AIDS-related non-Hodgkin Lymphoma Research Articles

Efficacy of an Anti-transferrin Receptor 1 Antibody Against AIDS-related Non-Hodgkin Lymphoma: A Brief Communication.

The transferrin receptor 1 (TfR1), also known as CD71, is a target for antibody-based cancer immunotherapy due to its high expression on the surface of cancer cells and its ability to internalize. We have previously developed a mouse/human chimeric IgG3 specific for human TfR1 genetically fused to avidin, as a vector to deliver biotinylated anticancer agents into malignant cells. However, we found that this fusion protein (ch128.1Av), and to a lesser extent the same antibody without avidin (ch128.1), exhibits direct cytotoxic activity in vitro against certain malignant hematopoietic cells through the induction of TfR1 degradation and lethal iron starvation. Importantly, both ch128.1 and ch128.1Av have also shown significant anticancer activity in 2 xenograft models of the B-cell malignancy multiple myeloma. It is interesting to note that ch128.1 exhibited superior anticancer activity in both models compared with ch128.1Av, even against malignant cells that show no sensitivity to ch128.1 in vitro. In the present study, we evaluated the efficacy of ch128.1 against an AIDS-related human Burkitt lymphoma cell line (2F7) to determine if ch128.1 can eliminate these cells in vitro and in an in vivo model of AIDS-related non-Hodgkin lymphoma (AIDS-NHL). Even though 2F7 cells expressed high TfR1 levels, these cells lacked sensitivity to the cytotoxicity induced by ch128.1 in vitro. However, ch128.1 showed significant anticancer activity against these AIDS-NHL cells in vivo by significantly prolonging the survival of immunodeficient mice bearing 2F7 tumors. Therefore, ch128.1 warrants further study as a candidate for the treatment of AIDS-NHL and other B-cell malignancies.

Dysregulated B-cell TLR2 expression and elevated regulatory B-cell frequency precede the diagnosis of AIDS-related non-Hodgkin lymphoma.

In antiretroviral therapy (ART)-treated patients, to determine if AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is preceded by: elevated frequency of potentially malignant abnormal activated/germinal center-like B cells, elevated serum prevalence of B-cell stimulatory Toll-like receptor (TLR) ligands resulting from HIV infection-associated microbial translocation, dysregulated B-cell TLR expression/signaling, and perturbations in the frequency of immunoregulatory cells. A case-control study nested with a cohort study of HIV-infected women. Prediagnostic AIDS-NHL cases (n = 12, collected 1-12 months before diagnosis) and controls (n = 42) from the Women's Interagency HIV Study cohort, were matched for HIV and ART status, age, race, and CD4 lymphocyte count. Serum levels of TLR ligands, the prevalence of malignancy-associated abnormal activated/germinal center-like (CD19CD10CD71CD86AID) B cells, TLR2 expression on B cells, expression of TLR2-modulating micro-RNA, and the frequency of regulatory T and B cells were assessed. Diagnosis of AIDS-NHL was preceded by a significantly elevated frequency of activated/germinal center-like CD19CD10CD71CD86AID B cells (P = 0.0072), elevated serum prevalence of the TLR2 ligand, and significantly elevated B-cell TLR2 expression (P = 0.0015), positively correlating with the frequency of activated/germinal center-like B cells (rho = 0.7273, P = 0.0144). In cases, a purified subset of activated/germinal center-like B cells exhibited decreased expression of microRNAs that modulate TLR2 signaling, including miR-21, 146a, 146b, and 155. Finally, cases also exhibited significantly elevated frequencies of antitumor immunity inhibitory regulatory B cells (P = 0.0024), but not regulatory T cells. Our findings suggest that increased microbial translocation and dysregulated TLR expression/signaling, coupled with an elevated frequency of regulatory B cells, precede the diagnosis of AIDS-NHL in HIV-infected ART-treated patients.

