B-cell lymphoma (DLBCL), which occurred in five cases. The other two cases were mantle cell lymphoma (MCL) and peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). One of the DLBCL cases was positive for HPV DNA and diffusely expressed P16 protein. During the follow up period, the MCL patient and an elderly DLBCL patient died. The remaining five patients were alive through the end of follow up., Conclusions: Most lymphomas of the tongue base manifest as an endogenous mass without membranous change. The most common subtype of NHLs of the tongue base is DLBCL, and the occurrence at this site may have a good prognosis. With proper therapy, even late stage tongue base lymphomas can be suppressed and remain in remission.

Epstein-Barr virus (EBV) is a member of the γ herpesvirus subfamily. It is widely spread, potentially oncogenic and has been studied in different human cancers such as gastric carcinoma, nasopharyngeal carcinoma and both Hodgkin's and non-Hodgkin's lymphomas. EBV replicates in the oral epithelium, and resting B lymphocytes trafficking through the pharynx develop a latent infection in which only EBV genes related to the B cell growth program are expressed: LMP1, -2a/b, BARTs, EBERs and EBNAs. EBNA1 binds a specific DNA sequence in the viral genome responsible for episome replication, segregation and persistence of the viral genome, and is involved in p53 degradation and oncogenesis. It is also involved in p53 degradation and oncogenesis. Since EBV infection is associated with the progression of malignancy in lymphoma, we used EBNA1-based PCR to determine the frequency of EBV infection in lymphoma specimens from patients with different types of lymphomas. Biopsies from lymphoma patients obtained from National Cancer Institute, Misurata and Tripoli Medical Centre (Libya) showed the presence of EBV in 31 of 40 cases (77%). EBV infection rates did not differ significantly between Hodgkin's lymphoma, and non-Hodgkin's lymphoma. The rates did not vary significantly between the sexes or age groups.

In this review, we focus on B-cell lymphoproliferative disorders (LPDs) and lymphomas associated with Epstein-Barr virus (EBV). In some of these diseases-such as EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified-virus detection is required for the diagnosis, while in others its detection is not necessary for diagnosis. EBV infection has three main latency patterns (types III, II, and I). Different latency patterns are found in different LPD types and are related to the host immune system status. For each of the LPDs/lymphomas, we discuss the clinical presentation, epidemiology, pathology, immunophenotype, and genetic or molecular basis. We provide data for a better understanding of the relationships among the discussed diseases and other information that can be useful in differential diagnosis. Not included in this review are classic Hodgkin lymphoma and some specific variants of DLBCL, as these entities are discussed in separate reviews in this issue., (Copyright © 2019 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Chronic hepatitis C virus (HCV) infection increases the risk for several types of cancer, including hepatocellular carcinoma (HCC) and B-cell non-Hodgkin lymphoma, as primary and second primary malignancies. HCV-infected patients with cancer, particularly those undergoing anticancer therapy, are at risk for development of enhanced HCV replication, which can lead to hepatitis flare and progression of liver fibrosis or cirrhosis. Risk factors for HCV infection include injection drug use, blood transfusion, or solid organ transplantation before 1992, receipt of clotting factor concentrates before 1987, long-term hemodialysis, chronic liver disease, HIV positivity, and occupational exposure. Widely available direct-acting antivirals are highly effective against HCV and well tolerated. Identification of HCV-infected individuals is the essential first step in treatment and eradication of the infection. One-time screening is recommended for persons born from 1945 to 1965; screening is also recommended for persons with risk factors. Recently, a public health recommendation has been drafted to screen all adults age 18 to 79 years. Two oncology organizations recommend screening all patients with hematologic malignancies and hematopoietic cell transplant recipients, and a recently published multicenter prospective study supports universal HCV screening for all patients with cancer. HCV screening entails testing for anti-HCV antibodies in serum and, when results are positive, HCV RNA quantitation to confirm infection. Direct-acting antiviral therapy eradicates HCV in almost all cases. Virologic cure of HCV prevents chronic hepatitis and progression to liver fibrosis or cirrhosis. HCV eradication also decreases the risk of developing HCV-associated primary and second primary malignancies, and it may allow HCV-infected patients access to important cancer clinical trials. Patients with HCV-related cirrhosis require lifelong surveillance for HCC, even after viral eradication.

