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Patients with prior colorectal polyps are at high risk for metachronous colorectal neoplasia, especially in the presence of obesity. We assessed the impact of 2 common bariatric surgeries, vertical sleeve gastrectomy and roux-n-Y gastric bypass, on the risk of colorectal neoplasia recurrence. This nationally representative analysis included 1183 postbariatric adults and 3193 propensity score–matched controls, who all had prior colonoscopy with polyps and polypectomy. Colorectal polyps reoccurred in 63.8% of bariatric surgery patients and 71.7% of controls at a mean follow-up of 53.1 months from prior colonoscopy. There was a reduced odds of colorectal polyp recurrence after bariatric surgery compared with controls (odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.58 to 0.83). This effect was most pronounced in men (OR = 0.58, 95% CI = 0.42 to 0.79), and post roux-n-Y gastric bypass (OR = 0.57, 95% CI = 0.41 to 0.79). However, the risk of rectal polyps or colorectal cancer remained consistent between groups. This study is the first to our knowledge to show a reduction in risk of polyp recurrence following bariatric surgery.

PDF - 123K, The risk of developing AIDS-NHL is elevated for those individuals who have higher levels of inflammatory biomarkers prior to AIDS-NHL diagnosis, excluding those who received cART.

Background: The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine whether elevated serum levels of molecules associated with B-cell activation precede the diagnosis of AIDS-associated NHL (AIDS-NHL).Methods: Serum levels of B-cell activation–associated molecules, interleukin (IL)6, IL10, soluble CD23 (sCD23), sCD27, sCD30, C-reactive protein (CRP), and immunoglobulin E were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to 3 time points per subject, 0 to 5 years prior to AIDS-NHL diagnosis.Results: Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared with HIV+ controls or with AIDS controls, after adjusting for CD4 T-cell number. Elevated serum levels of B-cell activation–associated molecules were seen to be associated with the development of systemic [non-CNS (central nervous system)] NHL, but not with the development of primary CNS lymphoma.Conclusions: Levels of certain B-cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B-cell activation contributes to the development of these hematologic malignancies.Impact: Marked differences in serum levels of several molecules are seen for several years prediagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL. Cancer Epidemiol Biomarkers Prev; 20(7); 1303–14. ©2011 AACR.

Background: HIV infection is associated with a marked increase in risk for non-Hodgkin lymphoma (AIDS-NHL). However, the mechanisms that promote the development of AIDS-NHL are not fully understood.Methods: In this study, serum levels of several cytokines and other molecules associated with immune activation were measured in specimens collected longitudinally during 1 to 5 years preceding AIDS-NHL diagnosis, in 176 AIDS-NHL cases and 176 HIV+ controls from the Multicenter AIDS Cohort Study (MACS).Results: Multivariate analyses revealed that serum levels of immunoglobulin free light chains (FLC), interleukin (IL)-6, IL-10, IP-10/CXCL10, neopterin, and TNF-α were elevated in those HIV+ individuals who went on to develop AIDS-NHL. In addition, the fraction of specimens with detectable IL-2 was increased and the fraction with detectable IL-4 was decreased in these subjects.Conclusions: These results suggest that long-term, chronic immune activation, possibly driven by macrophage-produced cytokines, precedes development of NHL in HIV+ individuals.Impact: FLC, IL-6, IL-10, IP-10/CXCL10, neopterin, and TNF-α may serve as biomarkers for AIDS-NHL. Cancer Epidemiol Biomarkers Prev; 23(2); 343–9. ©2013 AACR.

Supplementary Tables 1 and 2 from B-Cell Stimulatory Cytokines and Markers of Immune Activation Are Elevated Several Years Prior to the Diagnosis of Systemic AIDS–Associated Non-Hodgkin B-Cell Lymphoma

PDF - 122K, Geometrical mean serum values and confidence intervals of IL-5, IL-6, IL-8, IL-10, IL-17F, IL-20, IL-27, IFN-γ, IP-10, LIF, neopterin, sCD40L, TNFα, VEGF, κ and λ for HIV+ individuals who later developed AIDS-NHL and for HIV+ controls (p-values calculated with Student t-tests). Fraction of detectable values (shaded area) of IL-1β, IL-2, IL-4, IL-12, IL-17A, IL-23, IL-31, GM-CSF, and SDF-1α for HIV+ individuals who later developed AIDS-NHL and for HIV+ controls (p-values calculated using a chi-squared test).

Background: CXCL13 and CXCR5 are a chemokine and receptor pair whose interaction is critical for naïve B-cell trafficking and activation within germinal centers. We sought to determine whether CXCL13 levels are elevated before HIV-associated non-Hodgkin B-cell lymphoma (AIDS-NHL), and whether polymorphisms in CXCL13 or CXCR5 are associated with AIDS-NHL risk and CXCL13 levels in a large cohort of HIV-infected men.Methods: CXCL13 levels were measured in sera from 179 AIDS-NHL cases and 179 controls at three time-points. TagSNPs in CXCL13 (n = 16) and CXCR5 (n = 11) were genotyped in 183 AIDS-NHL cases and 533 controls. OR and 95% confidence intervals (CI) for the associations between one unit increase in log CXCL13 levels and AIDS-NHL, as well as tagSNP genotypes and AIDS-NHL, were computed using logistic regression. Mixed linear regression was used to estimate mean ratios (MR) for the association between tagSNPs and CXCL13 levels.Results: CXCL13 levels were elevated for more than 3 years (OR = 3.24; 95% CI = 1.90–5.54), 1 to 3 years (OR = 3.39; 95% CI = 1.94–5.94), and 0 to 1 year (OR = 3.94; 95% CI = 1.98–7.81) before an AIDS-NHL diagnosis. The minor allele of CXCL13 rs355689 was associated with reduced AIDS-NHL risk (ORTCvsTT = 0.65; 95% CI = 0.45–0.96) and reduced CXCL13 levels (MRCCvsTT = 0.82; 95% CI = 0.68–0.99). The minor allele of CXCR5 rs630923 was associated with increased CXCL13 levels (MRAAvsTT = 2.40; 95% CI = 1.43–4.50).Conclusions: CXCL13 levels were elevated preceding an AIDS-NHL diagnosis, genetic variation in CXCL13 may contribute to AIDS-NHL risk, and CXCL13 levels may be associated with genetic variation in CXCL13 and CXCR5.Impact: CXCL13 may serve as a biomarker for early AIDS-NHL detection. Cancer Epidemiol Biomarkers Prev; 22(2); 295–307. ©2012 AACR.

