AIDS-related Lymphoma Research Articles

The tumor virus landscape of AIDS-related lymphomas

AbstractImmunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in <10% of cases or undetectable by our methods. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency proteins are under increased immunosurveillance in the post-combined antiretroviral therapies era. Furthermore, EBV infection of lymphoma cells in HIV-positive individuals was associated with a distinct host gene expression program. These findings provide insight into the joint host-virus regulatory network of primary ARL tumor samples and expand our understanding of virus-associated oncogenesis. Our findings may also have therapeutic implications, as treatment may be personalized to target specific viral and virus-associated host processes that are only present in a subset of patients.

Changes in the influence of lymphoma- and HIV-specific factors on outcomes in AIDS-related non-Hodgkin lymphoma

We undertook the present analysis to examine the shifting influence of prognostic factors in HIV-positive patients diagnosed with aggressive non-Hodgkin lymphoma (NHL) over the last two decades. We carried out a pooled analysis from an existing database of patients with AIDS-related lymphoma. Individual patient data had been obtained prior from prospective phase II or III clinical trials carried out between 1990 until 2010 in North America and Europe that studied chemo(immuno)therapy in HIV-positive patients diagnosed with AIDS-related lymphomas. Studies had been identified by a systematic review. We analyzed patient-level data for 1546 patients with AIDS-related lymphomas using logistic regression and Cox proportional hazard models to identify the association of patient-, lymphoma-, and HIV-specific variables with the outcomes complete response (CR), progression-free survival, and overall survival (OS) in different eras: pre-cART (1989-1995), early cART (1996-2000), recent cART (2001-2004), and contemporary cART era (2005-2010). Outcomes for patients with AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma improved significantly over time, irrespective of baseline CD4 count or age-adjusted International Prognostic Index (IPI) risk category. Two-year OS was best in the contemporary era: 67% and 75% compared with 24% and 37% in the pre-cART era (P < 0.001). While the age-adjusted IPI was a significant predictor of outcome in all time periods, the influence of other factors waxed and waned. Individual HIV-related factors such as low CD4 counts (<50/mm(3)) and prior history of AIDS were no longer associated with poor outcomes in the contemporary era. Our results demonstrate a significant improvement of CR rate and survival for all patients with AIDS-related lymphomas. Effective HIV-directed therapies reduce the impact of HIV-related prognostic factors on outcomes and allow curative antilymphoma therapy for the majority of patients with aggressive NHL.

The Role of the Tumor Microenvironment in HIV-Associated Lymphomas

There has been considerable interest in the role of the lymphoma microenvironment. Despite the use of highly active antiretroviral therapy (HAART), AIDS-related diffuse large-B-cell lymphoma remains common and HIV-relatedHIV-associated classical Hodgkin's lymphoma is increasing in incidence. Less is known about the impact HIV and HAART have on the lymphoma microenvironment. AIDS-related diffuse large B-cell lymphoma is highly angiogenic, demonstrates increased lymphoblastic histology, proliferation, increased activated cytotoxic T cells, reduced CD4(+) and FOXP3(+) T cells, but no differences in tumor-associated macrophages. Early initiation of HAART improves immunosurveillance, but cases without viral antigens appear able to avoid immunologic reaction. Increased T cell infiltrates seen with HAART treatment in HIV-related classical Hodgkin's lymphoma may contribute to malignant cell growth.

Aids-related primary CNS non-Hodgkin's lymphoma in a patient with previous Epstein-Barr virus panuveitis. A clinico-pathological report

Clinical casePatient with AIDS and Epstein-Barr virus (EBV) uveitis. The PCR of the aqueous and vitreous humor was positive for EBV, and DNA quantification was 56.602×106copies/ml in the vitreous humor, 173,400copies/ml in the peripheral blood, and negative in the cerebrospinal fluid (CSF). The patient developed a non-Hodgkin's lymphoma (NHL), diagnosed in the autopsy. ConclusionThe EBV is a rare cause of uveitis and it may be necessary to perform a quantitative PCR to reach the diagnosis. High amounts of EBV DNA are associated with a greater incidence of NHL.