Dysregulated B-cell TLR2 expression and elevated regulatory B-cell frequency precede the diagnosis of AIDS-related non-Hodgkin lymphoma

Dysregulated B-cell TLR2 expression and elevated regulatory B-cell frequency precede the diagnosis of AIDS-related non-Hodgkin lymphoma

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.

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.

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.

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.

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

HIV-Associated Burkitt Lymphoma: Case Report and Literature Review

IntroductionHIV associated Burkitt lymphoma (BL) is a highly aggressive lymphoma. Compared to other AIDS related non-Hodgkin lymphoma's its clinical presentation is less predictable and characterized by rapid clinical changes. The paradigm shift to treat HIV associated disease with highly effective intensive chemotherapy regimens while managing immunosuppression has made it possible to achieve remission and long-term survival. Southern Louisiana has one the of the highest incidence rates of HIV and cancers in the US. The authors present a challenging case of a 33-year old HIV+ male from southern Louisiana with advanced stage BL. The patient presented with advanced disease and a poor performance status. His initial providers recommended palliation only and significant education was needed to allow aggressive treatment. The patient tolerated induction chemotherapy and remains in remission. This is a case based review of local and nationwide epidemiology and the trial data supporting different treatment options for HIV associated Burkitt lymphoma. CaseOur patient is a 33 year-old male who presented with severe cachexia, poor performance status and clinical symptomatic cord compression. He was diagnosed with advanced stage Burkitt lymphoma including bone marrow involvement. His CD4 count was 277 with an HIV viral load of 571,000 copies/mL. Although he had a poor performance status and his primary team favored palliation only he underwent induction chemotherapy with 4 cycles of infusional dose adjusted R-EPOCH with IT CNS chemoprophylaxis. HAART therapy with efavirenz/emtricitabine/tenofovir was started during his initial admission. He tolerated this regimen well, clinically dramatically improved being independent in his ADL/IADLs, and remains in remission. DiscussionThe pathogenesis of HIV-associated Burkitt lymphoma is linked to oncogenic virus co-infection (40% EBV association) and chronic HIV antigen stimulation that provoke expansion of polyclonal B-cells. This leads to oncogenic chromosomal translocations - most notably t(8;14) causing constitutive expression of oncogene c-Myc. HIV patients have a 60 to 200-fold increased incidence of NHL. Relative risk for BL in HIV patients is 261-fold higher compared to the general population. Unlike the nationwide reported 19 per 100,000 person-years, data from a large HIV clinic in southern Louisiana continues to show an incidence rate of 23 per 100,000 person-years. Louisiana continues to have comparatively high incidence rates in HIV (4th in US) and cancer (11th in US) with the highest rates in southern Louisiana parishes. It is important for community physicians, especially in these areas, to feel more confident when treating these HIV associated malignancies.Historically highly immunosuppressive chemotherapy has been avoided in HIV patients with lymphoma as studies in the 1990's showed increased toxicity. The addition of the monoclonal C20 antibody rituximabin the treatment of AIDS associated NHLs was also controversial, as trial results showed increase infectious death rates. However, these clinical trials confirmed similar death rates from infections in individuals with a CD4 count >50. In addition concomitant use of HAART with chemotherapy has improved overall survival. Although the more dose intense Burkitt regimens have not been studied extensively in HIV-associated BL, CODOX-M/IVAC and DA-EPOCH +/- Rituximab (depending on CD4 count) have shown good efficacy and tolerance and are treatment regimens of choice this disease. A recent trial with 14 patients with HIV associated BL receiving RD-CODOXM/IVAC had 86% progression free survival rate at 1 year; patients receiving concomitant HAART had 100% PFS rate at 1 year. In another trial, 10 HIV associated BL patients receiving DA-EPOCH-R showed a 100% overall survival rate at 57 months. ConclusionHIV associated Burkitt lymphoma should be treated with HAART and high dose chemotherapy. Long-term remission has been shown with regimens including CODOX-M/IVAC and DA-EPOCH +/-Rituximab (R use discouraged in low CD4 counts). This case based report outlines the relatively high prevalence of disease in Southern Louisiana and emphasizes that remission is possible in patients with poor performance status and advanced disease. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