PDF file - 106K, Spearman's correlation coefficients calculated for each time-window, separately in cases and controls; Association Between CXCL13 and CXCR5 tagSNPs and CXCL13 Serum Levels; Association between CXCL13 serum levels and HIV-associated non-Hodgkin lymphoma risk at three time-windows, stratified by SNP genotypes.

A small percentage of bladder cancers in the general population have been found to harbor DNA viruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer and have overall poorer outcome, harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from potential oncoviruses, we performed whole genome and transcriptome sequencing on bladder cancer specimens from 43 transplant patients. Nearly half of tumors from this patient population contained viral sequences. The most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). Immunohistochemistry revealed variable Large T antigen expression in BKPyV-positive tumors ranging from 100% positive staining of tumor tissue to less than 1%. In most cases of BKPyV-positive tumors, the viral genome appeared to be clonally integrated into the host chromosome consistent with microhomology-mediated end joining and coincided with focal amplifications of the tumor genome similar to other virus-mediated cancers. Significant changes in host gene expression consistent with the functions of BKPyV Large T antigen were also observed in these tumors. Lastly, we identified four mutation signatures in our cases with those attributable to APOBEC3 and SBS5 being the most abundant. Mutation signatures associated with the antiviral drug, ganciclovir, and aristolochic acid, a nephrotoxic compound found in some herbal medicines, were also observed. The results suggest multiple pathways to carcinogenesis in solid organ transplant recipients with a large fraction being virus-associated.Author SummarySolid organ transplant recipients are at a significantly increases risk for developing bladder cancer compared to the general population, suggesting a potential infectious origin to these tumors. This study identifies that BK polyomavirus, JC polyomavirus, human papillomaviruses, and anelloviruses are commonly found in bladder tumors of solid organ transplant recipients. In most cases when detected, BK polyomavirus is integrated into the tumor genome and associates with genomic structural changes and distinct gene expression through the activity of viral oncogenes. Additionally, mutational signature analysis suggests that a subset of tumors of solid organ transplant recipients develop through distinct mutagenic processes compared to the general population. Together these results indicate multiple distinct mechanisms of carcinogenesis in bladder cancers of solid organ transplant recipients that may have implications for prevention, treatment, and outcome.

Background IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. Methods We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984–1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. Results We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76–1.11]), cytomegalovirus infection (0.94 [.71–1.24]), herpes simplex virus infection (1.37 [.68–2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. Conclusions The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

IntroductionEarly reports highlighted racial/ethnic disparities in the severity of COVID-19 seen across the USA; the extent to which these disparities have persisted over time remains unclear. Our research objective was to understand temporal trends in racial/ethnic variation in severity of COVID-19 illness presenting over time.MethodsWe conducted a retrospective cohort analysis using longitudinal data from Cedars-Sinai Medical Center, a high-volume health system in Southern California. We studied patients admitted to the hospital with COVID-19 illness from 4 March 2020 through 5 December 2020. Our primary outcome was COVID-19 severity of illness among hospitalised patients, assessed by racial/ethnic group status. We defined overall illness severity as an ordinal outcome: hospitalisation but no intensive care unit (ICU) admission; admission to the ICU but no intubation; and intubation or death.ResultsA total of 1584 patients with COVID-19 with available demographic and clinical data were included. Hispanic/Latinx compared with non-Hispanic white patients had higher odds of experiencing more severe illness among hospitalised patients (OR 2.28, 95% CI 1.62 to 3.22) and this disparity persisted over time. During the initial 2 months of the pandemic, non-Hispanic blacks were more likely to suffer severe illness than non-Hispanic whites (OR 2.02, 95% CI 1.07 to 3.78); this disparity improved by May, only to return later in the pandemic.ConclusionIn our patient sample, the severity of observed COVID-19 illness declined steadily over time, but these clinical improvements were not seen evenly across racial/ethnic groups; greater illness severity continues to be experienced among Hispanic/Latinx patients.

ObjectivesWe investigated whether the effect of smoking on the incidence of smoking-related cancers differs by HIV-infection status, if sex modifies the impact of risk factors for smoking-related cancers, and the sex-specific attributable risk of smoking on cancer incidence.DesignData from two large prospective studies in the United States were analyzed: 6789 men in the Multicenter AIDS Cohort Study from 1984 through 2018 and 4423 women in the Women's Interagency HIV Study from 1994 through 2018.MethodsIncidence rates, relative risks, and adjusted population attributable fractions (PAFs) were calculated for smoking-related cancers.ResultsDuring study follow-up, there were 214 incident smoking-related cancers in the men and 192 in the women. The age-adjusted incidence ratess for smoking-related cancers were higher in the women (392/100 000) than for the men (198/100 000; P

International audience; Human immunodeficiency virus (HIV) infection is associated with an increased risk of non-Hodgkin lymphoma (NHL). Even in the era of suppressive antiretroviral treatment, HIV-infected individuals remain at higher risk of developing NHL compared to the general population. To identify potential genetic risk loci, we performed case-control genome-wide association studies and a meta-analysis across three cohorts of HIV+ patients of European ancestry, including a total of 278 cases and 1924 matched controls. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11), with the G>A polymorphism creating a new transcription factor binding site for BATF and JUND. These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.