The change in the incidence of lymphomas in function of the presence or absence of sustained virological response after anti-hepatitis C therapy in a cohort of human immunodeficiency (HIV)-hepatitis C (HCV) viruses coinfected patients was analyzed. A prospective cohort of 755 HIV-HCV coinfected patients who received their first anti-HCV therapy, based on interferon + ribavirin schemas, was evaluated. Incidence and histologic types of lymphomas were analyzed in two periods: (1) before administration of anti-HCV therapy and (2) after anti-HCV therapy. The association between lymphoma incidence and demographic, HIV- (minimum CD4+ cell count and CD4+ cell count at diagnosis of lymphoma, antiretroviral therapy, maximal HIV load and HIV load at diagnosis of lymphoma) and HCV-related variables (HCV load, genotype, sustained viral response to anti-HCV therapy) were analyzed. A total of 13 lymphomas [incidence rate (95% confidence interval), 0.72 (0.33-1.11) × 1000 person-years, time from HIV diagnosis to lymphoma diagnosis (median, interquartile range), 15 (11-19) years] were diagnosed. Nine of them were non-Hodgkin and four Hodgkin lymphomas. The median CD4+ T cell count at diagnosis of lymphoma was 457/mm 3 , with only two cases with values lower than 200/mm 3 . The incidence rate of non-Hodgkin lymphomas was similar pre- and post-anti HCV therapy [0.33 (0.00-0.65) vs 0.68 (0.08-1.26) × 1000 person-years, respectively, p > 0.05]. Patients with sustained virologic HCV response showed similar incidence rate of lymphomas than that of those without anti-HCV response. In conclusion, anti-HCV therapy does not modify the incidence rate of lymphomas in HIV-HCV coinfected patients.

Background: Epstein-Barr virus (EBV) is linked to a variety of malignancies; most endemic Burkitt lymphoma (BL) harbor EBV, whereas only a subset of the cases of sporadic BL is EBV positive., Procedure: We retrospectively determined the herpesvirus seroprevalence at the time of diagnosis in pediatric non-Hodgkin lymphoma (NHL) patients enrolled in NHL-BFM (Berlin-Frankfurt-Muenster) studies. We accessed the seroepidemiological data from 1147 patients that became available during 1990-2007. We included the records from patients 6 months to 18 years of age with BL, T-cell lymphoblastic lymphoma (T-LBL), lymphoblastic precursor B-cell lymphoma (pB-LBL), diffuse large B-cell lymphoma (DLBCL), or anaplastic large cell lymphoma (ALCL)., Results: EBV seropositivity was significantly more frequent in patients with BL than in those with T-LBL. EBV was more prevalent in patients younger than 6 years of age and in patients with BL than in those with non-BL or T-LBL. Event-free survival was significantly lower in varicella-zoster-seronegative patients, but there was no indication of an association to complications due to varicella zoster infection. We found no associations between herpes simplex virus, varicella zoster virus, or human cytomegalovirus seroprevalence and the pediatric Central European NHL cases., Conclusion: Early EBV exposure may increase the risk of BL in Central Europe. A higher involvement of EBV in European BL than originally reported appears at least probable. Our data support the thesis that the distinction between endemic and sporadic BL is artificial and should be replaced by the differentiation between EBV-positive and EBV-negative BL., (© 2019 Wiley Periodicals, Inc.)

Oncoviral infection is responsible for 12%-15% of cancer in humans. Convergent evidence from epidemiology, pathology, and oncology suggests that new viral etiologies for cancers remain to be discovered. Oncoviral profiles can be obtained from cancer genome sequencing data; however, widespread viral sequence contamination and noncausal viruses complicate the process of identifying genuine oncoviruses. Here, we propose a novel strategy to address these challenges by performing virome-wide screening of early-stage clonal viral integrations. To implement this strategy, we developed VIcaller, a novel platform for identifying viral integrations that are derived from any characterized viruses and shared by a large proportion of tumor cells using whole-genome sequencing (WGS) data. The sensitivity and precision were confirmed with simulated and benchmark cancer data sets. By applying this platform to cancer WGS data sets with proven or speculated viral etiology, we newly identified or confirmed clonal integrations of hepatitis B virus (HBV), human papillomavirus (HPV), Epstein-Barr virus (EBV), and BK Virus (BKV), suggesting the involvement of these viruses in early stages of tumorigenesis in affected tumors, such as HBV in TERT and KMT2B (also known as MLL4 ) gene loci in liver cancer, HPV and BKV in bladder cancer, and EBV in non-Hodgkin's lymphoma. We also showed the capacity of VIcaller to identify integrations from some uncharacterized viruses. This is the first study to systematically investigate the strategy and method of virome-wide screening of clonal integrations to identify oncoviruses. Searching clonal viral integrations with our platform has the capacity to identify virus-caused cancers and discover cancer viral etiologies., (© 2019 Chen et al.; Published by Cold Spring Harbor Laboratory Press.)