Genomic analysis of xCT-mediated regulatory network: Identification of novel targets against AIDS-associated lymphoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), a rapidly progressing malignancy mostly arising in HIV-infected patients. Even under conventional chemotherapy, PEL continues to portend nearly 100% mortality within several months, which urgently requires novel therapeutic strategies. We have previously demonstrated that targeting xCT, an amino acid transporter for cystine/glutamate exchange, induces significant PEL cell apoptosis through regulation of multiple host and viral factors. More importantly, one of xCT selective inhibitors, Sulfasalazine (SASP), effectively prevents PEL tumor progression in an immune-deficient xenograft model. In the current study, we use Illumina microarray to explore the profile of genes altered by SASP treatment within 3 KSHV(+) PEL cell-lines, and discover that many genes involved in oxidative stress/antioxidant defense system, apoptosis/anti-apoptosis/cell death, and cellular response to unfolded proteins/topologically incorrect proteins are potentially regulated by xCT. We further validate 2 downstream candidates, OSGIN1 (oxidative stress-induced growth inhibitor 1) and XRCC5 (X-ray repair cross-complementing protein 5), and evaluate their functional relationship with PEL cell survival/proliferation and chemoresistance, respectively. Together, our data indicate that targeting these novel xCT-regulated downstream genes may represent a promising new therapeutic strategy against PEL and/or other AIDS-related lymphoma.

Complete genome sequence of Pig-tailed macaque rhadinovirus 2 and its evolutionary relationship with rhesus macaque rhadinovirus and human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus.

Two rhadinovirus lineages have been identified in Old World primates. The rhadinovirus 1 (RV1) lineage consists of human herpesvirus 8, Kaposi's sarcoma-associated herpesvirus (KSHV), and closely related rhadinoviruses of chimpanzees, gorillas, macaques and other Old World primates. The RV2 rhadinovirus lineage is distinct and consists of closely related viruses from the same Old World primate species. Rhesus macaque rhadinovirus (RRV) is the RV2 prototype, and two RRV isolates, 26-95 and 17577, were sequenced. We determined that the pig-tailed macaque RV2 rhadinovirus, MneRV2, is highly associated with lymphomas in macaques with simian AIDS. To further study the role of rhadinoviruses in the development of lymphoma, we sequenced the complete genome of MneRV2 and identified 87 protein coding genes and 17 candidate microRNAs (miRNAs). A strong genome colinearity and sequence homology were observed between MneRV2 and RRV26-95, although the open reading frame (ORF) encoding the KSHV ORFK15 homolog was disrupted in RRV26-95. Comparison with MneRV2 revealed several genomic anomalies in RRV17577 that were not present in other rhadinovirus genomes, including an N-terminal duplication in ORF4 and a recombinative exchange of more distantly related homologs of the ORF22/ORF47 interacting glycoprotein genes. The comparison with MneRV2 has revealed novel genes and important conservation of protein coding domains and transcription initiation, termination, and splicing signals, which have added to our knowledge of RV2 rhadinovirus genetics. Further comparisons with KSHV and other RV1 rhadinoviruses will provide important avenues for dissecting the biology, evolution, and pathology of these closely related tumor-inducing viruses in humans and other Old World primates. This work provides the sequence characterization of MneRV2, the pig-tailed macaque homolog of rhesus rhadinovirus (RRV). MneRV2 and RRV belong to the rhadinovirus 2 (RV2) rhadinovirus lineage of Old World primates and are distinct but related to Kaposi's sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi's sarcoma. Pig-tailed macaques provide important models of human disease, and our previous studies have indicated that MneRV2 plays a causal role in AIDS-related lymphomas in macaques. Delineation of the MneRV2 sequence has allowed a detailed characterization of the genome structure, and evolutionary comparisons with RRV and KSHV have identified conserved promoters, splice junctions, and novel genes. This comparison provides insight into RV2 rhadinovirus biology and sets the groundwork for more intensive next-generation (Next-Gen) transcript and genetic analysis of this class of tumor-inducing herpesvirus. This study supports the use of MneRV2 in pig-tailed macaques as an important model for studying rhadinovirus biology, transmission and pathology.