Immune activation and inflammation are hallmarks of chronic HIV infection and are etiologically linked to major causes of morbidity and mortality among HIV-infected persons, including coronary artery disease and cancer. Systemic immune activation is dampened, but not resolved, with use of combination antiretroviral therapy (cART). Statins are cardioprotective drugs that also appear to have immunomodulatory and anti-inflammatory properties. We sought to understand the association between statin use, cART, and levels of circulating immune markers in a longitudinal cohort study. From 2004 to 2009, statin use was ascertained in male participants of the Multicenter AIDS Cohort Study (MACS) using interviewer-administered questionnaires. Twenty-four circulating markers of immune activation and inflammation were measured in archived serial samples from a subset of cohort members using multiplex assays. Propensity-adjusted generalized gamma models were used to compare biomarkers' distributions by statin use, and multivariable linear regression models were used to assess the effect of initiating statin on these biomarkers. Overall, 1,031 cART-exposed individuals with HIV infection were included in this study. Statin use was reported by 31.5% of cART-exposed participants. Compared to nonstatin users on cART, statin users on cART had lower levels of IP-10, IL-10, and IL-12p70, and the effect of statin use was decreased in participants using lipophilic statins (atorvastatin, simvastatin, fluvastatin, or lovastatin); these results were statistically significant (p

Shifts in the microbiome have been correlated with the physiology and pathophysiology of many organ systems both in humans and in mouse models. The gut microbiome has been typically studied through fecal specimen collections. The ease of obtaining fecal samples has resulted in many studies that have revealed information concerning the distal luminal gastrointestinal tract. However, few studies have addressed the importance of the microbiome in the proximal gut. Given that the duodenum is a major site for digestion and absorption, its microbiome is relevant to nutrition and liver disease and warrants further investigation. Here we detail a novel method for sampling the proximal luminal and mucosal gut microbiome in human subjects undergoing upper endoscopy by obtaining duodenal aspirate and biopsies. Specimen procurement is facile and unaffected by artifacts such as patient preparatory adherence, as might be the case in obtaining colonic samples during colonoscopy. The preliminary results show that the luminal and mucosal microbiomes differ significantly, which is likely related to environmental conditions and barrier functions. Therefore, a combination of duodenal aspirate and biopsies reveal a more comprehensive picture of the microbiome in the duodenum. Biopsies are obtained from the descending and horizontal segments of the duodenum, which are anatomically close to the liver and biliary tree. This is important in studying the role of bile acid biology and the gut-liver axis in liver disease. Biopsies and aspirate can be used for 16S ribosomal RNA sequencing, metabolomics, and other similar applications.

ObjectiveWe sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers.DesignObservational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires.SettingsA multisite healthcare delivery system located in Los Angeles County.ParticipantsA diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions.Main outcomesUsing Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection.ResultsWe observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, pConclusion and relevanceThe demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19.

Background: Obesity and diabetes have been independently linked to COVID-19 severity, but their joint impact has not been extensively investigated. This study examines the joint and mediating role of diabetes and weight in COVID-19 severity and mortality in a large sample of patients treated in a large urban hospital located in Southern California. Methods: A retrospective observational cohort study of patients who tested positive for COVID-19 between March 8, 2020 and January 25, 2021 was implemented. Participants were patients with a diagnosis of SARS-CoV-2 infection who received care within the Cedars-Sinai Health System in Los Angeles, CA. Inclusion criteria required objectively measured height, weight, and diabetic status to be present in the patients’ medical record (N=4224). Univariable and multivariable logistic regression models were used to identify associated risk factors, and a regression causal mediation analysis examined the role of diabetes in the association between obesity and illness severity. All analyses were stratified by age (

ImportanceAntibody testing is important for understanding patterns of exposure and potential immunity to SARS-CoV-2. Prior data on seroprevalence have been subject to variations in selection of individuals and nature as well as timing of testing in relation to exposures.ObjectiveWe sought to determine the extent of SARS-CoV-2 seroprevalance and the factors associated with seroprevelance across a diverse cohort of healthcare workers.DesignObservational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionaires.ParticipantsA diverse and unselected population of adults (n=6,062) employed in a multi-site healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions.ExposureExposure and infection with the SARS-CoV-2 virus, as determined by seropositivity.Main OutcomesUsing Bayesian and multi-variate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody titers, including pre-existing demographic and clinical characteristics; potential Covid-19 illness related exposures; and, symptoms consistent with Covid-19 infection.ResultsWe observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom in addition to fever, dry cough, anorexia, and myalgias. After adjusting for potential confounders, pre-existing medical conditions were not associated with antibody positivity. However, seroprevalence was associated with younger age, Hispanic ethnicity, and African-American race, as well as presence of either a personal or household member having a prior diagnosis of Covid-19. Importantly, African American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal Covid-19 diagnosis status, suggesting the contribution of unmeasured structural or societally factors. Notably, number of people, or children, in the home was not associated with antibody positivity.Conclusion and RelevanceThe demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modeling techniques, provide a vibrant picture of the demographic factors, exposures, and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to Covid-19.Key PointsQuestionWhat is the SARS-CoV-2 IgG seroprevalence rate across a large and diverse healthcare worker population, and which clinical, envionrmental, and symptom-based measures are associated with seropositivity?FindingsWe observed a seroprevalence rate of 4.1%. Adjusting for potential confounders, seropositivity was associated with younger age, Hispanic ethnicity, African-American race, and the symptom of anosmia, while not significantly associated with any pre-existing medical conditions.MeaningFactors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace.

Of individuals with SARS-CoV-2 IgG antibody testing performed, those who contemporaneously experienced a cluster of Covid-19 relevant symptoms in the 1-2 months preceding the antibody assay were more likely to test positive whereas those who experienced the symptom clustering in the prior 3-6 months were more likely to test negative. These findings suggest that antibodies likely wane over a period of months, particularly in relation to the timing of symptoms.

Worldwide, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest growing cancers. Epidemiological studies have not only shed light on the prevalence and incidence of the disease but have also unmasked important environmental risk factors, including the role of diabetes and dyslipidemia in disease pathogenesis. Genetic association studies have identified single nucleotide polymorphisms implicated in NAFLD-HCC, many of which are part of lipid metabolism pathways. Through these clinical studies and subsequently, translational and basic research, the role of statins as a chemoprotective agent has also emerged with ongoing clinical trials assessing their utility in HCC prevention and treatment. In this review, we summarize the recent epidemiological studies describing the burden of NAFLD-HCC in different patient populations and countries. We discuss the genetic and environmental risk factors for NAFLD-HCC and highlight the chemoprotective role of statins and aspirin. We also summarize what is known about NAFLD-HCC in the cirrhosis and non-cirrhosis populations and briefly address the role of surveillance in NAFLD-HCC patients.