Previous studies have reached conflicting results regarding the possibility that hepatitis C virus (HCV) infection may increase the risk of non-Hodgkin lymphoma (NHL). We performed a meta-analysis to clarify the relationship between HCV infection and development of NHL. The PubMed, Web of Science, and Embase databases were searched for relevant studies estimating the association between HCV infection and NHL risk through October 31, 2017. Fixed effects or random effects models were used to calculate the pooled odds ratio (OR) and its 95% confidence interval (CI). A total of 18 studies met the inclusion criteria. We found a positive association between HCV infection and NHL (pooled OR 1.69, 95% CI 1.40-2.03, P < .05). In conclusion, our meta-analysis suggested that HCV infection was associated with increased risk of developing NHL.

Backgound: A significant proportion of hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive patients with non-Hodgkin lymphoma (NHL) undergoing rituximab-based chemotherapy (R-CT) may suffer hepatitis B virus (HBV) reactivation., Aims: We wanted to assess efficacy and safety of lamivudine (LMV) prophylaxis to prevent this complication., Methods: Eighty-five consecutive HBsAg negative/anti-HBc positive NHL patients (71 years, 100% serum HBV DNA undetectable, 74% anti-HBs positive) received LMV coadministered with R-CT and for 18 months after the end of R-CT. Serum ALT, HBsAg, anti-HBs and HBV DNA were assessed every 4 months during and after end of LMV., Results: During 39 (2-108) months of study period, including 21 months of LMV and 27 additional months after LMV discontinuation, one patient (2%) had HBV reactivation, 31 months after stopping LMV and during administration of new immunosuppressive regimens, without LMV prophylaxis, owing to incomplete oncological response. A 50% decline of anti-HBs titers occurred in 22/63 (35%) patients, including 12 who became anti-HBs seronegative. Five (6%) patients had ALT increase during R-CT but none required R-CT discontinuation. Seventeen (20%) patients died, all for tumour progression., Conclusion: LMV prophylaxis is safe and effective in preventing HBV reactivation in HBsAg negative/anti-HBc positive NHL patients receiving R-CT., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

With the introduction of HAART, the life expectancy of the patients infected with HIV almost approached that of the general population. The incidence of certain HIV-Associated cancers as Kaposi Sarcoma (KS) and Non-Hodgkin Lymphoma (NHL) decreased, while an increase in Non-AIDS-Defining cancers (NADCs) has been documented. HIV infection is a risk factor for numerous cancers in PLWH. Breast cancer is the most common cancer worldwide among all women. The association between HIV infection and breast cancer has not been thoroughly investigated: when compared to the general population, people living with HIV/AIDS (PLWHA) have a similar or slightly lower risk of breast cancer. Screening tests are essential weapons to fight cancer burden and more effective therapeutic and preventive strategies are needed, especially among PLWHA. Further and more comprehensive studies are needed to better characterize breast cancer among PLWH.

Background and Purpose: Hepatitis C virus (HCV) can induce both hepatic and extrahepatic malignancies. A strong association between HCV and non-Hodgkin lymphomas (NHLs) has been demonstrated. The purpose of this article is to give emphasis on the clinical and imagistic particularities of the hepatitis C-associated NHL, revealing the importance of ultrasonography in discovering and characterizing splenic masses., Methods: We present the cases of 3 women (aged 72, 61, and 56 years, respectively), all of which had a history of chronic hepatitis C and were subsequently diagnosed with different forms of lymphoma. In all 3 cases, conventional ultrasound exploration showed inhomogeneous splenomegaly. Contrast-enhanced ultrasound and computerized tomography were performed soon after admission, both clinical and imaging findings leading to the suspicion of lymphoma. The bone marrow biopsy was relevant for the diagnosis lymphoma in 2 patients, whereas the third woman only presented age-related changes in cellularity. Splenectomy was later performed in this case, for both diagnostic and therapeutic purposes; histopathological examination and immunohistochemistry revealed malignant non-Hodgkin diffuse large B-cell lymphoma., Conclusions: The cooccurrence of HCV infection and splenic lymphoma is a frequently encountered scenery. Ultrasonography, both conventional and contrast-enhanced, plays an important role in the exploration of the spleen, representing a first-line imagistic method and a valuable means of characterizing different types of splenic lesions., Implications for Practice: This article states the importance of ultrasonographic evaluation regarding the splenic pathology, by revealing clinical and imagistic findings in 3 cases of hepatitis C-associated lymphoma.

