Publications by authors named "Charles S Rabkin"

117 Publications

Circulating immune- and inflammation-related biomarkers and early-stage noncardia gastric cancer risk.

Eur J Cancer Prev 2021 Jul 8. Epub 2021 Jul 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA Division of Cancer Information and Control Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute Department of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: In Helicobacter pylori-driven gastric cancer, mucosal colonization induces chronic inflammation that may variably progress to cancer. Prospective studies of circulating inflammation-related proteins have suggested weak associations with gastric cancer risk. To assess potential utility as a screening tool in clinical settings, we examined circulating levels of a wide range of key inflammation molecules for associations with early-stage gastric cancer.

Methods: We used pretreatment EDTA plasma from 239 individuals with early-stage noncardia gastric cancer (203 stage I and 36 stage II) and 256 age-frequency-matched H. pylori-seropositive cancer-free controls within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Levels of 92 biomarkers were measured by proximity extension assays using Olink's Proseek Immuno-oncology Panel. Odds ratios (ORs) for association with gastric cancer risk were calculated for quantiles (two to four categories) of each biomarker from unconditional logistic regression models, adjusted for age, sex, smoking and alcohol consumption. Two-sided P values <0.05 were considered as significant. The false discovery rate (FDR) was used to correct for multiple comparisons.

Results: Of 83 evaluable biomarkers, lower levels of TNFRSF12A (per quartile OR, 0.82; nominal P-trend = 0.02) and ADGRG1 (per quartile OR, 0.84; nominal P-trend = 0.03) were associated with early-stage gastric cancer but were not statistically significant after FDR correction.

Conclusion: Our study did not identify any inflammation-related biomarkers that may be useful for early disease detection. To date, this is the first assessment of circulating inflammation-related proteins in early-stage gastric cancer. Given the complex inflammation processes preceding malignant transformation, further investigation of other biomarkers is warranted.
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http://dx.doi.org/10.1097/CEJ.0000000000000706DOI Listing
July 2021

Associations of circulating mediators of inflammation, cell regulation and immune response with esophageal squamous cell carcinoma.

J Cancer Res Clin Oncol 2021 Jun 14. Epub 2021 Jun 14.

Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.

Background: Esophageal squamous cell carcinoma (ESCC) is the most common histologic subtype of esophageal cancer globally. The development of squamous cell carcinoma has important inflammatory influences and effects. We, therefore, examined circulating levels of inflammation- and immune-related proteins for associations with ESCC.

Methods: We used pre-treatment EDTA plasma from 80 ESCC patients (44% clinical stages I and II) and 80 cancer-free control individuals within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Levels of 184 biomarkers were measured by high-throughput multiplexed proximity extension assays using Olink's Proseek Cell Regulation and Immuno-Oncology Panels. ESCC odds ratios (OR) per quantile (based on two to four categories) of each biomarker were calculated by unconditional logistic regression models, adjusted for age, sex, cigarette smoking and alcohol consumption. Correlations among continuous biomarker levels were assessed by Spearman's rank correlation. All statistical tests were two-sided with p values < 0.05 considered as significant. Given the exploratory nature of the study, we did not adjust for multiple comparisons.

Results: Seven proteins were undetectable in nearly all samples. Of the remaining 177 evaluable biomarkers, levels of cluster of differentiation 40 (CD40, per quartile OR 1.64; p trend = 0.018), syntaxin 16 (STX16, per quartile OR 1.63; p trend = 0.008), heme oxygenase 1 (per quartile OR 1.59; p trend = 0.014), and γ-secretase activating protein (GSAP, per quartile OR 1.47; p trend = 0.036) were significantly associated with ESCC. Amongst these significant markers, levels of CD40, STX16, and GSPA were moderately correlated (Rho coefficients 0.46-0.55; p < 0.05).

Conclusion: Our case-control study expands the range of inflammation and immune molecules associated with ESCC. These novel findings warrant replication and functional characterization.
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http://dx.doi.org/10.1007/s00432-021-03687-3DOI Listing
June 2021

Association between ABO and Duffy blood types and circulating chemokines and cytokines.

Genes Immun 2021 Jul 8;22(3):161-171. Epub 2021 Jun 8.

Infections and Immunoepidemiology Branch, DCEG, NCI, Bethesda, MD, USA.

Blood group antigens are inherited traits that may play a role in immune and inflammatory processes. We investigated associations between blood groups and circulating inflammation-related molecules in 3537 non-Hispanic white participants selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Whole-genome scans were used to infer blood types for 12 common antigen systems based on well-characterized single-nucleotide polymorphisms. Serum levels of 96 biomarkers were measured on multiplex fluorescent bead-based panels. We estimated marker associations with blood type using weighted linear or logistic regression models adjusted for age, sex, smoking status, and principal components of population substructure. Bonferroni correction was used to control for multiple comparisons, with two-sided p values < 0.05 considered statistically significant. Among the 1152 associations tested, 10 were statistically significant. Duffy blood type was associated with levels of CXCL6/GCP2, CXCL5/ENA78, CCL11/EOTAXIN, CXCL1/GRO, CCL2/MCP1, CCL13/MCP4, and CCL17/TARC, whereas ABO blood type was associated with levels of sVEGFR2, sVEGFR3, and sGP130. Post hoc pairwise t-tests showed that individuals with type Fy(a+b-) had the lowest mean levels of all Duffy-associated markers, while individuals with type A blood had the lowest mean levels of all ABO-associated markers. Additional work is warranted to explore potential clinical implications of these differences.
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http://dx.doi.org/10.1038/s41435-021-00137-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185309PMC
July 2021

Prediagnostic circulating inflammation-related biomarkers and gastric cancer: A case-cohort study in Japan.

Cytokine 2021 Aug 10;144:155558. Epub 2021 May 10.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Gastric cancer is preceded by a chronic inflammatory process. Circulating levels of inflammation-related markers may reveal molecular pathways contributing to cancer development. Our study evaluated risk associations of gastric cancer with a wide range of systemic soluble inflammation and immune-response proteins. We performed a case-cohort analysis within the JPHC Study II, including a subcohort of 410 participants selected randomly within defined age and sex groups, and 414 individuals with incident gastric cancer. Ninety-two biomarkers were measured in baseline plasma using proximity extension assays. Gastric cancer multivariable hazard ratios were calculated for two to four quantiles used as ordinal variables of each biomarker by Cox proportional hazards regression models with age as the time metric. Of 73 evaluable biomarkers, three (CCL11, CCL20 and IL17C) were associated with increased gastric cancer risk and two (CCL23 and MMP1) with reduced cancer risk (P < 0.05). However, no association was statistically significant after a false discovery rate correction. This study largely expands the range of inflammation molecules evaluated for gastric cancer risk but failed to identify novel associations with this neoplasia.
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http://dx.doi.org/10.1016/j.cyto.2021.155558DOI Listing
August 2021

Identification of anti-Epstein-Barr virus (EBV) antibody signature in EBV-associated gastric carcinoma.