Autograft HIV-DNA Load Predicts HIV-1 Peripheral Reservoir After Stem Cell Transplantation for AIDS-Related Lymphoma Patients

Autologous stem cell transplantation (ASCT) is a widely used procedure for AIDS-related lymphomas, and it represents an opportunity to evaluate strategies curing HIV-1 infection. The association of autograft HIV-DNA load with peripheral blood HIV-1 reservoir before ASCT and its contribution in predicting HIV-1 reservoir size and stability during combination antiretroviral therapy (cART) after transplantation are unknown. Aiming to obtain information suggesting new functional cure strategies by ASCT, we retrospectively evaluated HIV-DNA load in autograft and in peripheral blood before and after transplantation in 13 cART-treated HIV-1 relapse/refractoring lymphoma patients. Among them seven discontinued cART after autograft infusion. HIV-DNA was evaluated by a sensitive quantitative real-time polymerase chain reaction (PCR). After debulking chemotherapy/mobilization, the autograft HIV-1 reservoir was higher than and not associated with the peripheral HIV-1 reservoir at baseline [median 215 HIV-DNA copies/10(6) autograft mononuclear cells, range 13-706 vs. 82 HIV-DNA copies/10(6) peripheral blood mononuclear cells (PBMCs), range 13-479, p = 0.03]. After high dose chemotherapy and autograft infusion, HIV-DNA levels reached a plateau between month 6 and 12 of follow-up. No association was found between peripheral HIV-DNA levels at baseline and after infusion in both cART interrupting and not interrupting patients. Only in the last subgroup, a stable significant linear association between autograft and peripheral blood HIV-1 reservoir emerged from month 1 (R(2) = 0.84, p = 0.01) to month 12 follow-up (R(2) = 0.99, p = 0.0005). In summary, autograft HIV-1 reservoir size could be influenced by the mobilization phase and predicts posttransplant peripheral HIV-1 reservoir size in patients on continuous cART. These findings could promote new research on strategies reducing the HIV-1 reservoir by using the ASCT procedure.

Inflammatory Cytokines, Hyperferritinemia and IgE Are Prognostic in Patients with KSHV-Associated Lymphomas Treated with Curative Intent Therapy