Purpose: Botswana has a high prevalence of HIV infection. Currently, there are few data regarding the sociodemographic factors, clinical characteristics, and outcomes of non-Hodgkin lymphoma (NHL)-an AIDS-defining cancer-in the country., Patients and Methods: This study used a prospective cancer registry to identify patients with a new diagnosis of NHL reporting for specialty cancer care at three hospitals in Botswana between October 2010 and August 2016. Treatment patterns and clinical outcomes were analyzed., Results: One hundred four patients with a new diagnosis of NHL were enrolled in this study, 72% of whom had HIV infection. Compared with patients not infected with HIV, patients infected with HIV were younger (median age, 53.9 v 39.1 years; P = .001) and more likely to present with an aggressive subtype of NHL (65.5% v 84.0%; P = .008). All patients infected with HIV received combined antiretroviral therapy throughout the course of the study, and similar chemotherapeutic regimens were recommended for all patients, regardless of subtype or HIV status (six to eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone; or cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). There was no difference in 1-year mortality among patients not infected with HIV and patients infected with HIV (unadjusted analysis, 52.9% v 37.1%; hazard ratio [HR], 0.73; P = .33; adjusted analysis, HR, 0.57; P = .14). However, when compared with a cohort of patients in the United States matched by subtype, stage, age, sex, and race, patients in Botswana fared worse (1-year mortality, 22.8% v 46.3%; HR, 1.89; P = .001)., Conclusion: Among patients with NHL reporting for specialty cancer care in Botswana, there is no association between HIV status and 1-year survival.

Background: HIV-associated lymphomas (HAL) remain an important cause of morbidity and mortality in HIV patients, especially in the setting of treatment-refractory disease. Hematopoietic cell transplantation (HCT) is considered a curative option for patients with refractory HAL., Patients and Methods: We report the efficacy of autologous HCT in 20 patients with HAL [non-Hodgkin lymphoma = 14 (70%), Hodgkin lymphoma = 6 (30%)]. At the time of transplantation, the median peripheral blood CD4 + count was 226 cells/μL. HIV virus load was undetectable in 14 (70%) of 20 patients., Results: The median follow-up of surviving patients was 47 months (range, 20-119 months). The median time to neutrophil engraftment was 11 days. The median progression-free survival and median overall survival have not been reached. At 4 years after transplantation, progression-free survival and overall survival were 65% and 70%, respectively. Six patients died from disease relapse or progression (n = 5) and infection (n = 1). Nonrelapse mortality was 0 and 5% at 100 days and 4 years after transplantation, respectively., Conclusion: Autologous HCT is an effective therapy for refractory/relapsed HAL with manageable toxicity, similar to non-HIV patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Oral tongue cancer incidence has increased among whites in the United States; however, the cause remains unknown. If an infectious agent is implicated, then elevated risk would be expected among immunosuppressed individuals., Methods: By using population-based registry linkage information from the US Transplant Cancer Match and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) Cancer Match studies, the authors examined the risk of oral tongue squamous cell carcinoma (SCC) among immunocompromised transplantation recipients and HIV-infected individuals. In addition, the risks of oropharyngeal SCC (strongly related to human papillomavirus infection; modestly affected by immunosuppression), other tobacco/alcohol-related oral cavity SCCs (not thought to be infection/immunosuppression-related), and non-Hodgkin lymphoma of oral cavity/pharynx (strongly related to Epstein-Barr virus; profoundly affected by immunosuppression) were evaluated., Results: Compared with the general population, the risk of non-Hodgkin lymphoma was strongly increased (standardized incidence ratio [SIR] > 8.0). The risk of all SCCs was modestly and similarly elevated among transplantation recipients (SIR range, 2.2-2.7; P heterogeneity  = .2); whereas, among HIV-infected individuals, the risk of oral tongue SCC was higher compared with the risk of other SCCs (SIR, 3.0 vs 1.7 [for oropharyngeal SCCs] and 2.3 [for other oral cavity SCCs]; P heterogeneity  < .001). The risk of SCCs was significantly higher among men, older individuals, and whites; and risk increased with the time since transplantation/AIDS onset. The risk of oral tongue SCC was significantly higher among HIV-infected men who have sex with men compared with the average risk in HIV-infected individuals (adjusted incidence rate ratio = 2.0)., Conclusions: Similar modest increases in the risk of oral tongue and other oral cavity SCCs do not suggest that an infectious agent or exposure profoundly affected by immunosuppression underlies the increase in oral tongue cancer. Cancer 2018;124:2515-22. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are increased in populations with immune dysfunction, including people living with HIV; however, there is little evidence for to what degree immunological and virological factors differently affect NHL and HL risk., Methods: Data from the Data Collection on Adverse events of Anti-HIV Drugs Study cohort were analyzed to identify independent risk factors for NHL and HL using hazard ratios (HRs), focusing on current and cumulative area under the curve (AUC) measures of immunological and virological status. Variables with different associations with NHL and HL were identified using marginal Cox models. All statistical tests were two-sided., Results: Among 41 420 people followed for 337 020 person-years, 392 developed NHL (incidence rate = 1.17/1000 person-years of follow-up [PYFU], 95% confidence interval [CI] = 1.06 to 1.30) and 149 developed HL (incidence rate = 0.44/1000 PYFU, 95% CI = 0.38 to 0.52). Higher risk of both NHL and HL was associated with lower current CD4 cell count (adjusted HR [aHR] of NHL for CD4 <100 vs > 599 cells/mm3 = 8.08, 95% CI = 5.63 to 11.61; HL = 4.58, 95% CI = 2.22 to 9.45), whereas higher current HIV viral load (aHR of NHL for HIV-VL >1000 vs < 50 copies/mL = 1.97, 95% CI = 1.50 to 2.59) and higher AUC of HIV-VL (aHR of NHL for highest vs lowest quintile = 2.91, 95% CI = 1.92 to 4.41) were associated with NHL only. Both current and AUC of HIV-VL were factors that had different associations with NHL and HL, where the hazard ratio for NHL was progressively higher than for HL with increasing HIV-VL category. Lower current CD4 cell count had a strong but similar association with both NHL and HL., Conclusions: CD4 depletion increased risk of both types of lymphomas while current and accumulated HIV-VL was associated with NHL only. This suggests that NHL development is related to both CD4 cell depletion and added immune dysfunction derived from ongoing HIV replication. This latter factor was not associated with HL risk.