TLR2-Activated B Cells are Phenotypically Similar to the Abnormal Circulating B Cells Seen Preceding the Diagnosis of AIDS-Related NHL Diagnosis

AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is a common AIDS-defining cancer. Prior studies suggest that chronic B-cell activation precedes AIDS-NHL diagnosis. Activation of B cells by multiple factors, including Toll-like receptor (TLR) signaling, leads to the expression of activation-induced cytidine deaminase (AID), a DNA mutating molecule that can contribute to oncogene translocations/mutations, leading to NHL. The goal of this study was to determine whether surface markers expressed on activated and/or germinal center B cells, and AID expression, were elevated on circulating B cells preceding AIDS-NHL and to determine if TLR signaling contributes to this activated B-cell phenotype. Stored viable peripheral blood mononuclear cell specimens, obtained before AIDS-NHL diagnosis, were assessed by multicolor flow cytometry. Additionally, B cells isolated from peripheral blood mononuclear cell were exposed to TLR ligands in vitro, after which B-cell phenotype was assessed by flow cytometry. An elevated fraction of B cells expressing CD10, CD71, or CD86 was seen in those who went on to develop AIDS-NHL. AID expression was detected in some who developed AIDS-NHL, but not in HIV+ or HIV- controls. TLR2-stimulated purified B cells exhibited the activated B-cell phenotype observed in HIV+ subjects before AIDS-NHL diagnosis. These results indicate that an elevated fraction of B cells display an activated/germinal center phenotype in those HIV+ subjects who go on to develop AIDS-NHL and suggest that TLR2-mediated activation may play a role in HIV infection-associated B-cell activation, potentially contributing to the genesis of AIDS-NHL.

Abstract 1240: A flexible antibody-based strategy targeting CD71 for the treatment of AIDS-related non-Hodgkin's lymphoma.

Abstract AIDS related non-Hodgkin's lymphoma (AIDS-NHL) remains a significant clinical problem in the era of effective multiple-agent highly active anti-retroviral therapy (HAART). While an overall decrease in the incidence of AIDS-NHL has been seen in the HAART era, the risk for AIDS-NHL remains elevated, and not all AIDS-NHL subtypes have decreased in incidence, with the incidence of Burkitt's lymphoma (BL) remaining unchanged. In fact, AIDS-NHL is now the most common AIDS-related cancer in developed countries, where NHL accounts for 23-30% of all AIDS-related deaths. We have previously developed an antibody-avidin fusion protein (ch128.1Av) specific for the human transferrin receptor 1 (TfR1/CD71), a receptor that is overexpressed on cancer cells due to their high demand for iron. This fusion protein exhibits an increased in vitro cytotoxicity against malignant hematopoietic cells compared to the parental antibody without avidin (ch128.1). This cytotoxicity is due to the ability of ch128.1Av to decrease cell surface TfR1, triggering its intracellular sequestration and degradation, with the subsequent induction of lethal iron deprivation. However, both ch128.1Av and ch128.1 confer protection in murine models of human disseminated multiple myeloma. ch128.1Av is also a universal delivery system and its cytotoxicity can be further enhanced by its conjugation with biotinylated drugs making it a unique molecule capable of a two-pronged attack against malignant cells through drug delivery and direct cytotoxic activity through iron starvation. The main goal of this study is to evaluate the potential use of ch128.1Av alone and as a delivery vehicle as a possible AIDS-NHL therapy. We found that, when used alone, ch128.1Av exhibits significant cytotoxic activity against two representative AIDS-NHL cell lines: 2F7 (AIDS-Burkitt's NHL) and RRBL (AIDS-diffuse large B-cell lymphoma). Importantly, the level of cytotoxicity was similar to that observed using the highly sensitive human B lymphoblastoid cell line IM-9. In addition, the cytotoxicity dramatically increases when this fusion protein is conjugated to biotinylated saporin 6 (b-SO6), a plant ribosome inactivating protein that blocks protein synthesis, resulting in an immunotoxin. We also found that non-activated (resting) B cells isolated from the peripheral blood of healthy individuals are resistant to ch128.1Av, but sensitive to ch128.1Av complexed to b-SO6, which can be explained by the different mechanisms of action of the fusion protein alone (iron starvation) and that of the immunotoxin (protein synthesis inhibition). We have previously reported ch128.1Av alone, or complexed to b-SO6, are not toxic to normal human hematopoietic stem cells, which can be explained by the lack of TfR1 expression on such cells. Our results suggest the potential use of anti-TfR1 antibody-mediated approaches as therapeutic interventions against AIDS-NHL. Citation Format: Tracy R. Daniels-Wells, Lai Sum Leoh, Daniel Widney, Dharma R. Thapa, Jose Leon Merino, Larry Magpantay, Otoniel Martínez-Maza, Manuel L. Penichet. A flexible antibody-based strategy targeting CD71 for the treatment of AIDS-related non-Hodgkin's lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1240. doi:10.1158/1538-7445.AM2013-1240