We describe the rationale, design, and implementation of baseline enrollment for a longitudinal, observational cohort study of healthcare workers. The importance of workplace as a characteristic of interest in population-based studies has become increasingly apparent over time. Most adults spend a majority of their waking hours living in their workplace environment, which serves as a source of unique as well as shared exposures, stressors, and related determinants of health. A rapidly expanding segment of the working population includes those individuals who work in the fields of healthcare. The healthcare workforce, at large, represents an increasingly diverse subset of the population with broad exposures; some exposures are specific to the workplace and others are common to persons living in the community. Importantly, healthcare workers tend to have general interest and willingness to participate in research, in addition to stable employment and easy access to on-site clinical research assessment locations. Accordingly, from a population of individuals working at a large medical delivery network, we enrolled over 6300 healthcare workers into a cohort study involving survey data collection on medical history, work environment, and family and living situation; this information was linked to participant electronic health record data and collected biospecimens.

Worldwide, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest growing cancers. Despite the rise in these disease entities, detailed long-term outcomes of large NAFLD-associated HCC cohorts are lacking. In this report, we compared the overall and recurrence-free survival rates of NAFLD HCC cases to patients with HBV and HCV-associated HCC cases. Distinguishing features of NAFLD-associated HCC patients in the cirrhosis and non-cirrhosis setting were also identified. We conducted a retrospective study of 125 NAFLD, 170 HBV and 159 HCV HCC patients, utilizing clinical, pathological and radiographic data. Multivariate regression models were used to study the overall and recurrence-free survival. The overall survival rates were significantly higher in the NAFLD-HCC cases compared to HBV-HCC (HR = 0.35, 95% CI 0.15–0.80) and HCV-HCC (HR = 0.37, 95% CI 0.17–0.77) cases. The NAFLD-HCC patients had a trend for higher recurrence-free survival rates compared to HBV and HCV-HCC cases. Within the NAFLD group, 18% did not have cirrhosis or advanced fibrosis; Hispanic ethnicity (OR = 12.34, 95% CI 2.59–58.82) and high BMI (OR = 1.19, 95% CI 1.07–1.33) were significantly associated with having cirrhosis. NAFLD-HCC cases were less likely to exhibit elevated serum AFP (p

Human immunodeficiency virus (HIV) infection is associated with greatly increased risk for development of non-Hodgkin lymphoma (NHL). Nearly all acquired immunodeficiency syndrome (AIDS)-associated NHL (AIDS-NHL) is of B-cell origin. Two major mechanisms are believed to contribute to the genesis of AIDS-NHL: (1) loss of immunoregulation of Epstein-Barr virus (EBV)+ B cells, resulting from impaired T-cell function late in the course of HIV disease and (2) chronic B-cell activation, leading to DNA-modifying events that contribute to oncogene mutations/ translocations. HIV infection has long been known to be associated with chronic inflammation and polyclonal B-cell activation, and more recently, microbial translocation. Microbial translocation is bacterial product leakage from gut lumen into the peripheral circulation, resulting in high levels of lipopolysaccharide (LPS) in the peripheral circulation, leading to chronic immune activation and inflammation. We review recent literature linking microbial translocation to lymphom-agenesis. This includes epidemiological studies of biomarkers of microbial translocation with risk of AIDS-NHL and emerging data on the mechanisms by which microbial translocation may lead to AIDS-NHL development.

AIM Cirrhosis is a leading cause of death worldwide, yet there are no well-established risk stratifying tools for lethal complications, including hepatocellular carcinoma (HCC). Patients with liver cirrhosis undergo routine endoscopic surveillance, providing ready access to duodenal aspirate samples that could be a source for identifying novel biomarkers. The aim of this study was to characterize the microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis to assess the feasibility of developing biomarkers for HCC risk stratification. METHODS Thirty patients with liver cirrhosis were enrolled in the Microbiome, Microbial Markers, and Liver Disease study between May 2015 and March 2017. Detailed clinical and epidemiological data were collected at baseline and at 6-monthly follow-up visits. Duodenal aspirate fluid was collected at baseline for microbial characterization using 16S ribosomal RNA sequencing and bile acid quantification using mass spectroscopy. RESULTS Alcohol-related cirrhosis was associated with reductions in the Bacteroidetes phylum, particularly Prevotella (13-fold reduction), and expansion of Staphylococcus (13-fold increase), compared to hepatitis C virus-related cirrhosis. Participants with hepatic encephalopathy (HE) had less microbial diversity compared to patients without HE (P

Background Chronic immune activation is a harbinger of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL), yet the underlying basis is unclear. Microbial translocation, the passage of microbial components from the gastrointestinal tract into the systemic circulation, is a source of systemic immune activation in HIV infection and may be an important contributor to chronic B-cell activation and subsequent AIDS-NHL development. Method We measured biomarkers of microbial translocation including bacterial receptors/antibodies, intestinal barrier proteins, and macrophage activation-associated cytokines/chemokines, in serum from 200 HIV-infected men from the Multicenter AIDS Cohort Study prior to their AIDS-NHL diagnosis (mean = 3.9 years; SD = 1.6 years) and 200 controls. Controls were HIV-infected men who did not develop AIDS-NHL, individually matched to cases on CD4 T-cell count, prior antiretroviral drug use, and recruitment year into the cohort. Results Biomarkers of bacterial translocation and intestinal permeability were significantly increased prior to AIDS-NHL. Lipopolysaccharide-binding protein (LPB), fatty acid-binding protein 2 (FABP2), and soluble CD14 were associated with 1.6-fold, 2.9-fold, and 3.7-fold increases in AIDS-NHL risk for each unit increase on the natural log scale, respectively. Haptoglobin had a 2.1-fold increase and endotoxin-core antibody a 2.0-fold decrease risk for AIDS-NHL (fourth versus first quartile). Biomarkers of macrophage activation were significantly increased prior to AIDS-NHL: B-cell activation factor (BAFF), IL18, monocyote chemoattractant protein-1 (MCP1), tumor necrosis factor-α (TNFα), and CCL17 had 2.2-fold, 2.0-fold, 1.6-fold, 2.8-fold, and 1.7-fold increases in risk for each unit increase on the natural log scale, respectively. Conclusion These data provide evidence for microbial translocation as a cause of the systemic immune activation in chronic HIV infection preceding AIDS-NHL development.

