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Background: Previous prospective studies of associations between circulating inflammation-related molecules and pancreatic cancer risk have included limited numbers of markers. Methods: We conducted a case–cohort study nested within the Japan Public Health Center-based Prospective Study Cohort II. We selected a random subcohort (n = 774) from a total of 23,335 participants aged 40 to 69 years who returned a questionnaire and provided blood samples at baseline. During the follow-up period from 1993 to 2010, we identified 111 newly diagnosed pancreatic cancer cases, including one case within the subcohort. Plasma concentrations of 62 inflammatory markers of chemokines, cytokines, and growth factors were measured by a Luminex fluorescent bead-based assay. Cox regression models were applied to estimate HR and 95% confidence intervals (CI) for pancreatic cancer risk for quartiles of marker levels adjusted for potential confounders. Results: The HR (95% CI) for the highest versus the lowest category of C–C motif ligand chemokine 8/monocyte chemoattractant protein 2 (CCL8/MCP2) was 2.03 (1.05–3.93; Ptrend = 0.048). After we corrected for multiple comparisons, none of the examined biomarkers were associated with pancreatic cancer risk at P-value Conclusions: We found no significant associations between 62 inflammatory markers and pancreatic cancer risk. Impact: The suggestive association with circulating levels of leukocyte recruiting cytokine CCL8/MCP2 may warrant further investigation.

Elevated systemic levels of soluble cluster of differentiation 14 (sCD14) have been associated with gallbladder cancer (GBC), but the association with sCD14 levels within the gallbladder has not been investigated. Here, we evaluated sCD14 in the bile of 41 GBC cases and 117 gallstone controls with data on 65 bile inflammation markers. We examined the relationship between bile sCD14 levels and GBC using logistic regression and stratified the analysis by stage. We included GBC-associated inflammatory biomarkers in the model to evaluate the influence of local inflammation. Bile sCD14 levels (third versus first tertile) were associated with GBC (adjusted odds ratio [OR]: 3.0, 95% confidence interval [CI]: 1.2–8.0). The association was equally strong for stage I/II (OR: 3.3, 95% CI: 0.9–15.6) and stage III/IV (OR: 3.2, 95% CI: 1.0–12.4) cancers. Including the GBC-associated inflammatory markers in the model removed the association between bile sCD14 and GBC (OR: 1.0, 95% CI: 0.3–3.5). The findings suggest that immune activation within the gallbladder may be related to GBC development, and the effect of sCD14 is influenced by inflammation. Similar associations across tumor stages suggest that elevated bile sCD14 levels may reflect changes early in GBC pathogenesis. Associations between GBC and sCD14 levels in both bile and plasma suggest sCD14 could be a potential biomarker for GBC.

INTRODUCTION: Whether existing serological assays are sufficiently robust to measure the lower antibody levels expected following single-dose HPV vaccination is unknown. METHODS: We evaluated seven assays measuring HPV-16/18 immunological responses overall and by number of doses in 530 serum samples from participants receiving varying doses of Cervarix or Gardasil up to 36-months post-vaccination. Serum was evaluated by simplex (HPV-16 ELISA, HPV-18 ELISA), multiplex (LIA-4, VLP-MIA, M9ELISA, GST-L1), and high-throughput pseudovirion-based neutralization assays (HT-PBNA), and results were compared to the gold standard HPV-16/18 secreted alkaline phosphatase neutralization assay (SEAP-NA). Reproducibility was assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Percent agreement, Pearson correlation and weighted-kappa were used to assess validity. Determinants of seronegativity were evaluated by chi-squared test. RESULTS: HPV-16: Seropositivity range was 97.1–99.5% for single dose and 98.8–99.8% overall. CV range was 4.0–18.0% for single dose and 2.9–19.5% overall. ICC range was 0.77–0.99 for single dose and 0.74–0.99 overall. Correlation with SEAP-NA range was 0.43–0.85 for single dose and 0.51–0.90 overall. Weighted-kappa range was 0.34–0.82 for single dose and 0.45–0.84 overall. HPV-18: Seropositivity range was 63.9–94.7% for single dose and 86.2–97.9% overall. CV range was 8.1–18.2% for single dose and 4.6–18.6% overall. ICC range was 0.75–0.99 for single dose and 0.83–0.99 overall. Correlation with SEAP-NA range was 0.31–0.99 for single dose and 0.27–0.96 overall. Weighted-kappa range was 0.35–0.83 for single dose and 0.45–0.84 overall. HPV-16 seronegativity was 10%, the strongest correlates of seronegativity were receiving a single vaccine dose and receiving Gardasil. CONCLUSIONS: These results support the utility of existing serological assays to monitor antibody responses following single-dose HPV vaccination.

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 (N = 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. P 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.

PURPOSE: Disentangling the effects of endogenous estrogens and inflammation on obesity-related diseases requires a clearer understanding of how the two biological mechanisms relate to each other. METHODS: We studied 155 healthy postmenopausal women not taking menopausal hormone therapy enrolled in the Prostate Lung Colorectal and Ovarian (PLCO) screening cancer trial. From a baseline blood draw, we measured endogenous estradiol and 69 inflammation biomarkers: cytokines, chemokines, adipokines, angiogenic factors, growth factors, acute phase proteins, and soluble receptors. We evaluated the estradiol–inflammation relationship by assessing associations across different models (linear, ordinal logistic, and binary logistic) using a variety of estradiol classifications. We additionally investigated the estradiol–inflammation relationship stratified by baseline obesity status (BMI < 30 stratum and BMI > 30 stratum). RESULTS: Associations of estradiol with 7 inflammation biomarkers met p < 0.05 statistical significance in linear and ordinal models: C-reactive protein (CRP), adiponectin, chemokine (C-X-C motif) ligand-6, thymus activation-regulated chemokine, eosinophil chemotactic protein, plasminogen activator inhibitor-1, and serum amyloid A. The positive association between estradiol and CRP was robust to model changes. Each standard deviation increase in endogenous estradiol doubled a woman’s odds of having CRP levels higher than the study median (odds ratio 2.29; 95% confidence interval 1.28, 4.09). Estradiol was consistently inversely associated with adiponectin. Other estradiol–inflammation biomarker associations were not robust to model changes. CONCLUSIONS: Endogenous estradiol appears to be associated with CRP and adiponectin; the evidence is limited for other inflammation biomarkers.