Circulating mediators of inflammation in AIDS-related non-Hodgkin lymphoma.

86 Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries, accounting for 3-6% of AIDS-defining illnesses and 23-30% of AIDS-related mortality. The risk of developing NHL is estimated to be 60 times greater in HIV-infected individuals in comparison to the general population and this rate has remained elevated despite the advent of HAART. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation. Methods: This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male patients diagnosed with high-grade B-cell NHL. Controls were matched to each case from among those participants who developed an AIDS-defining opportunistic infection in the absence of any malignancy. Matching criteria included age and CD4+ cell count. Sera obtained from each patient near the time of NHL or AIDS diagnosis was tested for a panel of 171 serum biomarkers using multiplexed bead-based immunoassays. Biomarker measurements were evaluated to identify significant alterations between the experimental groups, correlations with disease progression and interactions between biomarkers. Results: A subset of 21 biomarkers was identified to be significantly altered in A-NHL cases in comparison to the AIDS controls. This subset included cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators. Many of the biomarkers included in this subset were positively correlated with disease progression. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers. Conclusions: These findings support the current hypothesis that A-NHL develops in response to persistent immune stimulation and inflammation. A network of inflammatory mediators was identified demonstrating correlations with disease progression and overexpression in A-NHL patients. Further analysis of these biomarkers should enhance our ability to diagnose, monitor, and treat this disease.

148-P

Aim Despite the biological plausibility as suggested by animal experiments and HLA associations, genome-wide association studies (GWAS) in breast cancer (BC) have not reported any top hits from the HLA region. We revisited the results of the NIH CGEMS study to seek evidence for the involvement of the HLA region in the development of BC. Methods We screened the results from 1100 HLA region SNPs accessible through dbGAP. We used bioinformatic tools and examined existing experimental data to evaluate functionality of each SNP that showed an association at the traditional statistical threshold ( P Results 115 SNPs yielded statistical associations with BC. The smallest P value was 0.0007, and was noted for a few SNPs including BAG6 (BAT3) SNP rs3117582, which is a risk marker for lung cancer. Previously, we showed that this SNP is exclusively present on B8DR3 haplotype. Likewise, another B8DR3-specific SNP rs1270942, which is a risk marker for AIDS-related non-Hodgkin lymphoma was also associated ( P = 0.0007). A SNP (rs382259) in NOTCH4, a strong candidate gene, yielded a protective association ( P = 0.005). rs382259 is a proxy for HLA-DR11, which is a protective marker for BC as shown earlier. Two other SNPs (rs1233627 and rs3131043) showed associations in the present analysis and our re-analysis of WTCCC GWAS data ( P = 0.0002 to 0.04). Conclusions Like our recent re-analysis of WTCCC GWAS data, the current effort also yielded some meaningful signals from the HLA region that were originally dismissed because of the statistical threshold used in GWAS. Unique features of the HLA region such as extensive linkage disequilibrium resulting in “unfaithfulness” that generates larger P values for individual SNPs, functional polymorphisms that are not necessarily assessed in univariable analysis, and missing representation of HLA subregions in GWAS chips warrant specially designed HLA region association studies to uncover the missing heritability observed in GWAS in BC.