AIDS-related Kaposi’s sarcoma (AIDS-KS) risk remains substantially elevated compared with the general population, even among patients who receive effective combination antiretroviral therapy. This study investigated the role of inflammatory and immune activating biomarkers in AIDS-KS in men who have sex with men in the Multicenter AIDS Cohort study between 1984 and 2010. Concentrations of 24 serum biomarkers; IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, sGP130, sIL-2Rα, sIL-6R, eotaxin, MCP-1, MCP4, MIP 1β, TARC, BLC-BCA1, IP-10, GM-CSF, IFN-γ, BAFF, sCD14, CD27, sTNFR-2, sCRP, and TNF-α were tested longitudinally in 1,501 men. The concentrations of each biomarker were compared between AIDS-KS cases and controls at multiple time points, 0–1 years, 1–2 years, 2–3 year, 3–5 years and over 5 years, prior to KS diagnosis or study termination, using univariate non-parametric Kruskal-Wallis tests and logistic regression, adjusted for HBV and HCV co-infection, race/ethnicity, age at last visit, education, smoking and CD4+ cell count. In univariate analyses, concentrations of four markers were consistently higher in cases; sIL-2Rα, IP-10, sTNFR-2, MCP-1, and five were higher in controls; GM-CSF, IL-6, MIP-1β, sCRP, sGP130. In the adjusted models concentrations of four markers were significantly inversely associated with AIDS-KS risk including sGP130 (OR=0.14, 95% CI = 0.03–0.73, BAFF (OR=0.60, 95% CI =0.16–0.90), sCRP (OR=0.61, 95% CI = 0.43–0.87) and IL-6 (OR=0.51, 95% CI = 0.35–0.76). These results support a role for markers of immune activation and inflammation in AIDS-KS and may highlight pathways to be targeted for risk stratification or therapeutics.

Human immunodeficiency virus (HIV) infection is associated with a substantially increased risk of non-Hodgkin lymphoma (NHL). High plasma viral load, low CD4+ T cell counts and absence of antiretroviral treatment (ART) are known predictive factors for NHL. Even in the era of suppressive ART, HIV-infected individuals remain at increased risk of developing NHL compared to the general population. To search for human genetic determinants of HIV-associated NHL, we performed case-control genome-wide association studies (GWAS) in three cohorts of HIV+ patients of European ancestry and meta-analyzed the results. In total, 278 cases and 1924 matched controls were included. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11). The G>A polymorphism creates a new transcription factor binding site for BATF and JUND. Analyses of topologically associating domains and promoter capture Hi-C data revealed significant interactions between the rs7919208 region and the promoter of CXCL12, also known as stromal-derived factor 1 (SDF-1). These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.

PURPOSE OF REVIEW: The aim of this review is to summarize the recent literature on associations of small intestinal microbial and bile acid profiles with liver cirrhosis and its complications. RECENT FINDINGS: Recent studies into the duodenal microbiome of patients with cirrhosis have linked the microbiome to certain etiologies of chronic liver disease as well as complications of cirrhosis. In particular, microbial differences in the duodenum of patients with cirrhosis have been linked to the presence of hepatic encephalopathy and varices. SUMMARY: While the fecal microbiome of patients with liver cirrhosis is well characterized, the small intestinal microbiome of cirrhotic patients is an active area of research. This review focuses on the current understanding of the small intestinal microbiome in human cirrhosis as well as future directions of the field.

BACKGROUND: HIV infection is associated with increased susceptibility to common pathogens which may trigger chronic antigenic stimulation and hyperactivation of B-cells, events known to precede the development of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL). METHODS: To explore whether cumulative exposure to infectious agents contributes to AIDS-NHL risk, we tested sera from 199 AIDS-NHL patients (pre-NHL, average lead-time 3.9 years) and 199 matched HIV-infected controls from the Multicenter AIDS Cohort Study (MACS), for anti-IgG responses to 18 pathogens using multiplex serology. Odds ratios and 95% confidence intervals were estimated using conditional logistic regression models. RESULTS: We found no association between cumulative exposure to infectious agents and AIDS-NHL risk (OR 1.01, 95% CI 0.91–1.12). However, seropositivity for trichodysplasia spinulosa polyomavirus (TSPyV), defined as presence of antibodies to TSPyV capsid protein VP1, was significantly associated with a 1.6-fold increase in AIDS-NHL risk (OR 1.62, 95% CI 1.02–2.57). High Epstein-Barr virus (EBV) anti-VCA p18 antibody levels closer to the time of AIDS-NHL diagnosis (

Background MicroRNAs, small non-coding RNAs involved in gene regulation, are implicated in lymphomagenesis. We evaluated whether genetic variations in microRNA coding regions, binding sites, or biogenesis genes (collectively referred to as miRNA-SNPs) were associated with risk of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL), and serum levels of four lymphoma-related microRNAs. Methods Twenty-five miRNA-SNPs were genotyped in 180 AIDS-NHL cases and 529 HIV-infected matched controls from the Multicenter AIDS Cohort Study (MACS), and real-time polymerase chain reaction was used to quantify serum microRNA levels. Adjusted odds ratios (ORs) estimated using conditional logistic regression evaluated associations between miRNA-SNPs and AIDS-NHL risk. A semi-Bayes shrinkage approach was employed to reduce likelihood of false-positive associations. Adjusted mean ratios (MR) calculated using linear regression assessed associations between miRNA-SNPs and serum microRNA levels. Results DDX20 rs197412, a non-synonymous miRNA biogenesis gene SNP, was associated with AIDS-NHL risk (OR=1.34 per minor allele; 95% CI: 1.02–1.75), and higher miRNA-222 serum levels nearing statistical significance (MR=1.21 per minor allele; 95% CI: 0.98–1.49). MiRNA-196a2 rs11614913 was associated with decreased central nervous system (CNS) AIDS-NHL (CT vs. CC OR=0.52; 95% CI: 0.27–0.99). The minor allele of HIF1A rs2057482, which creates a miRNA-196a2 binding site, was associated with systemic AIDS-NHL risk (OR=1.73 per minor allele; 95% CI: 1.12–2.67), and decreased CNS AIDS-NHL risk (OR=0.49 per minor allele; 95% CI: 0.25–0.94). Conclusions This study suggests that a few miRNA-SNPs are associated with AIDS-NHL risk and may modulate miRNA expression. These results support a role for miRNA in AIDS-NHL and may highlight pathways to be targeted for risk stratification or therapeutics.