Infectious agents, such as HCV, account for ∼15% of human cancers. HCV infects not only hepatocytes but also extrahepatic cells. Chronic HCV infection can induce chronic inflammation with qualitative and quantitative alterations of the immune repertoire and tissue microenvironment, which could induce various neoplasias. Epidemiological studies and meta-analyses suggest an increased rate of extrahepatic cancers in patients with chronic HCV infection along with a higher risk of intrahepatic cholangiocarcinoma, pancreatic cancer and non-Hodgkin lymphoma (NHL), highlighting the need to screen for HCV infection in patients with these cancers. Development of B cell NHL has been associated with HCV infection, with a relative risk of ∼1.5. Direct transformation related to the presence of the virus and chronic antigenic stimulation are the two major non-exclusive mechanisms involved in HCV-related lymphomagenesis. HCV infection alters survival of patients with lymphoma, and sustained virologic response (SVR) substantially improves prognosis. Antiviral treatments might induce remission of indolent lymphoma when SVR is achieved even without chemotherapy, emphasizing the role of HCV in lymphomagenesis in this context. However, studies are needed to provide prospective evidence of a causal relationship between chronic HCV infection and other extrahepatic cancers and to determine whether the risk of extrahepatic cancers is reduced with SVR. In this Review, we report on recent studies analysing the risk of extrahepatic cancers associated with chronic HCV infection. Although there is no doubt regarding the direct and indirect causality between HCV and NHL, an increased risk of other cancers is less clear, with the exception of cholangiocarcinoma.

The human pegivirus (HPgV), classified in the Flaviviridae family - Pegivirus genus, is an RNA virus identified in 1995. HPgV is a lymphotrophic virus, with replication sites in bone marrow and lymphoid tissue, as well as in peripheral blood mononuclear cells (PBMCs). Transmission is through sexual and parenteral routes, and recent estimations suggest nearly 750 million people are infected with HPgV worldwide. Almost 25% of infected individuals can develop persistent infection. Until now, HPgV has been considered a non-pathogenic virus; however, epidemiological studies suggest a potential role in lymphoproliferative diseases, particularly in the development of non-Hodgkin lymphoma (NHL). The evidence of this is controversial and the role of HPgV in lymphomagenesis has not yet been demonstrated. Several studies report a high prevalence of HPgV infection in patients with NHL compared to controls and patients with other hematological diseases. Therefore, analytic studies show that HPgV could be related to an increased risk of NHL development. Conversely, other studies indicate no association between HPgV and NHL, so the role of HPgV in lymphomagenesis is not clear. This review summarizes the main findings related to HPgV's pathogenic potential and association with NHL.

Introduction: Epstein-Barr virus (EBV) is a ubiquitous virus that infects more than 90% of the world's population, and is implicated in lymphoma pathogenesis. However, in Zambia during the diagnosis of these lymphomas, the association of the virus with the lymphomas is not established. Since most patients with lymphomas have poor prognosis, the identification of the virus within the lymphoma lesion will allow for more targeted therapy. The aim of this study was to provide evidence of the presence of the EBV in lymphomas diagnosed at the University Teaching Hospital (UTH) in Lusaka, Zambia., Methods: One hundred and fifty archival formalin-fixed paraffin embedded suspected lymphoma tissues stored over a 4-year period in the Histopathology Laboratory at the UTH in Lusaka, Zambia, were analysed. Histological methods were used to identify the lymphomas, and the virus was detected using Polymerase Chain Reaction (PCR). Subtyping of the virus was achieved through DNA sequencing of the EBNA-2 region of the viral genome. Chi square or fisher's exact test was used to evaluate the association between EBV status, type of lymphoma and gender., Results: The majority of the lymphomas identified were non-Hodgkin's lymphoma (NHL) (80%) followed by Hodgkin's lymphoma (HL) (20%). EBV was detected in 51.8% of the cases, 54.5% of which were associated with NHL cases, while 40.9% associated with HL cases. The predominant subtype of the virus in both types of lymphomas was subtype 1. One of the lymphoma cases harboured both subtype 1 and 2 of the virus., Conclusion: This study showed that EBV is closely associated with lymphomas. Therefore, providing evidence of the presence of the virus in lymphoma tissues will aid in targeted therapy. To our knowledge this is the first time such data has been generated in Zambia., Competing Interests: The authors declare no competing interests.