Background The authors investigated the durability of vaccine efficacy (VE) against human papillomavirus (HPV)16 or 18 infections and antibody response among nonrandomly assigned women who received a single dose of the bivalent HPV vaccine compared with women who received multiple doses and unvaccinated women. Methods HPV infections were compared between HPV16 or 18-vaccinated women aged 18 to 25 years who received one (N = 112), two (N = 62), or three (N = 1365) doses, and age- and geography-matched unvaccinated women (N = 1783) in the long-term follow-up of the Costa Rica HPV Vaccine Trial. Cervical HPV infections were measured at two study visits, approximately 9 and 11 years after initial HPV vaccination, using National Cancer Institute next-generation sequencing TypeSeq1 assay. VE and 95% confidence intervals (CIs) were estimated. HPV16 or 18 antibody levels were measured in all one- and two-dose women, and a subset of three-dose women, using a virus-like particle-based enzyme-linked immunosorbent assay (n = 448). Results Median follow-up for the HPV-vaccinated group was 11.3 years (interquartile range = 10.9–11.7 years) and did not vary by dose group. VE against prevalent HPV16 or 18 infection was 80.2% (95% CI = 70.7% to 87.0%) among three-dose, 83.8% (95% CI = 19.5% to 99.2%) among two-dose, and 82.1% (95% CI = 40.2% to 97.0%) among single-dose women. HPV16 or 18 antibody levels did not qualitatively decline between years four and 11 regardless of the number of doses given, although one-dose titers continue to be statistically significantly lower compared with two- and three-dose titers. Conclusion More than a decade after HPV vaccination, single-dose VE against HPV16 or 18 infection remained high and HPV16 or 18 antibodies remained stable. A single dose of bivalent HPV vaccine may induce sufficiently durable protection that obviates the need for more doses.

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 (n = 446) and esophageal (n = 68) cancers and a random subcohort (n = 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 ( 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.

Inflammation is a driver of colorectal neoplasia; however, what particular inflammatory processes play a role in early carcinogenesis are unclear. We compared serum levels of 78 inflammation markers between 171 pathologically confirmed colorectal adenoma cases (including 48 incident cases) and 344 controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We used weighted multivariable logistic regression to compute odds ratio (OR) and 95% confidence interval (CI). We found 14 markers associated with risk of adenoma overall; three of these were also associated with incident adenoma: CC-chemokine cysteine motif chemokine ligand 20 (CCL20) [overall adenoma fourth versus first quartile: OR 4.8, 95% CI 2.0–12, Ptrend 0.0007; incident adenoma third versus first tertile: OR 4.6, 95% CI 1.0–22, Ptrend 0.03], growth-related gene oncogene products (GRO) [OR 3.8, 95% CI 1.6–9.3, Ptrend 0.006 and OR 3.6, 95% CI 1.1–12, Ptrend 0.04, respectively] and insulin [OR 2.9, 95% CI 0.8–10, Ptrend 0.05 and OR 7.8, 95% CI 1.3–46, Ptrend 0.03, respectively]. All statistical tests were two-sided. These results provide important new evidence implicating CCL20- and GRO-related pathways in early colorectal carcinogenesis and further support a role for insulin.

Summary Background Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Methods Women aged 18–25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov , NCT00867464 . Findings 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0–4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7–11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1–11·7), 4·6 years (4·3–5·3) for the original control group, and 6·2 years (5·5–6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2–100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0–99·6). Similar protection was observed against HPV 16/18-associated CIN3—specifically at year 11, vaccine efficacy was 100% (95% CI 78·8–100·0) and cumulative vaccine efficacy was 94·9% (73·7–99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine. Interpretation The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable. Funding US National Cancer Institute.

Blood levels of inflammation-related markers may reveal molecular pathways contributing to carcinogenesis. To date, prospective associations with colorectal cancer (CRC) risk have been based on few studies with limited sets of analytes. We conducted a case-cohort study within the Japan Public Health Center-based Prospective Study Cohort II, comparing 457 incident CRC cases during median 18 years follow-up with a random subcohort of 774 individuals. Baseline plasma levels of 62 cytokines, soluble receptors, acute-phase proteins, and growth factor markers were measured using Luminex bead-based assays. We estimated hazard ratios (HRs) associating each marker with CRC risk by Cox proportional hazards models adjusted for potential confounders. Subanalyses compared cases by years after blood draw (

Background: Evidence suggests that natural antibodies developed after HPV16 infection may protect some women but not men against subsequent HPV16 reacquisition. Less is known whether antibodies developed following HPV16 infection are protective among men who have sex with men (MSM). Methods: Four hundred seventy-five MSM from the Human Papillomavirus Infection in Men (HIM) study were tested for serum antibodies to HPV16 L1 using enzyme-linked immunosorbent assays, and for anal and genital HPV16 DNA using PCR consensus primer system (PGMY 09/11). Adjusted Cox regression was used to evaluate whether baseline HPV16 seropositivity impacts subsequent genital or anal HPV16 DNA. Results: The risk of subsequent genital HPV16 [aHR = 1.05, 95% confidence interval (CI) = 0.66–1.68] and anal HPV16 infections among MSM (aHR = 2.34, 95% CI = 0.92–5.98) was similar or nonsignificantly higher in HPV16-seropositive than HPV16-seronegative MSM. The risk of genital HPV16 was also similar between HPV16-seronegative and HPV16-seropositive MSM in the highest tertile of HPV16 antibody levels and when restricting to those with new sex partners during follow-up (P > 0.20). Among the 118 MSM who were HPV16 seropositive, 90% remained HPV16 seropositive up to 4 years later. When tested together, MSM with the highest antibody titers (top tertile) had similar levels to females (mean = 130.3 vs. 134.5 EU/mL, P = 0.84). Conclusions: Despite years of HPV16 seropositivity persistence and antibody titers comparable with females, this study suggested no evidence of HPV16 natural antibodies protecting against subsequent genital or anal HPV16 infection in MSM. Impact: This could help partially explain the high incidence of genital and anal HPV16 infection and related anal cancer seen in middle-aged and older MSM. Cancer Epidemiol Biomarkers Prev; 27(4); 496–502. ©2018 AACR.