Background Solid organ transplant recipients have heightened risk for diffuse large B cell lymphoma (DLBCL). The role of donor-recipient HLA mismatch and recipient HLA type on DLBCL risk are not well established. Methods We examined 172 231 kidney, heart, pancreas, and lung recipients transplanted in the United States between 1987 and 2010, including 902 with DLBCL. Incidence rate ratios (IRRs) were calculated using Poisson regression for DLBCL risk in relation to HLA mismatch, types, and zygosity, adjusting for sex, age, race/ethnicity, year, organ, and transplant number. Results Compared with recipients who had 2 HLA-DR mismatches, those with zero or 1 mismatch had reduced DLBCL risk, (zero: IRR, 0.76, 95% confidence interval [95% CI], 0.61-0.95; one: IRR, 0.83; 95% CI, 0.69-1.00). In stratified analyses, recipients matched at either HLA-A, -B, or -DR had a significantly reduced risk of late-onset (>2 years after transplantation), but not early-onset DLBCL, and there was a trend for decreasing risk with decreasing mismatch across all 3 loci (P = 0.0003). Several individual recipient HLA-A, -B, -C, -DR, and -DQ antigens were also associated with DLBCL risk, including DR13 (IRR, 0.74; 95% CI, 0.57-0.93) and B38 (IRR, 1.48; 95% CI, 1.10-1.93), confirming prior findings that these 2 antigens are associated with risk of infection-associated cancers. Conclusions In conclusion, variation in HLA is related to susceptibility to DLBCL, perhaps reflecting intensity of immunosuppression, control of Epstein-Barr virus infection among transplant recipients or chronic immune stimulation.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting 25% of Americans, and it is now the dominant cause of hepatocellular carcinoma (HCC). NAFLD prevalence is highest in Latinos (45%) and can climb as high as 70% among individuals with metabolic risk factors, such as diabetes and overweight/obesity. Little is known about the awareness and perceptions of the disease among Latino individuals at high risk. Methods: The goal of our study was to assess awareness of NAFLD as a disease entity among Latino individuals with and without metabolic risk factors in the community setting. We recruited participants who were constituents of faith-based organizations in the Los Angeles catchment area, which contains 9% of the nation’s Latino population. A self-administered 37-item paper questionnaire was collected from Latino adults from January to June 2019, available in Spanish and English. Results: The study population (n=195) was composed primarily of women (87% female, mean age of 45 years), and 35% had less than a high school education. Overall, 82% of participants had at least one known metabolic risk factor including overweight/obesity (77%), diabetes (25%), or high blood pressure (18%). Only 3% had received a prior diagnosis of NAFLD. Nearly half (47%) of participants were not aware of NAFLD, and the percentages were similar among participants with self-reported major risk factors of overweight/obesity, diabetes, or high blood pressure. Among participants who were aware of NAFLD, nearly all (96%) believe that it can cause a serious health problem, and the majority believe that it can be prevented (93%). Also, 57% of participants who were aware of NAFLD believe that they are at risk, and most (80%) were willing to undergo screening for NAFLD with either imaging or a blood test. The majority of participants believe that obesity (80%) and lack of exercise (78%) predispose to NAFLD, although a common misconception among participants was that NAFLD can be treated (53%). In logistic regression models, NAFLD awareness was associated with increasing level of education (P=0.046), and belief that one is at risk of NAFLD was positively associated with BMI (P=0.014). Conclusion: Within this high-risk population of Latinos, many of whom have at least one metabolic risk factor, a high percentage were unaware of NAFLD and many had misconceptions regarding risk factors and treatment options, suggesting that important knowledge gaps exist. NAFLD is a preventable liver disorder with limited treatment options, thus increasing awareness and knowledge may be key for early prevention strategies. Citation Format: Shehnaz Hussain, Jane Figueiredo, Zulfikarali Surani. Awareness of nonalcoholic fatty liver disease among Latino participants of community-based health screening [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C089.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum that progresses through stages of liver fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC). NAFLD has more than doubled in incidence over the last decade alongside the obesity pandemic, and Latinos are at least twice as likely to be affected. The key clinical challenge is how to efficiently screen high-risk communities to identify individuals with severe steatosis and advanced fibrosis or cirrhosis who would benefit from lifestyle modifications, therapeutics, or cancer surveillance. A high proportion of patients with NAFLD are asymptomatic for long periods of time with normal laboratory tests, thus non-invasive procedures for early identification are needed. Transient elastography (TE) is a validated non-invasive diagnostic tool which can identify patients with liver disease. Methods: From March-June 2019, we recruited 76 Latino participants attending a community health screening event in Los Angeles to determine the prevalence of undiagnosed liver disease. We utilized TE performed with a FibroScan® (Echosens) to produce liver stiffness measurement (LSM, a measure of fibrosis in kPa) and a controlled attenuation parameter (CAP, a measure of steatosis in dB/m) on fasting participants, and we collected a self-administered questionnaire for basic characteristics and past medical history, offered in Spanish or English. Results: A total of 74 participants had a valid test with a minimum of ten LSMs with an interquartile range/median value less than 0.3. The mean age of participants was 50 years, and 65% were female. For metabolic risk factors, 78% were overweight or obese, with a mean BMI of 29.5 kg/m2, and the percentage of participants with diabetes or high blood pressure was 29% and 15%, respectively. A minority of participants (4%) reported drinking alcohol 2-3 times per week or more. As for prior liver disease, 16% of participants reported a prior diagnosis of chronic liver disease: NAFLD (N=11), hepatitis B virus (N=1), or cholestatic disease (N=1). In subsequent analyses, we excluded participants with known liver disease. The TE data generated show that steatosis was present in 66% of participants (4% mild, 13% moderate, 49% severe steatosis), with a mean CAP of 273.9 dB/m. The mean LSM in this population was 5.8 kPa, with 22% of participants having kPa measure equivalent to a moderate fibrosis grade (F2 or greater). In univariate analyses, LSM was positively associated with BMI (P= 0.008) and CAP (P Citation Format: Shehnaz Hussain, Jihane Benhammou. Community-based screening for nonalcoholic fatty liver disease with transient elastography in Latinos without overt liver disease at high risk of hepatocellular carcinoma [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C090.