Background: In an autologous hematopoietic cell transplantation (AHCT) setting, routine cytomegalovirus (CMV) surveillance is not indicated except in high-risk situations. On the other hand, some studies reported increased CMV reactivation in AHCT setting as a result of incorporation of novel agents into treatment algorithms, such as bortezomib and rituximab. We retrospectively analyzed CMV reactivation and infection rates in patients with no high-risk features, who were treated with AHCT., Methods: During January 2010 to November 2015, all consecutive, CMV-seropositive patients were included. The viral copy numbers were measured twice a week from the start of the conditioning regimen until engraftment, once a week for the remaining time period until day 30 after AHCT and once weekly only for patients who had been diagnosed with CMV reactivation before and who developed primary/secondary engraftment failure during 31 to 60 days after AHCT., Results: One hundred one (61.6%) men and 63 (38.4%) women were included in the study. The median age of study cohort was 51 years (range, 16-71 years). The indications for AHCT were Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma in 44 (26.8%), 41 (25%), and 79 (48.2%) patients, respectively. CMV reactivation occurred in 60 (37%) patients, and 13 patients (8%) received pre-emptive ganciclovir treatment., Conclusions: On the basis of our results, it might be stated that CMV surveillance may be recommended during 40 days after AHCT in countries with a high CMV prevalence, even in patients without high-risk features regarding reactivation. Additionally, the risky conditions necessitating CMV screening after AHCT must be re-defined in the era of novel agents., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A serious challenge in cancer treatment is to reposition the activity of various already known drug candidates against cancer. There is a need to rewrite and systematically analyze the detailed mechanistic aspect of cellular networks to gain insight into the novel role played by various molecules. Most Human Immunodeficiency Virus infection-associated cancers are caused by oncogenic viruses like Human Papilloma Viruses and Epstein-Bar Virus. As the onset of AIDS-associated cancers marks the severity of AIDS, there might be possible interconnections between the targets and mechanism of both the diseases. We have explored the possibility of certain antiviral compounds to act against major AIDS-associated cancers: Kaposi's Sarcoma, Non-Hodgkin Lymphoma, and Cervical Cancer with the help of systems pharmacology approach that includes screening for targets and molecules through the construction of a series of drug-target and drug-target-diseases network. Two molecules (Calanolide A and Chaetochromin B) and the target "HRAS" were finally screened with the help of molecular docking and molecular dynamics simulation. The results provide novel antiviral molecules against HRAS target to treat AIDS defining cancers and an insight for understanding the pharmacological, therapeutic aspects of similar unexplored molecules against various cancers.

Background: The prognostic value of latent membrane protein 1 (LMP1) in non-Hodgkin lymphoma (NHL) has been evaluated in several studies. However, the conclusions remain controversial., Methods: We searched relevant literatures from Embase, PubMed, and China National Knowledge Infrastructure Platform databases and performed a meta-analysis to evaluate the prognostic significance of LMP1 expression in NHL. Pooled hazard ratio (HR), 95% confidence interval (CI), and P value were calculated. Nine relevant studies were analyzed in this meta-analysis. We performed a pooled analysis to assess the association between LMP1 expression and overall survival of NHL patients., Results: Our results revealed that LMP1-positive NHL patients had significantly poorer outcomes than LMP1-negative patients (HR = 2.13, 95% CI = 1.31-3.46, Pheterogeneity = 0.005, I = 63.5%). Furthermore, in the subgroup analysis stratified by country, a statistically significant association was found among Chinese (HR = 2.80, 95% CI = 1.53-5.15, Pheterogeneity = 0.342, I = 6.9%); however, no statistically significant relations were found among Japanese (HR = 1.55, 95% CI = 0.74-3.24, Pheterogeneity = 0.020, I = 65.7%)., Conclusion: The expression of LMP1 can be considered a poor predictor of survival in patients with NHL. In addition, LMP1 expression assessment could provide more detailed information for patients with NHL and could be used to optimize therapeutic schemes.