Gastric Cancer 2021 Jul 4;24(4):858-867. Epub 2021 Mar 4.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Bethesda, MD, 20892, USA.

Background: Around 10% of gastric carcinomas (GC) contain Epstein-Barr virus (EBV) DNA. We characterized the GC-specific antibody response to this common infection, which may provide a noninvasive method to detect EBV-positive GC and elucidate its contribution to carcinogenesis.

Methods: Plasma samples from EBV-positive (n = 28) and EBV-negative (n = 34) Latvian GC patients were immune-profiled against 85 EBV proteins on a multi-microbial Nucleic Acid Programmable Protein Array (EBV-NAPPA). Antibody responses were normalized for each sample as ratios to the median signal intensity (MNI) across all antigens, with seropositivity defined as MNI ≥ 2. Antibodies with ≥ 20% sensitivity at 95% specificity for tumor EBV status were verified by enzyme-linked immunosorbent assay (ELISA) and validated in independent samples from Korea and Poland (n = 24 EBV-positive, n = 65 EBV-negative).

Results: Forty anti-EBV IgG and eight IgA antibodies were detected by EBV-NAPPA in ≥ 10% of EBV-positive or EBV-negative GC patients, of which nine IgG antibodies were discriminative for tumor EBV status. Eight of these nine were verified and seven were validated by ELISA: anti-LF2 (odds ratio = 110.0), anti-BORF2 (54.2), anti-BALF2 (44.1), anti-BaRF1 (26.7), anti-BXLF1 (12.8), anti-BRLF1 (8.3), and anti-BLLF3 (5.4). The top three had areas under receiver operating characteristics curves of 0.81-0.85 for distinguishing tumor EBV status.

Conclusions: The EBV-associated GC-specific humoral response was exclusively directed against lytic cycle immediate-early and early antigens, unlike other EBV-associated malignancies such as nasopharyngeal carcinoma and lymphoma where humoral response is primarily directed against late lytic antigens. Specific anti-EBV antibodies could have utility for clinical diagnosis, epidemiologic studies, and immune-based precision treatment of EBV-positive GC.
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http://dx.doi.org/10.1007/s10120-021-01170-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206016PMC
July 2021

Trends in Hepatocellular Carcinoma Incidence and Risk Among Persons With HIV in the US and Canada, 1996-2015.

JAMA Netw Open 2021 02 1;4(2):e2037512. Epub 2021 Feb 1.

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.

Importance: People with HIV (PWH) are often coinfected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), leading to increased risk of developing hepatocellular carcinoma (HCC), but few cohort studies have had sufficient power to describe the trends of HCC incidence and risk among PWH in the combination antiretroviral therapy (cART) era.

Objective: To determine the temporal trends of HCC incidence rates (IRs) and to compare rates by risk factors among PWH in the cART era.

Design, Setting, And Participants: This cohort study used data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study, which was conducted between 1996 and 2015. NA-ACCORD pooled individual-level data from 22 HIV clinical and interval cohorts of PWH in the US and Canada. PWH aged 18 years or older with available CD4 cell counts and HIV RNA data were enrolled. Data analyses were completed in March 2020.

Exposures: HBV infection was defined as detection of either HBV surface antigen, HBV e antigen, or HBV DNA in serum or plasma any time during observation. HCV infection was defined by detection of anti-HCV seropositivity, HCV RNA, or detectable genotype in serum or plasma at any time under observation.

Main Outcomes And Measures: HCC diagnoses were identified on the basis of review of medical records or cancer registry linkage.

Results: Of 109 283 PWH with 723 441 person-years of follow-up, the median (interquartile range) age at baseline was 43 (36-51) years, 93 017 (85.1%) were male, 44 752 (40.9%) were White, 44 322 (40.6%) were Black, 21 343 (19.5%) had HCV coinfection, 6348 (5.8%) had HBV coinfection, and 2082 (1.9%) had triple infection; 451 individuals received a diagnosis of HCC by 2015. Between the early (1996-2000) and modern (2006-2015) cART eras, the crude HCC IR increased from 0.28 to 0.75 case per 1000 person-years. HCC IRs remained constant among HIV-monoinfected persons or those coinfected with HBV, but from 1996 to 2015, IRs increased among PWH coinfected with HCV (from 0.34 cases/1000 person-years in 1996 to 2.39 cases/1000 person-years in 2015) or those with triple infection (from 0.65 cases/1000 person-years in 1996 to 4.49 cases/1000 person-years in 2015). Recent HIV RNA levels greater than or equal to 500 copies/mL (IR ratio, 1.8; 95% CI, 1.4-2.4) and CD4 cell counts less than or equal to 500 cells/μL (IR ratio, 1.3; 95% CI, 1.0-1.6) were associated with higher HCC risk in the modern cART era. People who injected drugs had higher HCC risk compared with men who had sex with men (IR ratio, 2.0; 95% CI, 1.3-2.9), adjusted for HBV-HCV coinfection.

Conclusions And Relevance: HCC rates among PWH increased significantly over time from 1996 to 2015. PWH coinfected with viral hepatitis, those with higher HIV RNA levels or lower CD4 cell counts, and those who inject drugs had higher HCC risk.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.37512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890526PMC
February 2021

Secular Trends in Breast Cancer Risk Among Women With HIV Initiating ART in North America.

J Acquir Immune Defic Syndr 2021 05;87(1):663-670

Department of Epidemiology, Johns Hopkins University, Baltimore, MD.

Background: Studies suggest lower risk of breast cancer in women with HIV versus without HIV. These estimates may be biased by lower life expectancy and younger age distribution of women with HIV. Our analysis evaluated this bias and characterized secular trends in breast cancer among women with HIV initiating antiretroviral therapy. We hypothesized breast cancer risk would increase over time as mortality decreased.

Setting: Women with HIV prescribed antiretroviral therapy in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) from 1997 through 2016.

Methods: We estimated breast cancer hazard (cause-specific hazard ratios) and cumulative incidence accounting for competing risks (subdistribution hazard ratios) to assess changes in breast cancer risk over time. This was assessed overall (1997-2016) and within/across calendar periods. Analyses were adjusted for race/ethnicity and inverse probability weighted for cohort. Cumulative incidence was graphically assessed by calendar period and race/ethnicity.