The gut microbiome is a key factor in chronic liver disease progression. In prior research, we found that the duodenal microbiome was associated with sex, ethnicity, and cirrhosis complications. Here, we examined the association between diet and the duodenal microbiome in patients with liver cirrhosis. This study included 51 participants who completed a detailed food frequency questionnaire and donated duodenal biopsies for microbiome characterization by 16S ribosomal RNA gene sequencing. Data were analyzed for alpha diversity, beta diversity, and association of taxa abundance with diet quality and components using QIIME 2 pipelines. Diet quality was assessed through calculation of the Healthy Eating Index 2010. Participants with higher adherence to protein recommendations exhibited increased microbial richness and evenness (p = 0.03) and a different microbial profile compared to those with lower adherence (p = 0.03). Prevotella-9 and Agathobacter were increased in association with increased protein adherence. Fiber consumption was also associated with the duodenal microbial profile (p = 0.01), with several taxa exhibiting significantly decreased or increased abundance in association with fiber intake. Coffee drinking was associated with microbial richness and evenness (p = 0.001), and there was a dose&ndash, response association between coffee drinking and relative abundance of Veillonella (p = 0.01). We conclude that protein, fiber, and coffee are associated with diversity and composition of the duodenal microbiome in liver cirrhosis.

BackgroundChronic inflammation and immune activation are reported to play a key role in the etiology of non-Hodgkin lymphoma (NHL). We conducted a meta-analysis on the associations between prediagnosis circulating levels of immune stimulatory markers, interleukin 6 (IL-6), IL-10, tumor necrosis factor α (TNF-α), CXCL13, soluble CD23 (sCD23), sCD27, sCD30, and the risk of NHL.MethodsRelevant studies were identified from PubMed, EMBASE, and Web of Science up to January 1, 2017. We calculated summary odds ratio (OR) estimates for the association between one natural log increase in concentration of each biomarker and NHL using random-effects models for NHL as a composite outcome and for several histological subtypes of NHL.ResultsSeventeen nested case control studies were included. Elevated levels of several biomarkers were more strongly associated with increased odds of NHL: TNF-α, OR = 1.18 (95% confidence interval [CI] = 1.04 to 1.34); CXCL13, OR = 1.47 (95% CI = 1.03 to 2.08); sCD23, OR = 1.57 (95% CI = 1.21 to 2.05); sCD27, OR = 2.18 (95% CI = 1.20 to 3.98); sCD30, OR = 1.65 (95% CI = 1.22 to 2.22). In stratified analyses, IL-6, TNF-α, sCD27, and sCD30 were more strongly associated with NHL in HIV-infected individuals compared to HIV-uninfected individuals. Between-study heterogeneity was observed across multiple biomarkers for overall NHL and by subtypes.ConclusionThis meta-analysis provides evidence that elevated circulating levels of TNF-α, CXCL13, sCD23, sCD27, and sCD30 are consistently associated with an increased risk of NHL, suggesting the potential utility of these biomarkers in population risk stratification and prediction.

BackgroundHuman immunodeficiency virus type 1 (HIV-1) infection alters the human intestinal microbiome; however, behavioral factors driving these changes remain poorly defined. Here we examine the effects of substance use and sex behavior on the microbiome during HIV-1 infection.MethodsArchival rectal swab specimens, urine drug test results, and responses to substance use and sex behavior questionnaires were obtained from 37 HIV-positive participants at 2 time points, separated by 6 months, in a cohort examining the effects of substance use in men who have sex with men (MSM). Microbiome profiling was performed using 16S ribosomal RNA gene sequencing, and associations with behavioral factors were examined using 0-inflated negative binomial regression. Further analysis of selected variables of interest was performed using propensity scores to account for multiple confounders.ResultsUsing permutational multivariate analysis of variance, we found that receptive anal intercourse, methamphetamine use, and marijuana use were among the most important drivers of microbiome variation. Propensity score–adjusted analyses revealed that methamphetamine use and marijuana use displayed unique associations; methamphetamine use was associated with an increased abundance of Porphyromonas and Granulicatella organisms and a decreased abundance of Ruminococcus, Collinsella, and Parabacteroides organisms, whereas marijuana use was associated with an increased abundance of Ruminococcus, Clostridium cluster IV, Solobacterium, and Fusobacterium organisms and a decreased abundance of Acidaminococcus, Prevotella, Dialister, Anaerostipes, and Dorea organisms.ConclusionsDrug use and sex behavior are important factors associated with intestinal dysbiosis during chronic HIV-1 infection among young MSM.

Objective: To determine if changes in levels of serum microRNAs (miRNAs) were seen preceding the diagnosis of AIDS-related non-Hodgkin lymphoma (AIDS-NHL). Design: 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). Methods: 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. Results: 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. Conclusions: 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. Copyright © 2014 by Lippincott Williams & Wilkins.