Introduction: Primary effusion lymphoma (PEL) and large cell lymphoma arising in Kaposi sarcoma-associated herpesvirus associated multicentric Castleman disease (KSHV-MCD) are KSHV-associated non-Hodgkin lymphomas (together, KSHV-NHL) with overlapping clinical and pathologic features. KSHV-NHL have biologic profiles distinct from other AIDS-related lymphomas, a poor prognosis and no established therapy. Immune dysregulation, including KSHV-associated interleukin (IL)-6 syndromes, contribute to pathobiology and may affect outcomes. We hypothesized that biomarkers of KSHV-associated immune activation and lymphoproliferation could predict overall survival (OS) in patients with KSHV-NHL treated with modified dose-adjusted (DA)-EPOCH (continuous infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone).Methods:We analyzed OS in a retrospective series of 19 patients with pathology-confirmed KSHV-NHL diagnosed 2000-2013 who were evaluated in the HIV & AIDS Malignancy Branch Clinic and received curative intent modified DA-EPOCH regimens. Therapies combined with DA-EPOCH included rituximab, bevacizumab, and/or high dose methotrexate. All patients received combination antiretroviral therapy. Baseline clinical laboratories and immunologic biomarkers as well as treatment factors were evaluated for prognostic value. Continuous parameters were dichotomized near the median (med). OS was evaluated using Kaplan-Meier methods and 2-sided log-rank test. Multivariable analysis employed Cox regression with backward selection, initially including variables with a univariate p ² 0.10. Correlations between significant prognostic markers were evaluated by Spearman’s rank correlation.Results: Med age was 44 years (22-69); 1 woman, 18 men; 17 had PEL, with extracavitary involvement in 11; 2 had large cell lymphoma arising in KSHV-MCD. 42% had HIV viral load (VL) < 100 copies/mL. Med CD4 was 120 cells/uL (Table 1). Med number of chemotherapy cycles was 6 (range 1-13). Best response: 10 patients (53%) had complete response, 2 achieved stable disease and 7 progressed. With 3.3 years med potential follow up, med OS was 1.8 years and 3-year OS was 42.8%. Baseline predictors for inferior OS in univariate analysis, were elevated interferon-gamma (IFNg), IL-10, IL-6, immunoglobulin E (IgE), and KSHV VL (Figure 1). Elevated ferritin (p=0.07) and decreased platelets (p = 0.1) also predicted OS. Hemoglobin, albumin, C-reactive protein, serum free light chains (FLC), LDH, CD4 count, HIV viremia, IL-8, tumor necrosis factor-a (TNFa), and treatment factors did not predict OS. Moderately strong to strong correlation between IL-10, IL-6 and IFNg (r=0.64 - 0.91); IL6 and IL-10 with ferritin (r=0.51- 0.59); and IL-10 with IgE (r=0.54) but not ferritin with IgE (r=0.11) were observed and affected selection models. In a Cox model with backward selection, levels above the med for IgE (HR 30, p=0.01) and ferritin (HR=13, p=0.03) were jointly predictive of OS. Excluding IgE from the model, elevated IL-10 was the best predictor of OS.Conclusion: Modified DA-EPOCH resulted in 3-year OS of 43%. Improved targeted therapies are needed. Hyperferritinemea, elevated IgE and inflammatory human cytokine profiles associated with dysregulated KSHV-lytic activation (IL-10, IL-6 and KSHV-VL) and macrophage activation syndromes (ferritin, IFNg, IL-6 and IL-10) suggest that life-threatening abnormalities in both innate and acquired immunity are common in KSHV-NHL and contribute to pathogenesis and prognosis. IgE and ferritin require further evaluation in KSHV-associated diseases.Table 1Baseline characteristicsCharacteristicValueDemographicsAge, med (range)(IQR)44(22-69)Sex, M:F18:1Racen(%)White9 (47)Hispanic4 (21)African American4 (21)African Immigrant2 (11)Clinical Characteristicsn(%)KS14(74)KSHV-MCD5(26)HIV VL <100 copies/mL8(42)Laboratory parametersmedian (range)CD4+ cells/uL120(15-1072)Hemoglobin, g/dL9.3(7.4-13)Platelets x1000/uL105(10-361)Albumin, g/dL2.1(1.1-3.4)C-reactive protein, g/dL52.25(7.96-164)LDH,u/L198(87-999)IgG, mg/dL1990(641-4900)IgE, U/L67.4(1-46950)Serum FLC Kappa, mg/dL8.66(1.46-59.8)Serum FLC Lambda, mg/dL6.7(1.65-45.4)Ferritin mcg/L908(87-4500)KSHV VL, copies/106 PBMCs29727.5(40-1318182) [Display omitted] DisclosuresUldrick:Celgene Corporation: Research Funding. Off Label Use: Bevacizumab use in primary effusion lymphoma. Tosato:NIH: Has patent for KSHV-viral IL-6 assay Patents & Royalties. Yarchoan:Celgene: Research Funding.

Expression of activating receptors on natural killer cells from AIDS-related lymphoma patients.