Results: We observed 11,587 women during 1997-2016, contributing 63 incident breast cancer diagnoses and 1,353 deaths [73,445 person-years (median follow-up = 4.5 years)]. Breast cancer cumulative incidence was 3.2% for 1997-2016. We observed no secular trends in breast cancer hazard or cumulative incidence. There were annual declines in the hazard and cumulative incidence of death (cause-specific hazard ratios and subdistribution hazard ratios: 0.89, 95% confidence interval: 0.87 to 0.91) which remained within and across calendar periods.

Conclusions: These findings contradict the hypothesis of increasing breast cancer risk with declining mortality over time among women with HIV, suggesting limited impact of changing mortality on breast cancer risk. Additional inquiry is merited as survival improves among women with HIV.
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http://dx.doi.org/10.1097/QAI.0000000000002627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026587PMC
May 2021

Neutrophil-to-lymphocyte ratio and mortality in the United States general population.

Sci Rep 2021 01 11;11(1):464. Epub 2021 Jan 11.

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, MD, 6E204, USA.

The neutrophil-to-lymphocyte ratio (NLR) in peripheral blood reflects the balance between systemic inflammation and immunity and is emerging as a prognostic biomarker in many diseases, but its predictive role for mortality in the general population has not been investigated. We analyzed 1999-2014 National Health and Nutrition Examination Survey mortality-linked data, followed up until 2015. In participants aged > 30 with measurements of differential white blood cell counts, NLR was calculated and categorized into quartiles. Associations of increased NLR with overall or cause-specific mortality were assessed with Cox proportional hazard regression models, adjusted for potential confounders. Increased NLR was associated with overall mortality (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.10-1.17, per quartile NLR) and mortality due to heart disease (1.17, 1.06-1.29), chronic lower respiratory disease (1.24, 1.04-1.47), influenza/pneumonia (1.26, 1.03-1.54) and kidney disease (1.26, 1.03-1.54). NLR was associated with cancer mortality only in the first follow-up year (HR 1.48, 95% CI 1.11-1.98). The association with chronic lower respiratory disease mortality was stronger in individuals with prevalent lung diseases (HR 1.46, 95% CI 1.14-1.88, P = 0.01), while NLR showed positive associations with mortality from heart disease (1.21, 1.07-1.38) and cerebrovascular disease (1.30, 1.04-1.63) only among individuals without these conditions at baseline. NLR is associated with mortality overall and due to certain causes in the general population. Associations over short follow-up intervals and among individuals with conditions at baseline suggest effects of disordered inflammation and immunity on progression of those conditions, while other associations may reflect contributions to disease etiology.
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http://dx.doi.org/10.1038/s41598-020-79431-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801737PMC
January 2021

Identification of New Subpopulations in Native Americans and Mestizos From Peru.

Front Microbiol 2020 14;11:601839. Epub 2020 Dec 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States.

Region-specific subpopulations have been identified. It is proposed that the hspAmerind subpopulation is being displaced from the Americans by an hpEurope population following the conquest. Our study aimed to describe the genomes and methylomes of isolates from distinct Peruvian communities: 23 strains collected from three groups of Native Americans (Asháninkas [ASHA, = 9], Shimaas [SHIM, = 5] from Amazonas, and Punos from the Andean highlands [PUNO, = 9]) and 9 modern mestizos from Lima (LIM). Closed genomes and DNA modification calls were obtained using SMRT/PacBio sequencing. We performed evolutionary analyses and evaluated genomic/epigenomic differences among strain groups. We also evaluated human genome-wide data from 74 individuals from the selected Native communities (including the 23 strains donors) to compare host and bacterial backgrounds. There were varying degrees of hspAmerind ancestry in all strains, ranging from 7% in LIM to 99% in SHIM. We identified three subpopulations corresponding to each of the Native groups and a novel hspEuropePeru which evolved in the modern mestizos. The divergence of the indigenous strains recapitulated the genetic structure of Native Americans. Phylogenetic profiling showed that Orthogroups in the indigenous strains seem to have evolved differentially toward epigenomic regulation and chromosome maintenance, whereas OGs in the modern mestizo (LIM) seem to have evolved toward virulence and adherence. The prevalence of / genotype was similar across populations ( = 0.32): 89% in ASHA, 67% in PUNO, 56% in LIM and 40% in SHIM. Both and sequences showed that LIM strains were genetically differentiated ( < 0.001) as compared to indigenous strains. We identified 642 R-M systems with 39% of the associated genes located in the core genome. We found 692 methylation motifs, including 254 population-specific sequences not previously described. In Peru, hspAmerind is not extinct, with traces found even in a heavily admixed mestizo population. Notably, our study identified three new hspAmerind subpopulations, one per Native group; and a new subpopulation among mestizos that we named hspEuropePeru. This subpopulation seems to have more virulence-related elements than hspAmerind. Purifying selection driven by variable host immune response may have shaped the evolution of Peruvian subpopulations, potentially impacting disease outcomes.
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http://dx.doi.org/10.3389/fmicb.2020.601839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767971PMC
December 2020

Immunoproteomic Profiles in Gastric Cancer.

J Proteome Res 2021 01 27;20(1):409-419. Epub 2020 Oct 27.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20892-2590, United States.

Chronic infection is the major risk factor for gastric cancer (GC). However, only some infected individuals develop this neoplasia. Previous serology studies have been limited by investigating small numbers of candidate antigens. Therefore, we evaluated humoral responses to a nearly complete immunoproteome (1527 proteins) among 50 GC cases and 50 controls using Nucleic Acid Programmable Protein Array (NAPPA). Seropositivity was defined as median normalized intensity ≥2 on NAPPA, and 53 anti- antibodies had >10% seroprevalence. Anti-GroEL exhibited the greatest seroprevalence (77% overall), which agreed well with ELISA using whole-cell lysates of cells. After an initial screen by -NAPPA, we discovered and verified that 12 antibodies by ELISA in controls had ≥15% of samples with an optical reading value exceeding the 95th percentile of the GC group. ELISA-verified antibodies were validated blindly in an independent set of 100 case-control pairs. As expected, anti-CagA seropositivity was positively associated with GC (odds ratio, OR = 5.5; < 0.05). After validation, six anti- antibodies showed lower seropositivity in GC, with ORs ranging from 0.44 to 0.12 ( < 0.05): anti-HP1118/Ggt, anti-HP0516/HsIU, anti-HP0243/NapA, anti-HP1293/RpoA, anti-HP0371/FabE, and anti-HP0875/KatA. Among all combinations, a model with anti-Ggt, anti-HslU, anti-NapA, and anti-CagA had an area under the curve of 0.73 for discriminating GC . controls. This study represents the first comprehensive assessment of anti- humoral profiles in GC. Decreased responses to multiple proteins in GC may reflect mucosal damage and decreased bacterial burden. The higher prevalence of specific anti- antibodies in controls may suggest immune protection against GC development.
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http://dx.doi.org/10.1021/acs.jproteome.0c00466DOI Listing
January 2021

Timing of Antiretroviral Therapy Initiation and Risk of Cancer Among Persons Living With Human Immunodeficiency Virus.

