Cancer risk among people living with Human Immunodeficiency Virus (HIV) in Rwanda from 2007 to 2018.

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.

Epstein-Barr virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.

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.

A virome-wide clonal integration analysis platform for discovering cancer viral etiology.

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.

Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial).

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.

Chronic viral hepatitis, HIV infection and Non-Hodgkin lymphomas in West Africa, a case-control study.

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.

Characterization of hepatitis B virus infection and viral DNA integration in non-Hodgkin lymphoma.

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.

Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV-negative by routine methods: expanding the landscape of EBV-related lymphomas.

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.

Hepatitis virus B and C infections are associated with an increased risk of non-Hodgkin lymphoma: A nested case-control study using a national sample cohort.

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.

Germinotropic lymphoproliferative disorder: a systematic review.

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.

Molecular detection of Epstein-Barr virus in different types of lymphoma.

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.

Incidence of lymphoma in HIV-HCV-infected patients. Modifications in function of the anti-hepatitis C virus therapy.

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/mm3, with only two cases with values lower than 200/mm3. 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.

Seroepidemiological analysis and literature review of the prevalence of Epstein-Barr virus and herpesvirus infections in pediatric cases with non-Hodgkin lymphoma in Central Europe.

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.

Risk of oral tongue cancer among immunocompromised transplant recipients and human immunodeficiency virus-infected individuals in the United States.

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; Pheterogeneity = .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]; Pheterogeneity < .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.

Malignancies in HIV-Infected and AIDS Patients.

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.

High titers of anti-HBs prevent rituximab-related viral reactivation in resolved hepatitis B patient with non-Hodgkin's lymphoma.

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).

A clinicopathological study of primary central nervous system lymphomas & their association with Epstein-Barr virus.

BACKGROUND & OBJECTIVES: Primary central nervous system lymphomas (PCNSLs) are relatively uncommon, accounting for 2-3 per cent of primary brain tumours. Majority of these are diffuse large B cell lymphomas (DLBCL) occurring both in immunocompromised and immunocompetent patients. We undertook this study to classify PCNSL into germinal centre (GC) and non-germinal centre (NGC) type based on Hans classification and to find the role of Epstein-Barr virus (EBV) in pathogenesis both by conventional immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). METHODS: The consecutive cases of PCNSL during a 10 years period were analysed by IHC for CD45, CD20, CD3, B-cell lymphoma 2 and 6 (Bcl-2 and Bcl-6), B-cell specific octamer binding protein-1 (BOB-1), multiple myeloma oncogene-1 (MUM-1), EBV latent-membrane protein 1 (LMP-1), cyclin-D1, CD10, CD5 and CD23, as well as by CISH for EBV. RESULTS: During a period of 10 years, 65 PCNSL were diagnosed which comprised 0.69 per cent (65/9476) of all intracranial tumours. The mean age of presentation was 49 yr with sex ratio (M:F) of 1.4:1. Most common location was supratentorial region with predominant involvement of frontal lobe. Single lesions were seen in 38 (58.4%) and multifocal lesions in 27 (41.5%) patients. None of the patients were immunocompromised. All cases were B cell immunophenotype and were DLBCL except one case of follicular lymphoma. According to Hans classification, majority of them were NGC (n=51, 79.6%) and 13 (20.3%) were GC type. Bcl-2 expression was noted in 34 (52.3%) tumours. EBV was positive in three (4.6%) cases; two were detected both by IHC and CISH and one case by CISH only. INTERPRETATION & CONCLUSIONS: In Indian population, PCNSL occurs mainly in immunocompetent patients, and a decade earlier than in western population. Immunophenotyping revealed that all cases were DLBCL with predominance of NGC type. No prognostic difference was seen between GC and NGC DLBCL. Association of EBV was rare and this virus was possibly not involved in the pathogenesis of PCNSL in immunocompetent individuals. CISH was an easy, economical and less cumbersome method for detection of EBV in PCNSL.

Epstein-Barr virus and risk of non-Hodgkin lymphoma in the cancer prevention study-II and a meta-analysis of serologic studies.