Author(s): Safaeian, Mahboobeh; Sampson, Joshua N; Pan, Yuanji; Porras, Carolina; Kemp, Troy J; Herrero, Rolando; Quint, Wim; van Doorn, Leen Jan; Schussler, John; Lowy, Douglas R; Schiller, John; Schiffman, Mark T; Rodriguez, Ana Cecilia; Gail, Mitchell H; Hildesheim, Allan; Gonzalez, Paula; Pinto, Ligia A; Kreimer, Aimee R; Costa Rica HPV Vaccine Trial (CVT) Group | Abstract: BackgroundPreviously, we demonstrated similar human papillomavirus (HPV)16/18 vaccine efficacy estimates and stable HPV16/18 antibody levels four years postvaccination in a nonrandomized analysis of women who received a varying number of doses of the bivalent HPV16/18 vaccine. Here we extend data to seven years following initial vaccination.MethodsWe evaluated HPV16/18-vaccinated women who received one (n = 134), two (n 0/1 = 193, n 0/6 = 79), or three doses (n = 2043) to a median of 6.9 years postvaccination. Cervical HPV DNA was measured with the SPF10- DEIA-LiPA PCR system; HPV16/18-specific antibody levels were measured using enzyme-linked immunosorbent assays (n = 486). Infection and immunological measures were compared across vaccine dose groups. Prevalent HPV infection at year 7 was also compared with an unvaccinated control group (UCG). All statistical tests were two-sided.ResultsAmong women in the three-dose, two-dose 0/6 , two-dose 0/1 , and one-dose groups, cumulative incident HPV16/18 infection rates (No. of events/No. of individuals) were 4.3% (88/2036, 95% confidence interval [CI] = 3.5% to 5.3%), 3.8% (3/78, 95% CI = 1.0% to 10.1%), 3.6% (7/192, 95% CI = 1.6% to 7.1%), and 1.5% (2/133, 95% CI = 0.3% to 4.9%; P = 1.00, .85, .17 comparing the two-dose 0/6 , two-dose 0/1 , and one-dose groups to the three-dose group, respectively). The prevalence of other carcinogenic and noncarcinogenic HPV types, excluding HPV16/18/31/33/45, were high and not statistically different among all dose groups, indicating that the low incidence of HPV16/18 in the one- and two-dose groups was not due to lack of exposure. At seven years, 100% of participants in all dose groups remained HPV16 and HPV18 seropositive. A non-statistically significant decrease in the geometric mean of the HPV16 antibody levels between years 4 and 7 was observed among women in the three-dose group: -10.8% (95% CI = -25.3% to 6.6%); two-dose (0/6 months) group: -17.3% (95% CI = -39.3% to 12.8%), two-dose (0/1 month) group: -6.9% (95% CI = -22.1% to 11.2%), and one-dose group: -5.5% (95% CI = -29.7% to 27.0%); results were similar for HPV18.ConclusionsAt an average of seven years of follow-up, we observed similar low rates of HPV16/18 infections and slight, if any, decreases in HPV16/18 antibody levels by dose group.

There is a paucity of data on risk factors for lung cancer among never smokers. Here, we have carried out the first large study of circulating inflammation markers and lung cancer risk among female never smokers in Shanghai. A study of 248 lung cancer cases in female never smokers and 263 controls was nested within the Shanghai Women's Health Study (n = 75221), matched by dates of birth and blood collection (mean follow-up time = 7.5 years). Prediagnostic plasma levels of 65 inflammation markers were measured using a Luminex bead-based assay. Odds ratios (ORs) were estimated with multivariable logistic regression. Nine of 61 evaluable markers were statistically significantly associated with lung cancer risk among never smoking Chinese women (P-trend across categories0.05). Soluble interleukin-6 receptor [sIL-6R; highest versus lowest category OR = 2.37; 95% confidence interval (CI) 1.40-4.02) and chemokine (C-C motif) ligand 2/monocyte chemotactic protein 1; (OR = 1.62; 95% CI 0.94-2.80) were associated with an increased risk of lung cancer, whereas interleukin (IL)-21 (OR = 0.53; 95%CI 0.31-0.93), chemokine (C-X3-C motif) ligand 1/fractalkine (OR = 0.54; 95% CI 0.30-0.96), soluble vascular endothelial growth factor receptor 2 (sVEGFR2, OR = 0.45; 95% CI 0.26-0.76), sVEGFR3 (OR = 0.53; 95% CI 0.32-0.90), soluble tumor necrosis factor receptor I (OR = 0.49; 95% CI 0.29-0.83), IL-10 (OR = 0.60; 95% CI 0.34-1.05) and C-reactive protein (OR = 0.63; 95% CI 0.37-1.06) were associated with a decreased risk. sIL-6R remained significantly associated with lung cancer risk7.5 years prior to diagnosis. Markers involved in various aspects of the immune response were associated with subsequent lung cancer risk, implicating inflammation in the etiology of lung cancer among female never smokers.

Background Circulating inflammation markers are being increasingly measured in prospective cohorts to investigate cancer etiology. However, it is unclear how the measurements are affected by the freeze-thaw cycles of the specimens prior to marker analysis. Methods We compared concentrations of 45 inflammation markers between paired serum vials of 55 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial that have undergone one (T1), two (T2), and three (T3) freeze-thaw cycles at the time of assay. We computed the difference of analyte concentrations across paired vials (T1 vs. T2, T2 vs. T3) and tested whether the difference deviated from zero using the Wilcoxon signed-rank test. We also calculated Spearman rank correlation and weighted kappa statistics for T1 vs. T2 and T2 vs. T3 comparisons to assess agreement in rank ordering of subjects. Results Measurements between paired T1 and T2 samples were largely similar, with the difference not statistically deviating from zero for 36 of the 45 markers. In contrast, tests of the difference between paired T2 and T3 samples were statistically significant for 36 markers. However, the rank ordering of participants by marker concentration remained largely consistent across T2 and T3 samples, with Spearman correlation coefficients >0.8 for 42 markers and weighted kappas >0.7 for 37 markers. Conclusion We recommend that studies measuring inflammation markers use previously unthawed specimens to the extent possible, or match on the number of prior freeze-thaw cycles in nested case-control studies.