Clin Infect Dis 2021 06;72(11):1900-1909

Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.

Background: Persons living with human immunodeficiency virus (HIV; PLWH) experience a high burden of cancer. It remains unknown which cancer types are reduced in PLWH with earlier initiation of antiretroviral therapy (ART).

Methods: We evaluated AIDS-free, ART-naive PLWH during 1996-2014 from 22 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. PLWH were followed from first observed CD4 of 350-500 cells/µL (baseline) until incident cancer, death, lost-to-follow-up, or December 2014. Outcomes included 6 cancer groups and 5 individual cancers that were confirmed by chart review or cancer registry linkage. We evaluated the effect of earlier (in the first 6 months after baseline) versus deferred ART initiation on cancer risk. Marginal structural models were used with inverse probability weighting to account for time-dependent confounding and informative right-censoring, with weights informed by subject's age, sex, cohort, baseline year, race/ethnicity, HIV transmission risk, smoking, viral hepatitis, CD4, and AIDS diagnoses.

Results: Protective results for earlier ART were found for any cancer (adjusted hazard ratio [HR] 0.57; 95% confidence interval [CI], .37-.86), AIDS-defining cancers (HR 0.23; 95% CI, .11-.49), any virus-related cancer (HR 0.30; 95% CI, .16-.54), Kaposi sarcoma (HR 0.25; 95% CI, .10-.61), and non-Hodgkin lymphoma (HR 0.22; 95% CI, .06-.73). By 15 years, there was also an observed reduced risk with earlier ART for virus-related NADCs (0.6% vs 2.3%; adjusted risk difference -1.6; 95% CI, -2.8, -.5).

Conclusions: Earlier ART initiation has potential to reduce the burden of virus-related cancers in PLWH but not non-AIDS-defining cancers (NADCs) without known or suspected viral etiology.
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http://dx.doi.org/10.1093/cid/ciaa1046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315132PMC
June 2021

Genetic variation near CXCL12 is associated with susceptibility to HIV-related non-Hodgkin lymphoma.

Haematologica 2020 07 16. Epub 2020 Jul 16.

Ecole Polytechnique Federale de Lausanne and University of Lausanne, Switzerland

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.
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http://dx.doi.org/10.3324/haematol.2020.247023DOI Listing
July 2020

Metabolic Syndrome, Physical Activity, and Inflammation: A Cross-Sectional Analysis of 110 Circulating Biomarkers in Japanese Adults.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1639-1646. Epub 2020 May 28.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Background: Metabolic syndrome (MetS) is a systemic inflammatory state. Low physical activity (PA) could modify this patho-physiology or act as an independent contributor to inflammation. Previous studies of both conditions have identified altered levels of inflammation- and immune-related proteins based on limited sets of candidate markers.

Methods: We investigated associations of MetS and low PA with circulating inflammation markers in a stratified random sample of Japanese adults ( = 774, mean age 60.7 years) within the Japan Public Health Center-based Prospective Study (JPHC) Cohort II. AHA/NHLBI criteria were used to define MetS (19%) and the bottom quartile of PA was considered low. 110 circulating biomarkers, including cytokines, chemokines, and soluble receptors were measured by multiplex bead-based and proximity-extension assays. Associations of MetS and low PA with marker quantiles were adjusted for each other and for age, sex, study site, cigarette smoking, alcohol consumption, and blood sample fasting state by ordinal logistic regression. values were corrected for FDR.

Results: MetS was significantly associated with levels of six markers: IL18R1 [odds ratio 2.37; 95% confidence interval (CI), 1.45-3.87], CRP (2.07; 95% CI, 1.48-2.90), SAP (2.08; 95% CI, 1.47-2.95), CCL19/MIP3β (2.06; 95% CI, 1.48-2.88), CXCL12/SDF1α+β (0.48; 95% CI, 0.32-0.65), and CCL28 (0.44; 95% CI, 0.27-0.71). Low PA had no significant marker associations.

Conclusions: Positively associated markers with MetS are mostly Th1 immune response-related and acute phase proteins, whereas negatively associated markers are generally Th2-related.

Impact: MetS is associated with a broad range of alterations in immune and inflammatory biomarkers that may contribute to risks of various chronic diseases, independent of low PA.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528457PMC
August 2020

Low Epstein-Barr Virus Prevalence in Cardia Gastric Cancer Among a High-Incidence Chinese Population.

Dig Dis Sci 2021 Apr 4;66(4):1220-1226. Epub 2020 May 4.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Room 6E110, 9609 Medical Center Drive, Rockville, MD, 20892-9776, USA.

Background: Epstein-Barr virus (EBV) positivity is associated with better gastric cancer prognosis and is found in a relatively fixed 9% of tumors worldwide.

Aim: We aimed to examine the EBV status of gastric adenocarcinomas in a very high-incidence population and to compare prevalence between cardia and non-cardia anatomic subsites.

Methods: We evaluated 1035 adult gastric adenocarcinoma cases presenting during 1997-2005 to the Shanxi Cancer Hospital in Taiyuan, Shanxi Province, China. EBV-encoded RNA was detected in alcohol-fixed paraffin-embedded tumor specimens by in situ hybridization. Associations were assessed in case-case comparisons using the Chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables, with p values < 0.05 considered statistically significant. Adjusted odds ratios were calculated using logistic regression, and mortality hazard ratios (HRs) were estimated by Cox proportional hazards regression.

Results: Sixty-four percent of the evaluated cancers were found in the cardia. Cardia tumor localization was associated with male sex, advanced primary tumor stage, better differentiated histology, and intestinal-type Lauren classification. Four percent of the non-cardia and only 0.9% of cardia cancers were EBV-positive. EBV positivity was associated with better overall survival (adjusted HR 0.30, 95% CI 0.14-0.63).

Conclusions: Our study highlights unusually low EBV prevalence in gastric adenocarcinoma among a high-incidence population, particularly for cardia cancers. These findings suggest a unique risk factor profile for the high incidence of gastric cancer in this population.
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http://dx.doi.org/10.1007/s10620-020-06288-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685001PMC
April 2021

Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada.

J Int AIDS Soc 2020 04;23(4):e25484

Vanderbilt University Medical Center, Nashville, TN, USA.

Introduction: Weight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).

Methods: Adult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4 cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years.

Results: Among 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4 cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI).

Conclusions: PWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration.
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http://dx.doi.org/10.1002/jia2.25484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159248PMC
April 2020

Associations of Viral Seroreactivity with AIDS-Related Non-Hodgkin Lymphoma.

