A planned, prospective comparison of short-term quality of life outcomes among older patients with breast cancer treated with standard chemotherapy in a randomized clinical trial vs. an observational study: CALGB #49907 and #369901

Patients ≥65 years old (“older”) are often not included in randomized clinical trials (RCT), but when they are, care in an RCT might improve quality of life (QoL). We conducted a prospective comparison of QoL among older women receiving standard chemotherapy from the same cooperative group physicians in an RCT vs. an observational study (“off-trial”)

Circulating Markers of Immune Activation and Inflammation and AIDS-Associated Non-Hodgkin Lymphoma in the Multicenter AIDS Cohort Study (MACS)

Background: AIDS-associated non-Hodgkin lymphoma (AIDS-NHL) remains a significant public health challenge among HIV-infected individuals. Chronic inflammation and immune activation have been documented in the literature to play a crucial role in the etiology of AIDS-NHL. We summarized results from prior work in a meta-analysis of the associations between prospectively measured circulating levels of immune biomarkers and the risk of NHL among both HIV-infected and HIV-uninfected populations. Our second study characterized the temporal variation in 24 pre-AIDS-NHL diagnosis circulating markers of inflammation and immune activation. Finally, we assessed the predictive ability of a set of 13 biomarker levels and AIDS-NHL diagnosis.Methods: Meta-analysis: Our meta-analysis identified 17 relevant studies from inception of major biomedical databases (PubMed, EMBASE, and Web of Science) until January 1, 2017. We summarized published results using random-effects models for NHL and several histological subtypes of NHL. Longitudinal study: we summarized the slopes and means (intercepts) of biomarker trajectories using linear mixed models. Prediction Models: we calculated incremental discrimination ability (AUC) of models including biomarkers, individually and concurrently, relative to models including only participant characteristics and known risk factors of NHL.Results: Meta-analysis: Summarizing 17 nested case–control studies, we found elevated levels of several biomarkers associated with increased odds of NHL overall: TNF-α, OR=1.18 [95% CI: 1.04, 1.34]; CXCL13, OR=1.47 [95% CI: 1.03, 2.08]; sCD23, OR=1.57 [95% CI: 1.21, 2.05]; sCD27, OR=2.18 [95% CI: 1.20, 3.98]; sCD30, OR=1.65 [95% CI: 1.22, 2.22]; AIDS-NHL showing stronger associations with IL-6, TNF-α, sCD27, and sCD30. Longitudinal study: prior to HAART, geometric mean biomarkers are elevated for cases relative to controls for IL-2, TNF-α, IL-6, sCD27, sIL-2Rα, IP-10, CXCL13, CRP, and pre-HAART slopes were observed to be higher for cases relative to controls for sIL-6R, sTNFR2, IL-10. Following HAART initiation, geometric mean levels are elevated to a higher degree than pre-HAART for cases relative to controls for BAFF, TNF-α, sIL-2Rα, sTNFR2, IP-10, MCP-1, CRP. Prediction Modeling: Models including individual biomarkers yielded modest improvements in AUC statistics above a base-case model that comprised NHL risk factors and other participant characteristics. A model including IL-6, IL-10, TNF-α, IP10, and CXCL13, concurrently performed better than all other models including individual biomarkers: 0-1: AUC=0.943 95% CI: 0.910, 0.975; 1-3: AUC=0.895 95% CI: 0.856, 0.934; >3: AUC=0.836 95% CI: 0.787, 0.885. Increments in AUC above the risk factors only model were also improved relative to individual biomarker models: 0-1: difference in AUC=0.056 95% CI: 0.021, 0.091; 1-3: difference in AUC=0.032 95% CI: 0.007, 0.057; >3: difference in AUC=0.074 95% CI: 0.030, 0.118.Conclusion: Each study provided further novel evidence of the association between circulating biomarkers and AIDS-NHL risk, as well as the utility of biomarkers in risk prediction. Our meta-analysis provides an overarching summary of evidence that elevated circulating levels of several markers are associated with an increased risk of NHL. Longitudinal analyses illustrate novel differences between cases and controls in aspects of the trajectories of 24 markers. Our prediction models elucidate the ability of a set of 13 marker levels to discriminate between AIDS-NHL cases versus controls. The totality of new evidence we provide supports the notion that chronic inflammation and immune activation is associated with increased AIDS-NHL risk, and that these biomarkers may have utility in the development of clinical risk prediction models

Brief Report

BACKGROUND:Methamphetamine use increases the risk of HIV-1 infection among seronegative users and can exacerbate disease progression in HIV-positive users. The biological mechanisms underlying these associations remain unclear. In this cross-sectional pilot study, we examine the associations between recent methamphetamine use and inflammation in the rectal mucosa and peripheral blood compartments in HIV-1 seropositive and seronegative men who have sex with men. METHODS:HIV-seronegative and HIV-seropositive men who have sex with men participants were enrolled (N = 24). Recent methamphetamine use was determined by urine drug screen. Cytokines were quantified using multiplex arrays from collected plasma and rectal sponge samples, and peripheral blood T-cell activation was assessed by flow cytometry. RESULTS:Methamphetamine use was associated with consistently increased rectal inflammatory cytokines, specifically interleukin-6 and tumor necrosis factor-alpha, regardless of HIV-1 serostatus in this pilot study. This association was significant after adjusting for age, HIV-serostatus, and receptive anal intercourse frequency using regression analysis. Similar increases were not uniformly observed in peripheral blood. CONCLUSIONS:Methamphetamine use is associated with increased local mucosal inflammatory cytokine production. These findings may help explain the increased HIV-1 risk seen in methamphetamine users and contribute to increased inflammation among HIV-seropositive users

Markers of Immune Activation and Inflammation, and Non-Hodgkin Lymphoma: A Meta-Analysis of Prospective Studies.

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

HLA and Risk of Diffuse Large B cell Lymphoma After Solid Organ Transplantation

BackgroundSolid 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.MethodsWe 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.ResultsCompared 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.ConclusionsIn 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