Background Experimental and clinical studies have implicated certain chemokines and angiogenic cytokines in multiple myeloma (MM) pathogenesis. To investigate whether systemic concentrations of these markers are associated with future MM risk and progression from its precursor, monoclonal gammopathy of undetermined significance (MGUS), we conducted a prospective study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Methods We measured concentrations of 45 immunologic and pro-angiogenic markers in sera from 241 MM case patients, 441 participants with nonprogressing MGUS, and 258 MGUS-free control participants using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. We also evaluated absolute risk of progression using weighted Kaplan-Meier estimates. All statistical tests were two-sided. Results Prediagnostic levels of six markers were statistically significantly elevated among MM case patients compared with MGUS-free control participants using a false discovery rate of 10% (EGF, HGF, Ang-2, CXCL12, CCL8, and BMP-9). Of these, three angiogenesis markers were associated with future progression from MGUS to MM: EGF (fourth vs first quartile: OR = 3.01, 95% CI = 1.61 to 5.63, Ptrend = .00028), HGF (OR = 2.59, 95% CI = 1.33 to 5.03, Ptrend = .015), and Ang-2 (OR = 2.14, 95% CI = 1.15 to 3.98, Ptrend = .07). A composite angiogenesis biomarker score substantially stratified risk of MGUS progression to MM beyond established risk factors for progression, particularly during the first 5 years of follow-up (areas under the curve of 0.71 and 0.64 with and without the angiogenesis marker score, respectively). Conclusions Our prospective findings provide new insights into mechanisms involved in MM development and suggest that systemic angiogenesis markers could potentially improve risk stratification models for MGUS patients.

Background The Costa Rica HPV Vaccine Trial has documented cross-protection of the bivalent HPV vaccine against HPV31/33/45 up to 7 years after vaccination, even with one dose of the vaccine. However, the durability of such protection remains unknown. Here, we evaluate the efficacy of different schedules of the vaccine against HPV31/33/45 out to 11 years postvaccination, expanding to other nontargeted HPV types. Methods We compared the rates of HPV infection in vaccinated women with the rates in a comparable cohort of unvaccinated women. We estimated the average vaccine efficacy (VEavg) against incident infections and tested for a change in VE over time. Results Among 3-dose women, we observed statistically significant cross-protection against HPV31/33/45 (VEavg = 64.4%, 95% confidence interval [CI] = 57.7% to 70.0%). Additionally, we observed borderline, statistically significant cross-protection against HPV35 (VEavg = 23.2%, 95% CI = 0.3% to 40.8%) and HPV58 (VEavg = 21.2%, 95% CI = 4.2% to 35.3%). There was no decrease in VE over time (two-sided Ptrend > .05 for HPV31, -33, -35, -45, and -58). As a benchmark, VEavg against HPV16/18 was 82.0% (95% CI = 77.3% to 85.7%). Among 1-dose women, we observed comparable efficacy against HPV31/33/45 (VEavg = 54.4%, 95% CI = 21.0% to 73.7%). Acquisition of nonprotected HPV types was similar between vaccinated and unvaccinated women, indicating that the difference in HPV infection rates was not attributable to differential genital HPV exposure. Conclusions Substantial cross-protection afforded by the bivalent vaccine against HPV31/33/45, and to a lesser extent, HPV35 and HPV58, was sustained and remained stable after 11 years postvaccination, reinforcing the notion that the bivalent vaccine is an effective option for protection against HPV-associated cancers.

Inflammation is proposed to increase risk of developing endometrial cancer, but few prospective epidemiologic studies have investigated the relationship between circulating inflammation markers and endometrial cancer risk. In a nested case-control study within the PLCO Screening Trial we measured serum levels of 64 inflammation-related biomarkers in 284 incident endometrial cancer cases and 284 matched controls. Using multivariable logistic regression inflammation markers were evaluated individually and combined into a cross-validated inflammation score. Of 64 markers, 22 were associated with endometrial cancer risk at p

Most gallbladder cancer (GBC) cases arise in the context of gallstones, which cause inflammation, but few gallstone patients develop GBC. We explored inflammation/immune-related markers measured in bile and serum in GBC cases compared to gallstone patients to better understand how inflammatory patterns in these two conditions differ. We measured 65 immune-related markers in serum and bile from 41 GBC cases and 127 gallstone patients from Shanghai, China, and calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for GBC versus gallstones. We then focused on the markers that were significantly elevated in bile and serum to replicate the findings in serum from 35 GBC cases and 31 gallstone controls from Chile. Comparing the highest versus lowest quantile, 15 markers (23%) were elevated in both serum and bile from GBC versus gallstone patients in the Shanghai study (p

IMPORTANCE: Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms. OBJECTIVE: To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post–allogeneic transplant compared with female healthy volunteers. INTERVENTIONS: Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later. DESIGN, SETTING, AND PARTICIPANTS: This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019. MAIN OUTCOMES AND MEASURES: Anti-HPV-6, -11, -16, and -18–specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay. RESULTS: Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P

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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 (Ptrend

ObjectiveCross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk.DesignThis nested case–control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy.ResultsSoluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker–cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity–oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (pConclusionThis prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.

Although inflammation is central to gallbladder cancer (GBC) development and proliferation, no study has systematically investigated circulating inflammatory proteins and patient survival. We aimed to examine whether the circulating levels of inflammatory proteins is associated with all-cause mortality among such patients. We recruited 134 patients with newly diagnosed with GBC from 1997 to 2001 in a population-based study in Shanghai and an independent set of 35 patients from 2012 to 2013 in Chile. Cox proportional hazards regression models adjusted for covariates were used to evaluate the hazard ratios (HRs) for death by serum levels of 49 inflammatory proteins (quartiles). Of 49 evaluable proteins, eight were significantly associated with overall survival. Seven were associated with a poorer survival, while the highest levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were associated with an increase in survival (HR = 0.26, 95% CI = 0.14, 0.47). No substantial difference in the magnitude of the association was observed between early- and late-stages of GBC. Of seven proteins, five were validated in the patients from Chile. Reducing inflammation and targeting pathways associated with increased survival might improve GBC outcomes. The potential for using a TRAIL-related anticancer drug for GBC treatment merits further investigation.