Background: HIV infection is associated with a marked increase in risk for non-Hodgkin lymphoma (AIDS-NHL). However, the mechanisms that promote the development of AIDS-NHL are not fully understood. Methods: In this study, serum levels of several cytokines and other molecules associated with immune activation were measured in specimens collected longitudinally during 1 to 5 years preceding AIDS-NHL diagnosis, in 176 AIDS-NHL cases and 176 HIV+ controls from the Multicenter AIDS Cohort Study (MACS). Results: Multivariate analyses revealed that serum levels of immunoglobulin free light chains (FLC), interleukin (IL)-6, IL-10, IP-10/CXCL10, neopterin, and TNF-α were elevated in those HIV+ individuals who went on to develop AIDS-NHL. In addition, the fraction of specimens with detectable IL-2 was increased and the fraction with detectable IL-4 was decreased in these subjects. Conclusions: These results suggest that long-term, chronic immune activation, possibly driven by macrophage-produced cytokines, precedes development of NHL in HIV+ individuals. Impact: FLC, IL-6, IL-10, IP-10/CXCL10, neopterin, and TNF-α may serve as biomarkers for AIDS-NHL. Cancer Epidemiol Biomarkers Prev; 23(2); 343–9. ©2013 AACR.

Background: There is increasing evidence that chronic immune activation predisposes to non-Hodgkin lymphoma (NHL). Whether this association exists among women representative of the current HIV epidemic in the United States who are at high risk of HIV-associated NHL (AIDS-NHL), remains to be determined. Methods: We conducted a nested case–control study within the Women's Interagency HIV Study with longitudinally collected risk factor data and sera. Cases were HIV-infected women with stored sera collected at three time-windows 3 to 5 years, 1 to 3 years, and 0 to 1 year before AIDS-NHL diagnosis (n = 22). Three to six HIV-infected controls, without AIDS-NHL, were matched to each case on age, race, CD4+ T-cell count, and study follow-up time (n = 78). ORs and 95% confidence intervals (CI) for the association between one unit increase in log-transformed biomarker levels and AIDS-NHL were computed using random effect multivariate logistic regression models. Results: Elevated levels of sCD27 (OR = 7.21; 95% CI, 2.62–19.88), sCD30 (OR = 2.64; 95% CI, 1.24–5.64), and CXCL13 (OR = 2.56; 95% CI, 1.32–4.96) were associated with subsequent diagnosis of AIDS-NHL overall. Elevated sCD23 was associated with a two to three-fold increased risk of AIDS-NHL in certain subgroups, whereas elevated interleukin 6 was associated with a two-fold increased risk in the 0 to 1 year time-window, only. Conclusions: These findings support the hypothesis that chronic B-cell activation contributes to the development of AIDS-NHL in women. Impact: Soluble CD23 (sCD23), sCD27, sCD30, and CXCL13 may serve as biomarkers for AIDS-NHL. Cancer Epidemiol Biomarkers Prev; 22(11); 2084–93. ©2013 AACR.

Highly active antiretroviral therapy (HAART) has been successful in delaying the progression to AIDS in HIV-1-infected individuals. Exposure to HAART can result in metabolic side effects, such as dyslipidemia, in a subset of recipients. Longitudinal data and frozen peripheral blood mononuclear cell pellets were obtained from 1,945 men enrolled in the Multicenter AIDS Cohort. Individuals were genotyped for ancestry informative markers (AIMs) and stratified by biogeographical ancestry (BGA). Then serum levels of total cholesterol (TCHOL), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TRIG) were examined controlling for a number of HIV and HAART-related covariates using multivariate mixed-effects linear regression. HIV-1 infection, in the absence of HAART, was associated with altered lipid levels for all phenotypes tested when compared to HIV-negative men. HIV-1-infected men receiving HAART also had significantly different lipid levels compared to HIV-negative men, except for LDL-C. There were statistically significant interactions between BGA and HIV/HAART status for all lipids tested. BGA remained significantly associated with lipid levels after controlling for other HIV and HAART-related covariates. There was low concordance between self-reported race (SRR) and BGA in admixed populations. BGA performed better than SRR in our statistical models. Lipid profiles in untreated HIV-1-positive men and HIV-1-positive men receiving HAART differ from HIV-negative men and this effect varies by BGA. BGA performed better in our statistical analysis as a racial classifier but SRR remains a good clinical surrogate for BGA.

Background: Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes. Methods: We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation. Results: The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt's lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (

Given the important role of cell mediated immunity in viral clearance and control of premalignant lesions, we hypothesize that variation in the IL-12/IL-10 cytokine and cytokine receptor genes may influence cervical and vulvar cancer risk. We evaluated 76 tagSNPs from seven candidate genes (IL-10, IL-12A, IL-12B, IL-10RA, IL-10RB, IL-12RB1, and IL12RB2) in case–parent sets (n=43 cervical squamous cell carcinoma (SCC), n=96 cervical adenocarcinoma, n=53 vulvar SCC), additional cases (n=356 cervical SCC, n=406 cervical adenocarcinoma, and n=473 vulvar SCC) and population based controls (1,111). We calculated log-additive odds ratios (ORs) and 95% confidence intervals (CIs) for the association between tagSNP and cancer risk using a pseudo-likelihood based method which combined genotype information on cases, parents, and population controls. After correction for multiple comparisons, we identified several statistically significant SNP associations. Cervical SCC risk was associated with the minor alleles of the IL10RA rs9610 3’ UTR SNP (OR=1.76, 95% CI=1.15–2.68) and two synonymous IL12RB2 SNPs (rs4297265, OR=0.46, 95% CI=0.26–0.82; rs2229546, OR=0.43, 95% CI=0.21–0.87). Cervical adenocarcinoma risk was associated with the minor alleles of the IL10RA rs4252314 intronic SNP (OR=2.23, 95% CI=1.26–3.96) and IL12RB1 rs11575934 non-synonymous SNP (OR=1.51, 95% CI=1.12–2.05). Finally, the minor allele of the IL12B rs3181224 3’ UTR SNP was associated with a reduced risk of vulvar SCC (OR=0.30, 95% CI=0.12–0.74). These results raise the possibility that a shift in the balance of the immune response due to genetic variants in key cytokine genes could influence the development of cervical and vulvar cancer.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.