AIDS Res Hum Retroviruses 2020 05 2;36(5):381-388. Epub 2020 Mar 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Infection with human immunodeficiency virus (HIV) is associated with substantially increased incidence of non-Hodgkin lymphoma (NHL). This risk may be driven, in part, by reduced immune control over viral infections in the setting of acquired immunodeficiency syndrome (AIDS), although the lymphomagenic mechanisms are not yet established. We used bead-based multiplex assays to measure antibody seroreactivity to 32 viral antigens representing 22 different viral infections (human herpesviruses 1-8, hepatitis B and C virus, human T-lymphotropic virus type-1, and human polyomaviruses) in two prospective HIV cohorts. Incident ( = 28) and prevalent ( = 38) AIDS-related NHL cases were matched by age, sex, race, and CD4 count to 67 HIV-positive control individuals without AIDS-NHL. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of AIDS-NHL with the number of different viruses to which an individual was seropositive and seroreactivity to individual antigens. Seropositivity to an increasing number of viruses was inversely associated with AIDS-NHL (OR per virus = 0.84, 95% CI = 0.72-0.98). Seroreactivity to herpes simplex virus 2 2mgG unique antigen (OR = 0.47; 95% CI = 0.23-0.97) and to WU polyomavirus viral capsid protein (OR = 0.26, 95% CI = 0.10-0.65) was significantly lower in AIDS-NHL cases compared to controls. In this evaluation of antibodies to multiple viruses, we observed an inverse association between seropositivity to a larger number of viruses and AIDS-NHL. While in need of further evaluation, our data raise the novel hypothesis that insufficient exposures or impaired humoral immune responses to viral infections may be associated with AIDS-related lymphomagenesis.
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http://dx.doi.org/10.1089/AID.2019.0208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232664PMC
May 2020

Circulating Antibodies against Epstein-Barr Virus (EBV) and p53 in EBV-Positive and -Negative Gastric Cancer.

Cancer Epidemiol Biomarkers Prev 2020 02 12;29(2):414-419. Epub 2019 Nov 12.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Background: Epstein-Barr virus (EBV)-positive gastric cancers have clinicopathologic differences from EBV-negative tumors and lack mutation. Serologic profiles may inform viral contribution to carcinogenesis.

Methods: We compared humoral responses of EBV-positive ( = 67) and EBV-negative ( = 137) patients with gastric cancer from the International EBV-Gastric Cancer Consortium. Serum antibodies against four EBV proteins, nuclear (EBNA), viral capsid (VCA), early-diffuse (EA-D), and Zta replication activator (ZEBRA), and to p53 were assessed by multiplex assays. OR of antibody level tertiles (T1-T3) were adjusted by logistic regression. We also conducted a meta-analysis of reported anti-p53 seropositivity in gastric cancer.

Results: Consistent with EBV's ubiquity, 99% of patients were seropositive for anti-EBNA and 98% for anti-VCA, without difference by tumor EBV status. Seropositivity varied between patients with EBV-positive and EBV-negative tumors for anti-EA-D (97% vs. 67%, respectively, < 0.001) and anti-ZEBRA (97% vs. 85%, respectively, = 0.009). Adjusted ORs (vs. T1) for patients with EBV-positive versus EBV-negative tumors were significantly elevated for higher antibodies against EBNA (2.6 for T2 and 13 for T3), VCA (1.8 for T2 and 2.4 for T3), EA-D (6.0 for T2 and 44 for T3), and ZEBRA (4.6 for T2 and 12 for T3). Antibodies to p53 were inversely associated with EBV positivity (3% vs. 15%; adjusted OR = 0.16, = 0.021). Anti-p53 prevalence from the literature was 15%.

Conclusions: These serologic patterns suggest viral reactivation in EBV-positive cancers and identify variation of p53 seropositivity by subtype.

Impact: Anti-EBV and anti-p53 antibodies are differentially associated with tumor EBV positivity. Serology may identify EBV-positive gastric cancer for targeted therapies.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272980PMC
February 2020

Prediagnostic circulating inflammation biomarkers and esophageal squamous cell carcinoma: A case-cohort study in Japan.

Int J Cancer 2020 08 3;147(3):686-691. Epub 2019 Dec 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype of esophageal cancer worldwide. Measurements of circulating inflammation-related biomarkers may inform etiology or provide noninvasive signatures for early diagnosis. We therefore examined levels of inflammation molecules for associations with ESCC risk. Using a case-cohort study designed within the Japan Public Health Center-based Prospective Study, we measured baseline plasma levels of 92 biomarkers using a multiplex assay in a subcohort of 410 randomly selected participants and 66 participants with incident ESCC (including four cases that occurred in the subcohort). ESCC hazard ratios (HRs) were calculated for 2-4 quantiles of each biomarker by Cox proportional hazards regression models with age as the time metric, adjusted for sex, smoking and alcohol use. Twenty analytes were undetectable in nearly all samples. Of the remaining 72, 12 biomarkers (FGF19, ST1A1, STAMBP, AXIN1, CASP8, NT3, CD6, CDCP1, CD5, SLAMF1, OPG and CSF1) were associated with increased ESCC risk (p  < 0.05) with HRs per quantile 1.28-1.65. Seven biomarkers (CXCL6, CCL23, CXCL5, TGFA, CXCL1, OSM and CCL4) were inversely associated with HRs 0.57-0.72. FGF19, CASP8, STAMBP, ST1A1 and CCL-4 met statistical significance with false discovery rate correction. Associations did not differ <5 vs. ≥5 years between blood collection and ESCC diagnosis. CASP8, STAMBP and ST1A1 were strongly correlated (p < 0.05). Our study expands the range of inflammation molecules associated with the development of this highly lethal neoplasia. Correlations among these novel biomarkers suggest a possible shared pathway. These findings need replication and could further delineate ESCCs molecular mechanisms of carcinogenesis.
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http://dx.doi.org/10.1002/ijc.32763DOI Listing
August 2020

Life-Expectancy Disparities Among Adults With HIV in the United States and Canada: The Impact of a Reduction in Drug- and Alcohol-Related Deaths Using the Lives Saved Simulation Model.