Background: Elevated systemic exposure to gut-derived bacterial products has been associated with hepatic inflammation and chronic liver diseases, potentially increasing the risk of liver cancer. However, only one prior study prospectively examined exposure to bacterial products in the circulation and risk of liver cancer, with a relatively limited coverage of biomarkers. Methods: We conducted a nested case–control study (224 liver cancer cases and 224 matched controls) in a large cohort of Finnish male smokers followed from baseline (1985–1988) to 2014. The associations between a panel of biomarkers for bacterial translocation and the risk of liver cancer were assessed using multivariable-adjusted conditional logistic regression. The biomarkers included immunoglobulin (Ig) A, IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and the LPS-binding protein. Results: Anti-flagellin IgA [odds ratios (OR), 2.79; 95% confidence intervals (CI), 1.34–5.78; Ptrend = 0.01] and anti-LPS IgA (2.44; 95% CI, 1.33–4.48; Ptrend < 0.01) were significantly associated with risk of liver cancer. When restricting the analysis to histologically classified hepatocellular carcinoma, the ORs were 4.18 (95% CI, 1.60–10.92; Ptrend < 0.01) and 2.48 (95% CI, 1.16–5.29; Ptrend < 0.01), respectively. The results were not substantially changed after excluding cases diagnosed within the first 5 years of follow-up and those with hepatitis C virus infection. Conclusions: Antibodies to flagellin and LPS were associated with increased risk of liver cancer. Impact: Gut-derived bacterial translocation into the circulation may play a role in the development of primary liver cancer. Our findings could contribute to the understanding of primary liver cancer etiology and further prevention efforts.

Background: Coffee drinking has been inversely associated with mortality as well as cancers of the endometrium, colon, skin, prostate, and liver. Improved insulin sensitivity and reduced inflammation are among the hypothesized mechanisms by which coffee drinking may affect cancer risk; however, associations between coffee drinking and systemic levels of immune and inflammatory markers have not been well characterized. Methods: We used Luminex bead-based assays to measure serum levels of 77 immune and inflammatory markers in 1,728 older non-Hispanic Whites. Usual coffee intake was self-reported using a food frequency questionnaire. We used weighted multivariable logistic regression models to examine associations between coffee and dichotomized marker levels. We conducted statistical trend tests by modeling the median value of each coffee category and applied a 20% false discovery rate criterion to P values. Results: Ten of the 77 markers were nominally associated (P trend < 0.05) with coffee drinking. Five markers withstood correction for multiple comparisons and included aspects of the host response namely chemotaxis of monocytes/macrophages (IFNγ, CX3CL1/fractalkine, CCL4/MIP-1β), proinflammatory cytokines (sTNFRII), and regulators of cell growth (FGF-2). Heavy coffee drinkers had lower circulating levels of IFNγ [odds ratios (OR), 0.35; 95% confidence intervals (CI), 0.16–0.75], CX3CL1/fractalkine (OR, 0.25; 95% CI, 0.10–0.64), CCL4/MIP-1β (OR, 0.48; 95% CI, 0.24–0.99), FGF-2 (OR, 0.62; 95% CI, 0.28–1.38), and sTNFRII (OR, 0.34; 95% CI, 0.15–0.79) than non-coffee drinkers. Conclusions: Lower circulating levels of inflammatory markers among coffee drinkers may partially mediate previously observed associations of coffee with cancer and other chronic diseases. Impact: Validation studies, ideally controlled feeding trials, are needed to confirm these associations. Cancer Epidemiol Biomarkers Prev; 24(7); 1052–60. ©2015 AACR.

Transplant recipients have elevated cancer risk, perhaps partly due to direct carcinogenic effects of immunosuppressive medications. Experimental evidence indicates that calcineurin inhibitors given to transplant recipients increase cellular expression of transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VEGF), which could promote cancer. To assess the potential role of these pathways in the transplantation setting, we conducted a case-control study nested in a cohort of liver recipients. Cases had nonmelanoma skin cancer (N = 84), cancer of the lung (N = 29), kidney (N = 20), or colorectum (N = 17), or melanoma (N = 3). We selected N = 463 recipients without cancer as controls. TGF-β1 and VEGF levels were measured in sera obtained, on average, approximately 3 years before case diagnosis/control selection. We also measured platelet factor 4 (PF4), a marker of ex vivo platelet degranulation, because TGF-β1 and VEGF can be released from platelets, and we developed a statistical model to isolate the platelet-derived fraction from the remaining circulating component. Compared with controls, lung cancer cases had higher levels of TGF-β1 (median 22.8 vs. 19.4 ng/mL, P = 0.02) and VEGF (277 vs. 186 pg/mL, P = 0.02). However, lung cancer cases also had higher platelet counts (P = 0.08) and PF4 levels (P = 0.02), while residual serum levels of TGF-β1 and VEGF, after accounting for PF4, were unassociated with lung cancer (P = 0.40 and P = 0.15, respectively). Associations were not seen for other cancers. In conclusion, TGF-β1 and VEGF levels were increased in association with lung cancer among transplant recipients, which may be explained by increased platelet counts and platelet degranulation in lung cancer cases.

Background Inflammatory proteins could help identify individuals most likely to have gallbladder cancer (GBC) among those waiting for cholecystectomy. Methods We analyzed 49 circulating inflammation-related proteins in 144 patients with GBC and 150 patients with gallstones. We calculated age- and sex-adjusted odds ratios (ORs) and 95% CIs for protein quantiles and GBC versus gallstones. Using proteins associated with early GBC (stage 1–2) that were selected in stepwise logistic regression, we created an inflammation score and explored the potential utility for risk stratification. Results 26 proteins (53%) had P values for the trend across categories ≤0.001, with associations for a one category increase ranging from 1.52 (95% CI: 1.20–1.94) for C C motif ligand 4 to 4.00 (95% CI: 2.76–5.79) for interleukin (IL)-8. Soluble tumor necrosis factor receptor 2 (sTNFR2), IL-6, sTNFR1, C C motif ligand 20 (CCL20), vascular cell adhesion molecule 1, IL-16, and granulocyte colony-stimulating factor had P values ≤0.001 for early GBC. Of those, IL-6, IL-16, CCL20, and STNFR1 were included in the inflammation score. In a high-risk setting with a pre-test disease risk of 10% (e.g., elderly patients) and using an inflammation score cutoff that provides 90% sensitivity, 39% of patients on the waiting list would be predicted to be positive, and 23% of those would be predicted to have GBC. Conclusion These results highlight the strong associations of inflammatory proteins with GBC risk and their potential clinical utility. Larger studies are needed to identify the most effective combinations of inflammatory proteins for detecting early GBC and precursor lesions.