Introduction: In patients with lymphoma the detection of positive hepatitis B or C viruses (HBV and HCV) serology involves crucial therapeutic consequences. In HBV-infected patients the serological profile of active (HBsAg-positive) or resolved (HBsAg-negative/anti-HBcAb-positive) infection is associated to differential risk of viral reactivation during rituximab-based therapy and require appropriate strategies of monitoring and of antiviral prophylaxis. In HCV-associated NHL patients consolidated data demonstrated that interferon (IFN)-based antiviral therapy (AT) is able to induce lymphoma regression strictly related to viral eradication, while preliminary data of the new direct-acting antivirals (DAAs) are very promising. Areas covered: This review summarizes current evidences about HBV reactivation risk in patients undergoing rituximab-based treatments and appropriate options of antiviral prophylaxis with lamivudine, entecavir or tenofovir, as well as pre-emptive strategy in HBsAg-negative/HBcAb-positive patients. Moreover previous experiences with IFN-based AT as well as recent studies with DAAs in HCV-associated indolent lymphomas or diffuse large B-cell lymphoma (DLBCL) are reviewed. Expert opinion: Entecavir or tenofovir prophylaxis is recommended for HBsAg-positive patients, while universal prophilaxis with lamivudine may be preferred in HBsAg-negative/anti-HBc-positive patients. In asymptomatic patients with HCV-associated indolent lymphoma DAA-based AT should be used as first-line option, while in DLBCL its deliver after immunochemotherapy-induced complete remission is suggested.

Currently, HIV infection and AIDS are still one of the most important epidemic diseases around the world. As early in the initial stage of HIV epidemic, the high incidence of ADCs including Kaposi sarcoma and non-Hodgkin's lymphoma was the substantial amount of disease burden of HIV infection and AIDS. With the increasing accessibility of HAART and improving medical care for HIV infection and AIDS, AIDS-related illness including ADCs has dramatically decreased. Meanwhile, the incidence of NADCs rises in PLWH. Compared with the general population, most of cancers are more likely to attack PLWH, and NADCs in PLWH were characterized as earlier onset and more aggressive. However, the understanding for cancer development in PLWH is still dimness. Herein, we reviewed the current knowledge of epidemiology and pathogenesis for malignancies in PLWH summarized from recent studies. On the basis of that, we discussed the special considerations for cancer treatment in PLWH. As those malignancies could be the major issue for HIV infection or AIDS in the future, we expect enhanced investigations, surveillances, and clinical trial for improving the understanding and management for cancers developed in PLWH.

Combination of anti-retroviral therapy, high-dose chemotherapy (HCT) and autologous stem cell transplantation (ASCT) has led to an improved survival of HIV + non-Hodgkin lymphoma (NHL) patients. We compared T- and B-cell subset recovery and related capability to respond to in-vitro stimulation, as well as T-cell repertoire modifications of HIV + and HIV - NHL patients undergoing HCT and ASCT as first-line consolidation or salvage treatment, using sequential blood samples obtained before and at 3, 6, 12 and 24 months after ASCT. B lymphocyte recovery occurred earlier, reaching higher levels in HIV + patients as compared to HIV - patients and healthy controls; in particular, immature and naïve B cells were significantly higher in HIV + patients who had received rituximab in the pre-ASCT period. These lymphocytes equally responded to in-vitro stimulation. Newly produced T cells similarly increased in HIV + and HIV - NHL patients, but their levels remained constantly lower than in healthy controls. T lymphocytes showed a reduced proliferative capacity, but their repertoire was reassorted by the treatment. The functional and numeric B-cell recovery and the qualitative modifications of T-cell receptor repertoire may explain, at least in part, the success of this aggressive therapeutic approach in HIV + patients.

Purpose: The biology of HIV-associated cancers may differ depending on immunologic and virologic context during development. Therefore, an understanding of the burden of Kaposi's sarcoma (KS) and non-Hodgkin lymphoma (NHL) relative to antiretroviral therapy (ART), virologic suppression, and CD4 count is important., Patients and Methods: KS and NHL diagnoses during 1996 to 2011 were identified among patients with HIV infection in eight clinical cohorts in the United States. Among patients in routine HIV clinical care, the proportion of cases in categories of ART use, HIV RNA, and CD4 count at diagnosis were described across calendar time. Person-time and incidence rates were calculated for each category., Results: We identified 466 patients with KS and 258 with NHL. In recent years, KS was more frequently diagnosed after ART initiation (55% in 1996 to 2001 v 76% in 2007 to 2011; P-trend = .02). The proportion of patients with NHL who received ART was higher but stable over time (83% overall; P-trend = .81). An increasing proportion of KS and NHL occurred at higher CD4 counts (P < .05 for KS and NHL) and with undetectable HIV RNA (P < .05 for KS and NHL). In recent years, more person-time was contributed by patients who received ART, had high CD4 counts and had undetectable HIV RNA, whereas incidence rates in these same categories remained stable or declined., Conclusion: Over time, KS and NHL occurred at higher CD4 counts and lower HIV RNA values, and KS occurred more frequently after ART initiation. These changes were driven by an increasing proportion of patients with HIV who received effective ART, had higher CD4 counts, and had suppressed HIV RNA and not by increases in cancer risk within these subgroups. An improved understanding of HIV-associated cancer pathogenesis and outcomes in the context of successful ART is therefore important., Competing Interests: Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2016 by American Society of Clinical Oncology.)