Am J Epidemiol 2019 12;188(12):2097-2109

Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Improvements in life expectancy among people living with human immunodeficiency virus (PLWH) receiving antiretroviral treatment in the United States and Canada might differ among key populations. Given the difference in substance use among key populations and the current opioid epidemic, drug- and alcohol-related deaths might be contributing to the disparities in life expectancy. We sought to estimate life expectancy at age 20 years in key populations (and their comparison groups) in 3 time periods (2004-2007, 2008-2011, and 2012-2015) and the potential increase in expected life expectancy with a simulated 20% reduction in drug- and alcohol-related deaths using the novel Lives Saved Simulation model. Among 92,289 PLWH, life expectancy increased in all key populations and comparison groups from 2004-2007 to 2012-2015. Disparities in survival of approximately a decade persisted among black versus white men who have sex with men and people with (vs. without) a history of injection drug use. A 20% reduction in drug- and alcohol-related mortality would have the greatest life-expectancy benefit for black men who have sex with men, white women, and people with a history of injection drug use. Our findings suggest that preventing drug- and alcohol-related deaths among PLWH could narrow disparities in life expectancy among some key populations, but other causes of death must be addressed to further narrow the disparities.
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http://dx.doi.org/10.1093/aje/kwz232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036649PMC
December 2019

Clinicopathological characteristics of Epstein-Barr virus-positive gastric cancer in Latvia.

Eur J Gastroenterol Hepatol 2019 Nov;31(11):1328-1333

Institute of Clinical and Preventive Medicine.

Objective: Epstein-Barr virus (EBV)-associated gastric cancer has been proposed to be a distinct gastric cancer molecular subtype. The prognostic significance of EBV infection in gastric cancer remains unclear and needs further investigation. Our study aimed to analyze EBV-positive and EBV-negative gastric cancer patients regarding their personal and tumor-related characteristics, and compare their overall survival.

Methods: Gastric cancer patients consecutively treated at the Riga East University Hospital during 2009-2016 were identified retrospectively. Tumor EBV status was determined by in-situ hybridization for EBV-encoded RNA (EBER). Information about clinicopathological characteristics was obtained from patient questionnaires, hospital records. Overall survival was ascertained through 30 July 2017. Cox proportional hazard regression models adjusted for personal and tumor-related covariates compared survival between EBV-positive and EBV-negative patients.

Results: There were a total of 302 gastric cancer patients (61% males) with mean and SD age 63.6 ± 11.5 years. EBER positivity was present in 8.6% of tumors. EBV-positive gastric cancer patients had better survival at 80 months [adjusted hazard ratio = 0.37, 95% confidence interval (CI) = 0.19-0.72] compared to EBV-negative patients. Worse survival was observed for patients with stage III (hazard ratio = 2.76, 95% CI = 1.67-4.56) and stage IV (hazard ratio = 10.02, 95% CI = 5.72-17.57) compared to stage I gastric cancer, and overlapping and unspecified subsite (hazard ratio = 1.85; 95% CI = 1.14; 3.00) compared to distal tumors.

Conclusion: Tumor EBV positivity is a favorable prognostic factor in gastric cancer.
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http://dx.doi.org/10.1097/MEG.0000000000001521DOI Listing
November 2019

Autoimmune Diseases and Gastric Cancer Risk: A Systematic Review and Meta-Analysis.

Cancer Res Treat 2019 Jul 3;51(3):841-850. Epub 2019 May 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Purpose: Autoimmunity is an alternative etiology of gastric inflammation, the initiating event in the gastric carcinogenic cascade. This mechanism may be an increasingly important cause of gastric cancer with the waning prevalence of its primary etiologic factor, chronic Helicobacter pylori infection.

Materials And Methods: PubMed and EMBASE were searched up to September 2018. Autoimmunity and 96 specific manifestations were considered for associations with gastric cancer risk. Random effects analysis was used to calculate pooled relative risk estimates (RR) and 95% confidence intervals (CI).

Results: We found a total of 52 observational studies representing 30 different autoimmune diseases. Overall, the presence of an autoimmune condition was associated with a gastric cancer pooled RR of 1.37 (95% CI, 1.24 to 1.52). Among the 24 autoimmune conditions with two or more independent reports, nine were significantly associated with increased gastric cancer risk: dermatomyositis (RR, 3.69; 95% CI, 1.74 to 7.79), pernicious anemia (RR, 2.84; 95% CI, 2.30 to 3.50), Addison disease (RR, 2.11; 95% CI, 1.26 to 3.53), dermatitis herpetiformis (RR, 1.74; 95% CI, 1.02 to 2.97; n=3), IgG4-related disease (RR, 1.69; 95% CI, 1.00 to 2.87), primary biliary cirrhosis (RR, 1.64; 95% CI, 1.13 to 2.37), diabetes mellitus type 1 (RR, 1.41; 95% CI, 1.20 to 1.67), systemic lupus erythematosus (RR, 1.37; 95% CI, 1.01 to 1.84), and Graves disease (RR, 1.27; 95% CI, 1.06 to 1.52).

Conclusion: Our analysis documents the wide range of autoimmune diseases associated with gastric cancer. These associations may reflect unreported links between these conditions and autoimmune gastritis. Further studies are warranted to investigate potential causal mechanisms.
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http://dx.doi.org/10.4143/crt.2019.151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639229PMC
July 2019

Association of Immunosuppression and Human Immunodeficiency Virus (HIV) Viremia With Anal Cancer Risk in Persons Living With HIV in the United States and Canada.

Clin Infect Dis 2020 03;70(6):1176-1185

Department of Environmental Health Sciences, Yale School of Public Health, Yale School of Medicine, New Haven, Connecticut.

Background: People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk.

Methods: We studied 102 777 PLWH during 1996-2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion.

Results: Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for <50 vs ≥500 cells/µL, 13.4; 95% confidence interval [CI], 3.5-51.0) and proportion of time CD4 <200 cells/µL from approximately 8.5 to 4.5 years in the past (a cumulative measure; HR for 100% vs 0%, 3.1; 95% CI, 1.5-6.6).

Conclusions: Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk.
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http://dx.doi.org/10.1093/cid/ciz329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319056PMC
March 2020

Circulating Inflammation Markers and Risk of Gastric and Esophageal Cancers: A Case-Cohort Study Within the Japan Public Health Center-Based Prospective Study.

Cancer Epidemiol Biomarkers Prev 2019 04 15;28(4):829-832. Epub 2019 Mar 15.

Division of Cancer Epidemiology and Genetics, NCI, Rockville, Maryland.

Background: Circulating inflammation proteins may be important mediators or markers of carcinogenic mechanisms. There have been few studies with limited numbers of analytes in patients with upper gastrointestinal (GI) tract tumors. We therefore evaluated risk associations of gastric and esophageal cancers with prediagnostic levels of a wide range of these molecules.

Methods: We performed a case-cohort analysis within the Japan Public Health Center-Based Prospective Study Cohort II, including incident cases of gastric ( = 446) and esophageal ( = 68) cancers and a random subcohort ( = 774). A total of 64 biomarkers were measured in baseline plasma using Luminex bead-based assays. The median time between blood collection and diagnosis was 8.1 years for gastric cancer and 9.4 years for esophageal cancer. HRs for association with each marker were adjusted for potential confounders using Cox regression.