a b s t r a c t Background: Investigations of vaccine efficacy and immunogenicity for adult females receiving fewer than three doses of human papillomavirus (HPV) vaccine have suggested protection against infection and precancerous lesions. We investigated the immunogenicity of bivalent HPV vaccines among adolescent girls from Uganda who received one, two, or three vaccine doses. Methods: Young girls vaccinated through a government program in Uganda were invited to participate. HPV16- and HPV18-specific antibodies were measured at ≥24 months after the last vaccine dose using an enzyme linked immunoassay in girls who received one (n = 36), two (n = 145), or three (n = 195) doses. Results: Nearly all subjects (99%) were HPV16 and HPV18 seropositive at the time of blood-draw. Geometric mean antibody levels (GMTs) were: HPV161-dose = 230 EU/mL, HPV162-dose = 808 EU/mL, and HPV163-dose = 1607 EU/mL; HPV181-dose = 87 EU/mL, HPV182-dose = 270 EU/mL, and HPV183-dose = 296 EU/mL. The GMT ratio for 2:3 doses was 0.50 (HPV16) and 0.68 (HPV18) and did not meet the non-inferiority criteria (i.e., lower bound of 97.5% confidence interval of the GMT ratio greater than 0.50). The GMT ratio for 1:3 doses for HPV16 and HPV18 was inferior, but absolute GMTs for one dose were higher than adult women who received one dose (HPV16 = 124 EU/mL, HPV18 = 69 EU/mL) where efficacy has been demonstrated. Conclusions: Even though immunogenicity with less than three doses did not meet a priori non-inferiority thresholds, antibody levels measured ≥24 months after last dose were similar to those of adult women who have been followed for more than eight years for efficacy. © 2014 Published by Elsevier Ltd.

Despite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating inflammation markers with lung cancer.We conducted a nested case-control study (n = 526 lung cancer patients and n = 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median = 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively.Of 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk (P trend across marker categories.05), including acute-phase proteins (C-reactive protein [CRP], serum amyloid A [SAA]), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 [sTNFRII]), anti-inflammatory cytokines (interleukin 1 receptor antagonist [IL-1RA]), lymphoid differentiation cytokines (interleukin 7 [IL-7]), growth factors (transforming growth factor alpha [TGF-A]), and chemokines (epithelial neutrophil-activating peptide 78 [ENA 78/CXCL5], monokine induced by gamma interferon [MIG/CXCL9], B cell-attracting chemokine 1 [BCA-1/CXCL13], thymus activation regulated chemokine [TARC/CCL17], macrophage-derived chemokine [MDC/CCL22]). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR = 0.71; 95% confidence interval = 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile [Q] 1 = 1.1% vs Q4 = 3.1%) and current smokers (Q1 = 2.3% vs Q4 = 7.9%) even after adjustment for smoking.Some circulating inflammation marker levels are associated with prospective lung cancer risk.

Bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial

Although severe immune dysregulation is an established risk factor for non-Hodgkin lymphoma (NHL), the importance of subclinical immunologic effects is unclear. We compared baseline serum levels of 67 immune and inflammation markers between 301 patients with NHL diagnosed 5+ years after blood collection and 301 control patients within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We observed associations with NHL for elevated B-cell-attracting chemokine 1 (BCA-1; fourth quartile vs first: odds ratio [OR], 2.7; 95% confidence interval [CI], 1.7-4.2; Ptrend = 1.0 × 10(-6)), soluble tumor necrosis factor receptor 2 (sTNFR2; OR, 3.4; 95% CI, 2.0-5.8; Ptrend = 1.1 × 10(-6)), and soluble vascular endothelial growth factor receptor 2 (sVEGFR2; OR, 2.3; 95% CI, 1.4-3.9; Ptrend = .0005) that remained significant after Bonferroni correction, simultaneous model adjustment, and restriction to cases diagnosed 8 to 13 years after blood collection. Associations with other markers were observed, although none remained associated with NHL after adjustment for BCA-1, sTNFR2, and sVEGFR2. Our findings suggest that circulating BCA-1, sTNFR2, and sVEGFR2 are associated with NHL risk well in advance of diagnosis. Additional research is needed to replicate these findings and elucidate the underlying biologic mechanisms.

Although persistent carcinogenic human papillomavirus (HPV) infection is necessary for cervical carcinogenesis, the cofactors involved in HPV persistence and disease progression are poorly understood. Chronic cervical inflammation may increase risk, but few studies have measured immune markers (cytokines, chemokines and soluble receptors) in cervical secretions. We evaluated the performance of 74 multiplexed, bead-based immune markers in cervical secretions from three groups of women with biopsy evaluation of cervical intraepithelial neoplasia (CIN), (i) 25% detectability and >80% interclass correlation coefficients (ICCs) acceptable for epidemiologic studies. Within-batch coefficients of variation (CVs) of ≥25% indicated room for assay improvement. Secondarily, we explored associations between marker levels and CIN/HPV status adjusted for matching variables, assay batch, age and number of sexual partners. Sixty-two markers (84%) had >25% detectability and ICCs > 80%. Of those, 53 (85%) had CVs < 25%. Using these preliminary data, we found that HPV positivity was associated with increased eotaxin-1 [odds ratio (OR): 15.63, 95% confidence interval (CI): 1.26-200.00] and G-CSF (OR: 12.99, 95% CI: 1.10-142.86) among CIN-negative women. There was suggestive evidence that higher chemoattractant marker levels were associated with CIN2/3 (e.g., MIP-1delta, OR: 4.48, 95% CI: 0.87-23.04 versus