Conclusion: Although this study did not show higher risk of oropharyngeal malignancy in HIV patients overall, they still had much higher prevalence of NHL as well as HL than HIV negative patients. Presence of cervical lymphadenopathy is unreliable in differentiating malignant oropharyngeal tumours from benign lymphoid hyperplasia in HIV patients., Objectives: The aim of this study was to compare the histology of oropharyngeal masses between HIV positive and negative patients., Methods: A retrospective review of 119 patients who underwent oropharyngeal biopsies in a tertiary institution between 2007-2014 and whose HIV status was known (HIV positives =47; negatives =72)., Results: Malignancies occurred in 63.8% of HIV patients and 65% of the negative group (p = 0.87). While non-Hodgkin's lymphoma (NHL), squamous cell carcinoma (SCC), and Hodgkin's lymphoma (HL) constituted 40%, 27%, and 17% of malignancies in HIV patients, respectively; in the HIV-negative group, it was 53%, 13%, and 2% for SCC, NHL, and HL, respectively (p = 0.039, 0.017, and 0.035, respectively). Reactive lymphoid proliferation accounted for 82.4% of the benign masses in the HIV positive group. Malignant tumours were recorded more in younger patient in the HIV positive than the negative group (p = 0.001).

Reovirus is a potent oncolytic virus in many human neoplasms that has reached phase II and III clinical trials. Our laboratory has previously reported the oncolytic effects of reovirus in canine mast cell tumour (MCT). In order to further explore the potential of reovirus in veterinary oncology, we tested the susceptibility of reovirus in 10 canine lymphoma cell lines. Reovirus-induced cell death, virus replication and infectivity were confirmed in four cell lines with variable levels of susceptibility. The level of Ras activation varied among the cell lines with no correlation with reovirus susceptibility. Reovirus-susceptible cell lines underwent apoptosis as proven by propidium iodide (PI) staining, Annexin V-FITC/PI assay, cleavage of PARP and inhibition of cell death by caspase inhibitor. A single intratumoral injection of reovirus suppressed the growth of canine lymphoma subcutaneous tumour in NOD/SCID mice. Unlike canine MCT, canine lymphoma is less susceptible to reovirus., (© 2014 John Wiley & Sons Ltd.)

Rituximab, an anti-CD20 monoclonal antibody, is associated with an increased risk of hepatitis B virus (HBV) reactivation. This study aimed to determine the predictive factors for rituximab-related HBV reactivation in resolved hepatitis B patients, defined as HBsAg-negative, anti-HBc-positive, and undetectable HBV DNA. Among 840 consecutive patients with CD20-positive B-cell lymphoma who received rituximab-based chemotherapy from 2003 through 2014 at Seoul National University Hospital, 732 patients were excluded because either anti-HBc was not assessed or they were HBsAg-seropositive. This retrospective study included 108 resolved hepatitis B patients. During a median 33.5-month follow-up period, eight cases of HBV reactivation occurred only among the patients with low anti-HBs titers (<100 mIU/ml) at baseline and those who did not receive antiviral prophylaxis. Using multivariate analyses, antiviral prophylaxis and baseline anti-HBs titers were the protective factors for HBV reactivation (hazard ratio [HR], 0.90 and 0.95, respectively). Among those who did not receive antiviral prophylaxis, patients with high baseline anti-HBs (≥100 mIU/ml) experienced significantly lower risk of HBV reactivation (HR, 0.49; P = 0.006) than the patients with low baseline anti-HBs (<100 mIU/ml) whose cumulative HBV reactivation rates at 6 and 24 months after chemotherapy were 8.3% and 17.3%, respectively. High anti-HBs titer at baseline and antiviral prophylaxis prevented HBV reactivation, suggesting antiviral prophylaxis should be considered according to baseline anti-HBs titer. Meticulous follow-up for ALT and HBV DNA without antiviral prophylaxis might be possible for the patients with high baseline anti-HBs (≥100 mIU/ml)., (© 2015 Wiley Periodicals, Inc.)