BackgroundAbnormal NK phenotype and cytotoxic functions have been described in acute myeloid leukemia, chronic lymphocytic leukemia, myeloma and myelodysplastic syndromes. Defective NK cytotoxicity is due to decreased expression of the Natural Cytotoxicity Receptors (NCRs), 2B4/CD244/p38, or NKG2D. This prompted us to test the expression of these molecules on circulating NK cells from patients with AIDS-related lymphomas (RL) in comparison with HIV + patients without lymphoma, healthy subjects and HIV-negative patients with lymphoma.MethodsBlood samples were analyzed by flow cytometry for NCRs, 2B4/CD244/p38 and NKG2D expression on NK cells defined as CD3-/CD56+ lymphocytes. We also analyzed by quantitative PCR specific RNA for NKp30/NCR3 and NKp46/NCR1.ResultsWe could not detect any defect in NKp46/NCR1 expression between all groups. NKp44/NCR2, NKp30/NCR3 and NKG2D had lower expression in AIDS-RL in comparison with HIV + patients without lymphoma when compared to patients with similar (>0.3 G/L) CD4+ lymphocyte levels. Expression of 2B4/CD244/p38 was lower in AIDS-RL than in HIV-negative lymphoma. Comparison of specific NKp30/NCR3 and NKp46/NCR1 RNA showed increased steady state levels, despite decreased surface expression for NKp30/NCR3, suggesting abnormal post-transcriptional regulatory mechanisms.ConclusionsWe show a more pronounced defect in NK activating molecule when HIV infection is associated with lymphoma than when only one condition (HIV positivity or lymphoma) is present. Defective NK phenotype, in addition to CD4+ depletion and dysfunction, may participate to the increased incidence of lymphoma in HIV patients.

Autologous stem cell transplantation in HIV-related lymphoma in the rituximab era - a feasibility study in a monocentric cohort.

IntroductionSince the introduction of highly active antiretroviral therapy (HAART) [1] and later on the availability of anti-CD20 monoclonal antibody treatment [2], the therapeutic options as well as the prognosis of AIDS related lymphoma (ARL) have been improved. There is however no uniform agreement on how to treat patients who do not achieve a partial remission, who experience a relapse or who have very aggressive subtypes. Autologous hematopoietic stem cell transplantation (ASCT) has become an option for those patients. We retrospectively examined ARL patients to elucidate the feasibility of high-dose chemotherapy and autologous stem cell transplantation.Patients and methodsData of seven male and one female HIV+ patients with ARL was collected and informed consent was obtained. Age, HIV disease characteristics (CD4 count, HIV-RNA-PCR, ART) and transplantation-related details (histopathology, myeloablative therapy, neutrophil engraftment and NCI-CTCAE during/after transplantation as well as follow up and survival) were obtained from the patients’ medical records. ResultsEight patients were treated with the intent of ASCT. The median age was at 64 years. Four patients had experienced prior AIDS. The median CD4 NADIR was at 157/µl, the median CD4 count at diagnosis of lymphoma at 81/µl. Five patients were receiving combination antiretroviral therapy (cART) at the time of lymphoma diagnosis, four of which had achieved a viral load of less than 50/µl. Two patients have died, due to (Nr. 8) a transplant-related complication (non-infectious leukoencephalophathy). The other patient died of an unknown reason (351 days after transplantation). The median survival is at 345 days to date. The time until engraftment was well at 11 days. Grade 3/4 haematological toxicity was present in all patients. Five out of three patients developed infectious complications, but there were no infection-related deaths. One patients (Nr. 4) developed a Kaposi Sarcoma reactivation that necessitated further chemotherapy.ConclusionsASCT is feasible in high risk ARL with good engraftment. Toxicity was substantial and studies are needed to define which patients have an unduly high risk of toxicity.