Inflammation is increasingly thought to be associated with diabetes; however, only a few inflammation markers have been assessed concurrently in relation to history of diabetes. In the most comprehensive evaluation of inflammation markers and diabetes to date using a Luminex bead-based assay, we measured 78 inflammation-, immune-, and metabolic-related markers detectable in at least 10% of serum samples collected from participants from the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) screening trial (n = 1,814). At baseline, 6.6% (n = 120) of PLCO participants self-reported a history of diabetes. Cross-sectional associations between these markers and self-reported diabetes were assessed using weighted logistic regression adjusting for sex, smoking status, blood draw age and year, body mass index, and cohort sub-study. Including chemokines [C-C motif ligand (CCL) 19, CCL20, CCL21, C-X-C motif ligand (CXCL) 6, CXCL10, and CXCL11] and soluble cytokine and chemokine receptors [soluble (s) interleukin (IL) 6 receptor (R), soluble tumor necrosis factor receptor (sTNFR) 1, sTNFR2, and sIL-R2], ten inflammation-related markers, were nominally associated with diabetes (P

Background: Chronic inflammation is etiologically related to several cancers. We evaluated the performance [ability to detect concentrations above the assay's lower limit of detection, coefficients of variation (CV), and intraclass correlation coefficients (ICC)] of 116 inflammation, immune, and metabolic markers across two Luminex bead–based commercial kits and three specimen types. Methods: From 100 cancer-free participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Trial, serum, heparin plasma, and EDTA plasma samples were utilized. We measured levels of 67 and 97 markers using Bio-Rad and Millipore kits, respectively. Reproducibility was assessed using 40 blinded duplicates (20 within-batches and 20 across-batches) for each specimen type. Results: A majority of markers were detectable in more than 25% of individuals on all specimen types/kits. Of the 67 Bio-Rad markers, 51, 52, and 47 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs of less than 20%. Likewise, of 97 Millipore markers, 75, 69, and 78 markers in serum, heparin plasma, and EDTA plasma, respectively, had across-batch CVs of less than 20%. When results were combined across specimen types, 45 Bio-Rad and 71 Millipore markers had acceptable performance (>25% detectability on all three specimen types and across-batch CVs Conclusions: Inflammation and immune markers can be measured reliably in serum and plasma samples using multiplexed Luminex-based methods. Impact: Multiplexed assays can be utilized for epidemiologic investigations into the role of inflammation in cancer etiology. Cancer Epidemiol Biomarkers Prev; 20(9); 1902–11. ©2011 AACR.

Objective: Severe immune dysregulation is a strong risk factor for multiple myeloma (MM), and experimental studies have implicated chemokines and pro-angiogenic cytokines in MM pathogenesis. We investigated whether circulating immune markers were prospectively associated with MM and its precursor, monoclonal gammopathy of undetermined significance (MGUS), in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Methods: We characterized levels of 43 immune markers in banked sera from 243 MM cases, 506 subjects with MGUS (including those with light-chain disease) who did not progress to MM, and 258 MGUS-free controls using Luminex-based multiplex assay panels. Odds ratios (ORs) and 95% confidence intervals (CIs) for MM and MGUS were estimated using multivariate-adjusted polytomous logistic regression models. Results: Relative to MGUS-free controls, we observed statistically significant associations with MM risk for six markers using a false discovery rate of 10%, including several chemokines (MCP-2/CCL8, fourth quartile vs first: OR 2.1; 95% CI 1.2-3.7; Ptrend=0.017 and SDF-1/CXCL12, 2.6; 1.5-4.4; Ptrend=2.9x10-4), angiogenesis markers (ANG-2, 3.0; 1.7-5.3; Ptrend=1.3x10-4 and HGF, 3.0; 1.7-5.1; Ptrend=2.8x10-5), and growth factors (EGF, 3.2; 1.9-5.5; Ptrend=1.9x10-6 and BMP-9, 2.3; 1.4-4.0; Ptrend=3.3x10-4). Associations with these markers remained after restricting to MM cases diagnosed ≥8 years after blood collection although risk estimates were somewhat attenuated (Ptrend≤0.07). MCP-2/CCL8, SDF-1/CXCL12, and HGF were also significantly elevated among those with MGUS compared with MGUS-free controls (Ptrend≤0.04). Four markers were associated with progression from MGUS to MM after adjusting for clinical characteristics such as M-protein concentration, serum free light-chain ratio, and immunoglobulin type (ANG-2, fourth quartile vs first: OR 2.5, 95% CI 1.4-4.6; HGF, 2.6, 1.4-5.0; EGF, 3.3, 1.8-6.0; and BMP-9, 1.9, 1.0-3.4); dose-response trends were statistically significant for all four markers (Ptrend≤0.03). Conclusions: This is, to our knowledge, the first prospective study to investigate circulating immunologic markers in relation to MM risk and progression from MGUS to MM. Our findings provide insights into potential biological mechanisms associated with MM development and may have clinical utility for improving risk stratification models assessing the likelihood of progression from MGUS to clinically manifest MM. Citation Format: Jonathan N. Hofmann, Ola Landgren, Hormuzd Katki, Troy Kemp, Loredana Santo, Charlene McShane, Qing Lan, Nathaniel Rothman, Ligia Pinto, Ruth Pfeiffer, Allan Hildesheim, Mark Purdue. Circulating immunologic markers and risk of multiple myeloma and its precursor disease: A nested case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4943.

Background: We conducted two independent nested case-control studies to identify circulating inflammation markers reproducibly associated with lung cancer risk and to investigate the utility of replicated markers for lung cancer risk stratification. Methods: Nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the previously published discovery study included 526 lung cancer patients and 592 control subjects and the replication study included 526 lung cancer case patients and 625 control subjects. Control subjects were matched by sex, age, smoking, study visit, and years of blood draw and exit. Serum levels of 51 inflammation markers were measured. Odds ratios (ORs) were estimated with conditional logistic regression. All statistical tests were two-sided. Results: Of 11 markers identified in the discovery study, C-reactive protein (CRP) (odds ratio [OR] [highest vs. lowest category] = 1.77, 95% confidence interval [CI] = 1.23 to 2.54), serum amyloid A (SAA) (OR = 1.88, 95% CI = 1.28 to 2.76), soluble tumor necrosis factor receptor-2 (sTNFRII) (OR = 1.70, 95% CI = 1.18 to 2.45), and monokine induced by gamma interferon (CXCL9/MIG) (OR = 2.09, 95% CI = 1.41 to 3.00) were associated with lung cancer risk in the replication study ( P trend < .01). In pooled analyses, CRP, SAA, and CXCL9/MIG remained associated with lung cancer more than six years before diagnosis (P trend < .05). The incorporation of an inflammation score combining these four markers did not improve the sensitivity (77.6% vs 75.8%, P = .33) or specificity (56.1% vs 56.1%, P = .98) of risk-based lung cancer models. Conclusions: Circulating levels of CRP, SAA, sTNFRII, and CXCL9/MIG were reproducibly associated with lung cancer risk in two independent studies within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, underscoring an etiologic role for inflammation in lung carcinogenesis, though replication is needed in other populations. Markers did not improve lung cancer risk stratification beyond standard demographic and behavioral characteristics.