Study on effectiveness of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory AIDS-related non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma (NHL) remains the second most common malignant complication in patients with human immunodeficiency virus (HIV) infection. Even though NHL is commonly chemosensitive to primary treatment, failure or relapse still occurs in a large number of patients. We conducted this retrospective study to evaluate the efficacy and safety of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory AIDS-related NHL (AIDS-NHL). Forty-eight patients with relapsed or refractory AIDS-NHL were treated with intravenous combination chemotherapy with GDP. The overall objective response rate was 54.1% (95% confidence interval, CI, 40.1-68.3%), with 10 complete responses and 16 partial responses. The 2-year overall survival rate (OS) was 70.8% (95% CI 58.0-83.7%), and the 5-year OS was 41.7% (95% CI 27.7-55.6%). The 2-year progression-free survival rate (PFS) was 37.5% (95% CI 23.8-51.2%), and the 5-year PFS was 25.0% (95% CI 12.8-37.3%). The median progression-free survival was 8.8 months (95% CI 0-20.3 months), and the median overall survival was 40.6 months (95% CI 22.6-58.6 months). Patients with B cell tumors who relapsed but had no B symptoms were clinical stage I/II, had infiltration fewer than two extranodal sites, had CD4⁺ counts >200 cells/μL, and had lactate dehydrogenase (LDH) less than the upper limit of normal benefited from GDP. The level of LDH had a significant impact on the response rate to chemotherapy with GDP (P = 0.015). Myelosuppression was the main side effect; the incidence of grade 3-4 anemia was 8.3%; leukopenia, 37.5%; and thrombocytopenia, 48.3%. Univariate and multivariate analyses were performed to determine variables for OS and PFS. This study confirms that GDP is an effective and safe salvage regimen in relapsed or refractory AIDS-NHL, was associated with modest declines in CD4⁺ lymphocyte counts, and did not promote HIV-1 viral replication.

AIDS-Related Non-Hodgkin's Lymphoma in Sub-Saharan Africa: Current Status and Realities of Therapeutic Approach.

Today AIDS-related non-Hodgkin's lymphoma (AR-NHL) is a significant cause of morbidity and mortality in HIV-infected patients the world over, and especially in sub-Saharan Africa. While the overall incidence of AR-NHL since the emergence of combination antiretroviral therapy (cART) era has declined, the occurrence of this disease appears to have stabilized. In regions of the world where access to cART is challenging, the impact on disease incidence is less clear. In the resource-rich environment it is clinically well recognized that it is no longer appropriate to consider AR-NHL as a single disease entity and rather treatment of AIDS lymphoma needs to be tailored to lymphoma subtype. While intensive therapeutic strategies in the resource-rich world are clearly improving outcome, in AIDS epicenters of the world and especially in sub-Saharan Africa there is a paucity of data on treatment and outcomes. In fact, only one prospective study of dose-modified oral chemotherapy and limited retrospective studies with sufficient details provide a window into the natural history and clinical management of this disease. The scarcities and challenges of treatment in this setting provide a backdrop to review the current status and realities of the therapeutic approach to AR-NHL in sub-Saharan Africa. More pragmatic and risk-adapted therapeutic approaches are needed.