AIDS-Related Non-Hodgkin Lymphoma: Imaging Feature Analysis of 27 Cases and Correlation with Pathologic Findings

Some tumor types are related to HIV, including non-Hodgkin lymphoma (NHL). The morbidity and mortality of NHL has remained high, even after highly active antiretroviral therapy (HAART) was introduced. We collected cases of AIDS with NHL, and evaluated the imaging features and strategies for diagnosis. There were 27 patients with AIDS and tumors confirmed by pathology. There were 9 patients with Burkitt lymphoma, 16 with diffuse large B cell lymphomas (DLBCLs), and 2 with primary central nervous system (PCNS) lymphomas. All of the patients underwent a series of imaging studies. Three radiologists analyzed the images, and any disagreement was discussed until consensus was reached. The radiologic manifestations of AIDS with NHL were mainly masses and lymphadenopathy, 3 patients having one mass and 12 two or more masses. 7 patients had lymphadenopathy in one site and 3patients had lymphadenopathy in two or more sites. Coarse mucosal folds, thickening of the gastrointestinal wall, and lumen narrowing were typical manifestations of NHL within the gastrointestinal tract. There were 4 patients with masses and 5 with lymphadenopathy inthe 9 with Burkitt lymphoma, and 11 patients with masses 5 with lymphadenopathy in the 16 with DLBCLs. NHL is a malignancy that usually occurs in patients with AIDS. Imaging is an important method by which to evaluate lesions, masses, and lymphadenopathy. Fine needle aspiration biopsy and stereotaxis biopsy are useful methods by which to diagnose NHL.

A new prognostic score for AIDS-related lymphomas in the rituximab-era.

While the International Prognostic Index is commonly used to predict outcomes in immunocompetent patients with aggressive B-cell non-Hodgkin lymphomas, HIV-infection is an important competing risk for death in patients with AIDS-related lymphomas. We investigated whether a newly created prognostic score (AIDS-related lymphoma International Prognostic Index) could better assess risk of death in patients with AIDS-related lymphomas. We randomly divided a dataset of 487 patients newly diagnosed with AIDS-related lymphomas and treated with rituximab-containing chemoimmunotherapy into a training (n=244) and validation (n=243) set. We examined the association of HIV-related and other known risk factors with overall survival in both sets independently. We defined a new score (AIDS-related lymphoma International Prognostic Index) by assigning weights to each significant predictor [age-adjusted International Prognostic Index, extranodal sites, HIV-score (composed of CD4 count, viral load, and prior history of AIDS)] with three risk categories similar to the age-adjusted International Prognostic Index (low, intermediate and high risk). We compared the prognostic value for overall survival between AIDS-related lymphoma International Prognostic Index and age-adjusted International Prognostic Index in the validation set and found that the AIDS-related lymphoma International Prognostic Index performed significantly better in predicting risk of death than the age-adjusted International Prognostic Index (P=0.004) and better discriminated risk of death between each risk category (P=0.015 vs. P=0.13). Twenty-eight percent of patients were defined as low risk by the ARL-IPI and had an estimated 5-year overall survival (OS) of 78% (52% intermediate risk, 5-year OS 60%; 20% high risk, 5-year OS 50%).