Results: In separate models, sEGFR and TSLP were nominally associated with gastric cancer risk, and CRP, CXCL11/ITAC, and CCL15/MIP1D were associated with esophageal cancer. However, no association satisfied statistical significance after FDR correction. Associations did not differ by time from blood collection to cancer (<5 vs. ≥5 years).

Conclusions: Our study failed to identify associations of circulating inflammation markers with risk of upper GI tract tumors.

Impact: To date, this is the largest assessment of inflammation-related proteins with gastric and esophageal cancer risks. However, the evaluated molecules may not fully represent the complex inflammation processes preceding malignant transformation. Further investigation of other markers in prospective studies is warranted, as demonstration of associations may have important implications for prevention and treatment of these cancers.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1157DOI Listing
April 2019

Association of immunosuppression and HIV viraemia with non-Hodgkin lymphoma risk overall and by subtype in people living with HIV in Canada and the USA: a multicentre cohort study.

Lancet HIV 2019 04 27;6(4):e240-e249. Epub 2019 Feb 27.

Department of Environmental Health Sciences, Yale School of Public Health, Yale School of Medicine, New Haven, CT, USA.

Background: Research is needed to better understand relations between immunosuppression and HIV viraemia and risk for non-Hodgkin lymphoma, a common cancer in people living with HIV. We aimed to identify key CD4 count and HIV RNA (viral load) predictors of risk for non-Hodgkin lymphoma, overall and by subtype.

Methods: We studied people living with HIV during 1996-2014 from 21 Canadian and US cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. To determine key independent predictors of risk for non-Hodgkin lymphoma, we assessed associations with time-updated recent, past, cumulative, and nadir or peak measures of CD4 count and viral load, using demographics-adjusted, cohort-stratified Cox models, and we compared models using Akaike's information criterion.

Findings: Of 102 131 people living with HIV during the study period, 712 people developed non-Hodgkin lymphoma. The key independent predictors of risk for overall non-Hodgkin lymphoma were recent CD4 count (ie, lagged by 6 months; <50 cells per μL vs ≥500 cells per μL, hazard ratio [HR] 3·2, 95% CI 2·2-4·7) and average viral load during a 3-year window lagged by 6 months (a cumulative measure; ≥100 000 copies per mL vs ≤500 copies per mL, HR 9·6, 95% CI 6·5-14·0). These measures were also the key predictors of risk for diffuse large B-cell lymphoma (recent CD4 count <50 cells per μL vs ≥500 cells per μL, HR 2·4, 95% CI 1·4-4·2; average viral load ≥100 000 copies per mL vs ≤500 copies per mL, HR 7·5, 95% CI 4·5-12·7). However, recent CD4 count was the sole key predictor of risk for CNS non-Hodgkin lymphoma (<50 cells per μL vs ≥500 cells per μL, HR 426·3, 95% CI 58·1-3126·4), and proportion of time viral load was greater than 500 copies per mL during the 3-year window (a cumulative measure) was the sole key predictor for Burkitt lymphoma (100% vs 0%, HR 41·1, 95% CI 9·1-186·6).

Interpretation: Both recent immunosuppression and prolonged HIV viraemia have important independent roles in the development of non-Hodgkin lymphoma, with likely subtype heterogeneity. Early and sustained antiretroviral therapy to decrease HIV replication, dampen B-cell activation, and restore overall immune function is crucial for preventing non-Hodgkin lymphoma.

Funding: National Institutes of Health, Centers for Disease Control and Prevention, US Agency for Healthcare Research and Quality, US Health Resources and Services Administration, Canadian Institutes of Health Research, Ontario Ministry of Health and Long Term Care, and the Government of Alberta.
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http://dx.doi.org/10.1016/S2352-3018(18)30360-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531288PMC
April 2019

Contributions of traditional and HIV-related risk factors on non-AIDS-defining cancer, myocardial infarction, and end-stage liver and renal diseases in adults with HIV in the USA and Canada: a collaboration of cohort studies.

Lancet HIV 2019 02 22;6(2):e93-e104. Epub 2019 Jan 22.

University of North Carolina, Chapel Hill, NC, USA.

Background: Adults with HIV have an increased burden of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease. The objective of this study was to estimate the population attributable fractions (PAFs) of preventable or modifiable HIV-related and traditional risk factors for non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes.

Methods: We included participants receiving care in academic and community-based outpatient HIV clinical cohorts in the USA and Canada from Jan 1, 2000, to Dec 31, 2014, who contributed to the North American AIDS Cohort Collaboration on Research and Design and who had validated non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, or end-stage renal disease outcomes. Traditional risk factors were tobacco smoking, hypertension, elevated total cholesterol, type 2 diabetes, renal impairment (stage 4 chronic kidney disease), and hepatitis C virus and hepatitis B virus infections. HIV-related risk factors were low CD4 count (<200 cells per μL), detectable plasma HIV RNA (>400 copies per mL), and history of a clinical AIDS diagnosis. PAFs and 95% CIs were estimated to quantify the proportion of outcomes that could be avoided if the risk factor was prevented.

Findings: In each of the study populations for the four outcomes (1405 of 61 500 had non-AIDS-defining cancer, 347 of 29 515 had myocardial infarctions, 387 of 35 044 had end-stage liver disease events, and 255 of 35 620 had end-stage renal disease events), about 17% were older than 50 years at study entry, about 50% were non-white, and about 80% were men. Preventing smoking would avoid 24% (95% CI 13-35) of these cancers and 37% (7-66) of the myocardial infarctions. Preventing elevated total cholesterol and hypertension would avoid the greatest proportion of myocardial infarctions: 44% (30-58) for cholesterol and 42% (28-56) for hypertension. For liver disease, the PAF was greatest for hepatitis C infection (33%; 95% CI 17-48). For renal disease, the PAF was greatest for hypertension (39%; 26-51) followed by elevated total cholesterol (22%; 13-31), detectable HIV RNA (19; 9-31), and low CD4 cell count (13%; 4-21).

Interpretation: The substantial proportion of non-AIDS-defining cancers, myocardial infarction, end-stage liver disease, and end-stage renal disease outcomes that could be prevented with interventions on traditional risk factors elevates the importance of screening for these risk factors, improving the effectiveness of prevention (or modification) of these risk factors, and creating sustainable care models to implement such interventions during the decades of life of adults living with HIV who are receiving care.

Funding: National Institutes of Health, US Centers for Disease Control and Prevention, the US Agency for Healthcare Research and Quality, the US Health Resources and Services Administration, the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long Term Care, and the Government of Alberta.
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http://dx.doi.org/10.1016/S2352-3018(18)30295-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589140PMC
February 2019

Gastric Cancer: an Evolving Disease.