Epstein-Barr virus (EBV) causes rare, malignant lymphomas. The role of EBV in other non-Hodgkin lymphomas (NHLs) remains unclear, but mildly reduced immune function could lead to reactivation of EBV and subsequent NHL. We examined the association between prospectively-collected plasma EBV antibodies and NHL risk in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort and conducted a meta-analysis of our and published results. The CPS-II study included 225 NHL cases and 2:1 matched controls. No associations were observed between EBV serostatus or antibody levels and risk of NHL overall. However, when including only the three most common types of NHL (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma), high compared to low early antigen (EA-D) diffuse and BZLF1-encoded replication activator antibodies were associated with approximately 60% higher risk of NHL. Odds ratios (ORs) for EBV nuclear antigen-1 and viral capsid antigen (VCA)-p18 were elevated but not statistically significant. In the meta-analysis, both EA (summary OR = 1.52, 95% confidence interval (CI): 1.16-2.00) and VCA (summary OR = 1.20, 95% CI: 1.00-1.44) were positively associated with NHL risk. These results suggest EBV may be associated with a wider spectrum of NHL subtypes, but further study is needed to confirm and fully understand these associations.

Immunologic evidence of a strong association between non-Hodgkin lymphoma and simian virus 40.

BACKGROUND: Non-Hodgkin lymphoma (NHL), the most common cancer of the lymphatic system, is of unknown etiology. The identification of etiologic factors in the onset of NHL is a key event that could facilitate the prevention and cure of this malignancy. Simian virus 40 (SV40) has been considered an oncogenic agent in the onset/progression of NHL. METHODS: In this study, an indirect enzyme-linked immunosorbent assay with 2 synthetic peptides that mimic SV40 antigens of viral capsid proteins 1 to 3 was employed to detect specific antibodies against SV40. Serum samples were taken from 2 distinct cohorts of NHL-affected patients (NHL1 [n = 89] and NHL2 [n = 61]) along with controls represented by oncologic patients affected by breast cancer (BC; n = 78) and undifferentiated nasopharyngeal carcinoma (UNPC; n = 64) and 3 different cohorts of healthy subjects (HSs; HS1 [n = 130], HS2 [n = 83], and HS3 [n = 87]). RESULTS: Immunologic data indicated that in serum samples from NHL patients, antibodies against SV40 mimotopes were detectable with a prevalence of 40% in NHL1 patients and with a prevalence of 43% in NHL2 patients. In HSs of the same median age as NHL patients, the prevalence was 16% for the HS1 group (57 years) and 14% for the HS2 group (65 years). The difference was statistically significant (P < .0001 and P < .001). Interestingly, the difference between NHL1/NHL2 patients and BC patients (40%/43% vs 15%, P < .001) and between NHL1/NHL2 patients and UNPC patients (40%/43% vs 25%, P < .05) was significant. CONCLUSIONS: Our data indicate a strong association between NHL and SV40 and thus a need for innovative therapeutic approaches for this hematologic malignancy.

Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients.

Limited comparative data exist for the treatment of HIV-associated non-Hodgkin lymphoma. We analyzed pooled individual patient data for 1546 patients from 19 prospective clinical trials to assess treatment-specific factors (type of chemotherapy, rituximab, and concurrent combination antiretroviral [cART] use) and their influence on the outcomes complete response (CR), progression free survival (PFS), and overall survival (OS). In our analysis, rituximab was associated with a higher CR rate (odds ratio [OR] 2.89; P < .001), improved PFS (hazard ratio [HR] 0.50; P < .001), and OS (HR 0.51; P < .0001). Compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), initial therapy with more dose-intense regimens resulted in better CR rates (ACVBP [doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone]: OR 1.70; P < .04), PFS (ACVBP: HR 0.72; P = .049; "intensive regimens": HR 0.35; P < .001) and OS ("intensive regimens": HR 0.54; P < .001). Infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH) was associated with significantly better OS in diffuse large B-cell lymphoma (HR 0.33; P = .03). Concurrent use of cART was associated with improved CR rates (OR 1.89; P = .005) and trended toward improved OS (HR 0.78; P = .07). These findings provide supporting evidence for current patterns of care where definitive evidence is unavailable.