Unique Clinical Implications of HIV-Related Lymphoma

Since the introduction of combination antiretroviral therapy (cART) almost two decades ago, a number of changes have taken place in the spectrum of cancer affecting HIV-infected individuals. Although the incidence and proportion of deaths related to non-AIDS-defining malignancies, mostly infection-related cancers, are increasing, lymphoma is still a major complication of HIV-infection and is the most frequent neoplastic cause of death among HIV-infected individuals [1,2]. A decline in the incidence of lymphoma has been observed in the cART era, along with a concomitant increase in CD4 counts and a decrease of HIV RNA at lymphoma diagnosis. In general, the incidence of non-Hodgkin lymphoma (NHL) initially declined but has eventually stabilized. Nevertheless, the changes in the incidence of AIDS-related lymphoma (ARL) have been heterogeneous among the different lymphoma types. Cases of diffuse large B-cell lymphoma (DLBCL), especially primary CNS lymphoma, have decreased, while the proportion of Burkitt’s lymphoma (BL) cases have increased [3–5]. The incidence of Hodgkin’s lymphoma (HL) has remained stable and even increased in some cohorts [6,7]. This heterogeneity could be explained by the fact that the use of cART has decreased the proportion of HIV-infected individuals with low CD4 counts and, as a consequence, lymphomas that typically presented in severe immunosuppressed patients have diminished as well. This is the case of primary effusion lymphomas, plasmablastic lymphomas and primary CNS lymphoma, all having a higher incidence among patients with severe immunosuppression and poor HIV control. On the other hand, cART would act by increasing CD4 counts thereby facilitating the development of lymphomas with favorable biology and more likely to be cured, such as BL and HL [8]. Some changes have been observed in the presentation of HIV-associated lymphoma in the cART era. Regarding the transmission risk factor, there seems to have been an increase in the proportion of men who have sex with men and a decrease of intravenous drug users [5], probably due to the changes in the spectrum of HIV infection transmission in the population. Patients are older at lymphoma diagnosis, with higher

Serum MicroRNAs in HIV-Infected Individuals as Pre-Diagnosis Biomarkers for AIDS-NHL

To determine if changes in levels of serum microRNAs (miRNAs) were seen preceding the diagnosis of AIDS-related non-Hodgkin lymphoma (AIDS-NHL). Serum miRNA levels were compared in 3 subject groups from the Multicenter AIDS Cohort Study: HIV-negative men (n = 43), HIV-positive men who did not develop NHL (n = 45), and HIV-positive men before AIDS-NHL diagnosis (n = 62, median time before diagnosis, 8.8 months). A total of 175 serum-enriched miRNAs were initially screened to identify differentially expressed miRNAs among these groups and the results validated by quantitative polymerase chain reaction. Receiver-operating characteristic analysis was then performed to assess biomarker utility. Higher levels of miR-21 and miR-122, and a lower level of miR-223, were able to discriminate HIV-infected from the HIV-uninfected groups, suggesting that these miRNAs are biomarkers for HIV infection but are not AIDS-NHL specific. Among the HIV-infected groups, a higher level of miR-222 was able to discriminate diffuse large B-cell lymphoma (DLBCL) and primary central nervous system lymphoma (PCNSL) subjects from HIV-infected subjects who did not develop NHL, with area under the receiver-operating characteristic curve of 0.777 and 0.792, respectively. At miR-222 cutoff values of 0.105 for DLBCL and 0.109 for PCNSL, the sensitivity and specificity were 75% and 77%, and 80% and 82%, respectively. Altered serum levels of miR-21, miR-122, and miR-223 are seen in HIV-infected individuals. Higher serum level of miR-222 has clear potential as a serum biomarker for earlier detection of DLBCL and PCNSL among HIV-infected individuals.

CNS involvement in patients with AIDS-related lymphomas.

8570 Background: CNS involvement (CNSi) at baseline and CNS relapse (CNSr) appears increased in pts with AIDS-related lymphomas (ARL) although this has not been systematically examined. The aim of ...

Survival of patients with different AIDS-related lymphoma subtypes.

8548 Background: Previous data indicated that the overall survival (OS) of patients (pts) with AIDS-related Burkitt lymphoma (BL) is inferior to that of diffuse large B-cell lymphoma (DLBCL), and t...