B-cell activation induced microRNA-21 is elevated in circulating B cells preceding the diagnosis of AIDS-related non-Hodgkin lymphomas

We show that microRNA-21 is significantly elevated in peripheral B cells of HIV-infected individuals who go on to develop AIDS-related non-Hodgkin lymphoma (n=13, <3 years prior to diagnosis) when compared with HIV-negative (n=18) or HIV-positive controls (n=21) (P<0.01). Moreover, miR-21 is overexpressed in activated B cells and can be induced by interleukin 4 alone, or with CD40 or immunoglobulin M co-stimulation, and lipopolysaccharides, suggesting that miR-21 may help maintain B-cell hyperactivation, contributing to lymphomagenesis.

A comparative investigation of methods for longitudinal data with limits of detection through a case study

The statistical analysis of continuous longitudinal data may be complicated since quantitative levels of bioassay cannot always be determined. Values beyond the limits of detection (LOD) in the assays may not be observed and thus censored, rendering complexity to the analysis of such data. This article examines how both left-censoring and right censoring of HIV-1 plasma RNA measurements, collected for the study on AIDS-related Non-Hodgkin's lymphoma (AR-NHL) in East Africa, affects the quantification of viral load and explores the natural history of viral load measurements over time in AR-NHL patients receiving anticancer chemotherapy. Data analyses using Monte Carlo EM algorithm (MCEM) are compared to analyses where the LOD or LOD/2 (left censoring) value is substituted for the censored observations, and also to other methods such as multiple imputation, and maximum likelihood estimation for censored data (generalized Tobit regression). Simulations are used to explore the sensitivity of the results to changes in the model parameters. In conclusion, the antiretroviral treatment was associated with a significant decrease in viral load after controlling the effects of other covariates. A simulation study with finite sample size shows MCEM is the least biased method and the estimates are least sensitive to the censoring mechanism.

AIDS-Related Non-Hodgkin's Lymphoma in the Era of Highly Active Antiretroviral Therapy.

In economically developed countries, AIDS-related lymphoma (ARL) accounts for a large proportion of malignances in HIV-infected individuals. Since the introduction of highly active anti-retroviral therapy (HAART) in 1996, epidemiology and prognosis of ARL have changed. While there is a slight increase in the incidence of Hodgkin's lymphoma in HIV-infected individuals, use of HAART has contributed to a decline in the incidence of non-Hodgkin's lymphoma (NHL) and also a decrease in the overall incidence of ARL. Strategies that employ HAART, improved supportive care, and the use of Rituximab with multi-agent chemotherapy have contributed to improved rates of complete remission and survival of patients with ARL that rival those seen in stage and histology matched HIV negative NHL patients. Most recent clinical trials demonstrate better outcomes with the use of rituximab in ARL. Tumor histogenesis (germinal center vs. non-germinal center origin) is associated with lymphoma-specific outcomes in the setting of AIDS-related diffuse-large B cell lymphoma. High-dose chemotherapy (HDCT) and autologous stem cell rescue (ASCT) can be effective for a subset of patients with relapsed ARL. HIV sero-status alone should not preclude consideration of ASCT in the setting of ARL relapse. Clinical trials investigating the role of allogeneic hematopoietic stem cell transplant in ARL are currently underway.

Clinical Use of Rituximab in Patients with HIV Related Lymphoma and Multicentric Castlemans Disease

The use of immunotherapy in the treatment of non-Hodgkin lymphomas has improved response rates and survival in this population. With widespread rituximab use and longer-term follow-up of patients receiving rituximab, infectious complications are increasing. These complications are of great concern in the AIDS-related lymphoma population. We review the data on activity and infectious toxicity of rituximab to date and as it pertains to the treatment of AIDS-related non-Hodgkin lymphoma and Multicentric Castleman's disease.

Protein Kinase C-Beta Inhibition Induces Apoptosis and Inhibits Cell Cycle Progression in Acquired Immunodeficiency Syndrome–Related Non-Hodgkin Lymphoma Cells

IntroductionAcquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL) constitutes an aggressive variety of lymphomas characterized by increased extranodal involvement, relapse rate, and resistance to chemotherapy. Protein kinase C-beta (PKCβ) targeting showed...