Curr Treat Options Gastroenterol 2018 Dec;16(4):561-569

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr., BG 9609/6E338, Rockville, MD, 20852, USA.

Purpose Of Review: Prevalence of Helicobacter pylori, the primary risk factor for gastric cancer, is declining globally. Paralleling this trend, gastric cancer incidence is also decreasing. Historically, the populations most affected by this neoplasia have been males, Asians, and groups with low socioeconomic status. This review provides an update on recently published literature regarding changes in gastric cancer epidemiology.

Recent Findings: Gastric cancer incidence trends vary by age, sex, race/ethnicity, and tumor anatomical location. Overall incidence appears to be leveling off among young birth cohorts in Western populations, where H. pylori has declined considerably. The changes are more prominent for females and for tumors arising beyond the esophageal-gastric junction. The classical incidence pattern of gastric cancer is evolving. While uncertain, several hypotheses may explain the changing burden of disease. The mix of gastric cancer risk factors appears to be shifting, with H. pylori no longer the sole etiological driver. These changes may eliminate the previous predilection of males and lead to increases in overall gastric cancer rates. Analytical studies addressing known and novel factors related to major societal transitions may provide clues to understanding re-emergence of this serious public health problem.
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http://dx.doi.org/10.1007/s11938-018-0203-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453722PMC
December 2018

Circulating inflammation-related markers and advanced gastric premalignant lesions.

J Gastroenterol Hepatol 2019 May 18;34(5):852-856. Epub 2018 Nov 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Background And Aim: Chronic Helicobacter pylori infection causes gastric mucosal inflammation as an important antecedent of gastric cancer. We aimed to evaluate associations of blood markers of inflammation with gastric intestinal metaplasia and dysplasia in H. pylori-infected individuals.

Methods: We compared pre-treatment serum levels of immune-related and inflammation-related markers between 99 individuals with intestinal metaplasia or dysplasia and 75 control individuals with non-atrophic gastritis within an H. pylori eradication trial in Mexico. Serum levels of 28 markers measured with Luminex bead-based assays were categorized in tertiles as low (T1), middle (T2), and high (T3). Logistic regression models were used to calculate age-adjusted and sex-adjusted odds ratios and 95% confidence intervals. All statistical tests were two-sided, and significance values were adjusted for multiple comparisons using false discovery rate methods.

Results: Five markers were nominally associated (P  < 0.05) with the presence of advanced premalignant gastric lesions. Adjusted odds ratios (95% confidence interval) of T2 and T3 versus T1 were 4.09 (1.65-10.17) and 3.08 (1.23-7.68) for CCL3/MIP1A, 3.21 (1.33-7.75) and 2.69 (1.10-6.57) for CCL20/MIP3A levels, 1.79 (0.77-4.18) and 2.39 (1.02-5.60) for IL-1β, 1.34 (0.56-3.19) and 3.02 (1.29-7.12) for IL-4, and 1.07 (0.44-2.59) and 3.07 (1.32-7.14) for IL-5, respectively. Two (IL-4 and IL-5) of the five markers had false discovery rate adjusted P  < 0.2.

Conclusions: Our results suggest that certain Th2 and other cytokines may have a role in promoting carcinogenesis in the setting of H. pylori infection. Additional research is needed to replicate these findings, extend to pre-diagnostic samples, and elucidate the underlying mechanisms.
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http://dx.doi.org/10.1111/jgh.14518DOI Listing
May 2019

Serially measured pre-diagnostic levels of serum cytokines and risk of brain cancer in active component military personnel.

Br J Cancer 2018 10 9;119(7):893-900. Epub 2018 Oct 9.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USA.

Background: There is growing evidence that history of allergic or autoimmune disease is associated with reduced risk of glioma, but few prospective studies have explored the biological basis. To assess associations with immune conditions and levels of 14 cytokines in serial prediagnostic serum samples, we conducted a study of glioma/brain cancer nested in a cohort of active component military personnel.

Methods: A total of 457 case-control sets were ascertained from the Department of Defense (DoD) Automated Central Tumour Registry, Defense Medical Surveillance System (DMSS) database, and DoD Serum Repository. These were individually matched on sex, race/ethnicity, birth year, number of serum samples (1, 2 or 3), and date(s) of sample collection. We obtained diagnoses of pre-existing immune-related conditions from the DMSS database and measured cytokines using Meso Scale Discovery assays. Statistical analyses included conditional logistic regression.

Results: Overall association between glioma and prior immune-related conditions was null. Higher levels of IL-15 and IL-16 were independently associated with lower glioma risks (P = 0.002 and P = 0.001); both associations were more pronounced in individuals with prior immune conditions (P = 0.0009 and P = 0.031).

Conclusions: Associations with pre-diagnostic levels of IL-15 and IL-16 and their modification by diagnosis of immune-related conditions support the importance of immune alterations in glioma aetiology years before diagnosis.
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http://dx.doi.org/10.1038/s41416-018-0272-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189110PMC
October 2018

Reduced Cancer Survival Among Adults With HIV and AIDS-Defining Illnesses Despite No Difference in Cancer Stage at Diagnosis.

J Acquir Immune Defic Syndr 2018 12;79(4):421-429

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Background: It is not known whether immune dysfunction is associated with increased risk of death after cancer diagnosis in persons with HIV (PWH). AIDS-defining illness (ADI) can signal significant immunosuppression. Our objective was to determine differences in cancer stage and mortality rates in PWH with and without history of ADI.

Methods: PWH with anal, oropharynx, cervical, lung cancers, or Hodgkin lymphoma diagnoses from January 2000 to December 2009 in the North American AIDS Cohort Collaboration on Research and Design were included.

Results: Among 81,865 PWH, 814 had diagnoses included in the study; 341 (39%) had a history of ADI at time of cancer diagnosis. For each cancer type, stage at diagnosis did not differ by ADI (P > 0.05). Mortality and survival estimates for cervical cancer were limited by n = 5 diagnoses. Adjusted mortality rate ratios showed a 30%-70% increase in mortality among those with ADI for all cancer diagnoses, although only lung cancer was statistically significant. Survival after lung cancer diagnosis was poorer in PWH with ADI vs. without (P = 0.0001); the probability of survival was also poorer in those with ADI at, or before other cancers although not statistically significant.

Conclusions: PWH with a history of ADI at lung cancer diagnosis had higher mortality and poorer survival after diagnosis compared to those without. Although not statistically significant, the findings of increased mortality and decreased survival among those with ADI (vs. without) were consistent for all other cancers, suggesting the need for further investigations into the role of HIV-related immune suppression and cancer outcomes.
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http://dx.doi.org/10.1097/QAI.0000000000001842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203623PMC
December 2018
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