Targeting xCT, a cystine-glutamate transporter induces apoptosis and tumor regression for KSHV/HIV-associated lymphoma

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of primary effusion lymphoma (PEL), which represents a rapidly progressing malignancy arising in HIV-infected patients. Conventional chemotherapy for PEL treatment induces unwanted toxicity and is ineffective — PEL continues to portend nearly 100% mortality within a period of months, which requires novel therapeutic strategies. The amino acid transporter, xCT, is essential for the uptake of cystine required for intracellular glutathione (GSH) synthesis and for maintaining the intracellular redox balance. Inhibition of xCT induces growth arrest in a variety of cancer cells, although its role in virus-associated malignancies including PEL remains unclear. In the current study, we identify that xCT is expressed on the surface of patient-derived KSHV+ PEL cells, and targeting xCT induces caspase-dependent cell apoptosis. Further experiments demonstrate the underlying mechanisms including host and viral factors: reducing intracellular GSH while increasing reactive oxygen species (ROS), repressing cell-proliferation-related signaling, and inducing viral lytic genes. Using an immune-deficient xenograft model, we demonstrate that an xCT selective inhibitor, Sulfasalazine (SASP), prevents PEL tumor progression in vivo. Together, our data provide innovative and mechanistic insights into the role of xCT in PEL pathogenesis, and the framework for xCT-focused therapies for AIDS-related lymphoma in future.

Clinical Outcomes of AIDS-related Burkitt Lymphoma: A Multi-institution Retrospective Survey in Japan

Acquired immunodeficiency syndrome-related non-Hodgkin lymphoma is treated similarly to non-acquired immunodeficiency syndrome lymphoma, but it is not clear whether highly intensive regimens are beneficial for acquired immunodeficiency syndrome-related Burkitt lymphoma. We conducted a multicenter retrospective survey to clarify the clinical outcomes of acquired immunodeficiency syndrome-related Burkitt lymphoma in the combined antiretroviral therapy era in Japan. We retrospectively analyzed the outcome of 33 patients with acquired immunodeficiency syndrome-related Burkitt lymphoma, who were diagnosed at five regional hospitals for human immunodeficiency virus/acquired immunodeficiency syndrome in Japan between January 2002 and December 2010. The median follow-up period was 20.0 months (range 0.5-92.7 months). Six (18.2%) patients were treated with cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate, ifosphamide, etoposide and high-dose cytarabine, and 23 (69.7%) patients were treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, high-dose methotrexate and high-dose cytarabine. The overall response rate for all patients was 78.8%, with a complete response rate of 72.7%. The two-year overall survival rate was 68.1%. There was no significant difference in overall survival between chemotherapeutic regimens with rituximab (n = 20) and without rituximab (n = 13) (P = 0.49). The two-year overall survival rate was 66.7% for patients receiving cyclophosphamide, vincristine, doxorubicin, dexamethasone, etoposide, ifosfamide and cytarabine, and was 72.6% for patients receiving cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine (P = 0.72). There was one treatment-related death. Highly intensive chemotherapy would bring a high remission rate and prolonged overall survival for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma.

British HIV Association guidelines for HIV‐associated malignancies 2014

<scp>B</scp>ritish <scp>HIV</scp> Association guidelines for <scp>HIV</scp>‐associated malignancies 2014

AIDS-Related Lymphoma

Patients with HIV are at increased risk of malignancy, particularly lymphoma, which is the most common malignancy leading to death. With the advent of highly active antiretroviral therapy (HAART), patients live longer but have a longer duration of antigenic stimulation, increasing the prevalence of AIDS-related lymphoma (ARL) in the population living with HIV. Highly active antiretroviral therapy plays a direct role in preserving the immune system, helping to decrease the incidence of ARL. We present a case of a female patient with HIV (CD4 count of 576 cells/mm3) diagnosed with a stage III-B non-Hodgkin lymphoma in 2009 while off HAART. She was subsequently started on HAART, leading to full resolution of her lymphoma without any chemotherapeutic intervention. She was last seen in the clinic in December 2013 without any evidence of recurrence of her lymphoma. To our knowledge, this is the first case report of a stage III-B non-Hodgkin lymphoma in an HIV-infected patient, which resolved with only HAART.