Elevated serum sCD23 and sCD30 up to two decades prior to diagnosis associated with increased risk of non-Hodgkin lymphoma

Background: Regular aspirin use may decrease cancer risk by reducing chronic inflammation. However, associations between aspirin use and circulating markers of inflammation have not been well studied. Methods: Serum levels of 78 inflammatory markers were measured in 1,819 55- to 74-year-old men and women in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Data were combined from three completed case–control studies and reweighted to the PLCO screening arm. Self-reported aspirin and ibuprofen use (number of tablets taken per day/week/month) over the previous 12 months was collected at baseline. Associations between (i) nonregular ( Results: Aspirin use was nominally associated with (Ptrend across categories ≤ 0.05) decreased levels of chemokine C-C motif ligand 15 [CCL15; OR, 0.5; 95% confidence intervals (CI), 0.3–0.8; moderate versus nonregular use]; soluble vascular endothelial growth factor receptor 2 (sVEGFR2; OR, 0.7; 95% CI, 0.4–1.0); soluble tumor necrosis factor receptor 1 (sTNFR1; OR, 0.6; 95% CI, 0.4–0.9) and increased levels of CCL13 (OR, 1.3; 95% CI, 0.8–2.1); CCL17 (OR, 1.1; 95% CI, 0.7–1.9) and interleukin 4 (IL4; OR, 1.6; 95% CI, 0.9–2.8). Trends were not statistically significant following correction for multiple comparisons. Likewise, no statistically significant associations were observed between ibuprofen use and marker levels. Conclusions: No significant associations were observed between regular aspirin use and the inflammatory markers assessed. Impact: Additional studies are needed to better understand the relationship between aspirin use, chronic inflammation, and cancer risk. Cancer Epidemiol Biomarkers Prev; 24(5); 825–32. ©2015 AACR.

Background: Epidemiologic studies examining circulating levels of inflammatory markers in relation to obesity and physical inactivity may aid in our understanding of the role of inflammation in obesity-related cancers. However, previous studies on this topic have focused on a limited set of markers. Methods: We evaluated associations between body mass index (BMI) and vigorous physical activity level, based on self-report, and serum levels of 78 inflammation-related markers. Markers were measured using a bead-based multiplex method among 1,703 men and women, ages 55–74 years, and with no prior history of cancer at blood draw, and selected for case–control studies nested within the Prostate, Lung, Ovarian, and Colorectal Cancer Screening Trial. Analyses were adjusted for age, sex, smoking, case–control study, physical activity, and BMI. Results: Twelve markers were positively associated with BMI after FDR correction. ORs and 95% confidence interval (CI) for highest versus lowest levels of CCL2/MCP-1, CXCL5/ENA-78, sTNFRII, CXCL10/IP-10, CXCL6/GCP2, CCL13/MCP-4, amylin, CRP, C-peptide, CCL19/MIP-3b, insulin, and leptin were: 1.50 (1.14–1.98), 1.52 (1.12–2.05), 1.61 (1.17–2.20), 1.69 (1.25–2.28), 1.74 (1.24–2.44), 1.75 (1.22–2.50), 1.91 (1.31–2.78), 2.41 (1.36–4.25), 2.78 (1.83–4.24), 3.30 (2.28–4.78), 4.05 (2.51–6.55), and 50.03 (19.87–125.99) per 5 kg/m2, respectively. Only CXCL12/SDF-1a was associated with physical activity (≥3 vs. Conclusions: BMI was associated with a wide range of circulating markers involved in the inflammatory response. Impact: This cross-sectional analysis identified serum markers could be considered in future studies aimed at understanding the underlying mechanisms linking inflammation with obesity and obesity-related cancers. Cancer Epidemiol Biomarkers Prev; 23(12); 2840–9. ©2014 AACR.

Objective Pro-inflammatory mechanisms may explain the increased ovarian cancer risk linked to more lifetime ovulations, endometriosis, and exposure to talc and asbestos, as well as decreased risk with non-steroidal anti-inflammatory drugs. Limited data are available to estimate ovarian cancer risk associated with levels of circulating inflammatory markers. Methods We conducted a nested case–control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Pre-diagnostic serum levels of 46 inflammation-related biomarkers (11 with a priori hypotheses; 35 agnostic) were measured in 149 incident ovarian cancer cases and 149 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression and adjusted for identified covariates. Results Increased ovarian cancer risk was associated with elevated levels of C-reactive protein (CRP) [tertile (T)3 vs. T1: OR (95% CI) 2.04 (1.06–3.93), p-trend=0.03], interleukin (IL)-1α [detectable vs. undetectable: 2.23 (1.14–4.34)] and tumor necrosis factor alpha (TNF-α) [T3 vs. T1: 2.21 (1.06–4.63), p-trend=0.04]. Elevated IL-8 was non-significantly associated with risk [T3 vs. T1: 1.86 (0.96–3.61), p-trend=0.05]. In analyses restricted to serous ovarian cancer (n=83), the associations with CRP and IL-8 remained or strengthened [CRP T3 vs. T1: 3.96 (1.14–11.14), p-trend=0.008; IL-8 T3 vs. T1: 3.05 (1.09–8.51), p-trend=0.03]. Elevated levels of CRP and TNF-α remained positively associated with ovarian cancer risk in analysis restricted to specimens collected at least 5years before diagnosis (n=56). Conclusion These results suggest that CRP, IL-1α, IL-8, and TNF-α are associated with increased risk of subsequently developing ovarian cancer.

Background Several assays are used to measure type-specific serological responses to human papillomavirus (HPV), including the bead-based glutathione S-transferase (GST)-L1 multiplex serology assay and virus-like particle (VLP)-based ELISA. We evaluated the high-throughput GST-L1, which is increasingly used in epidemiologic research, as a measure of cumulative HPV infection and future immune protection among HPV-unvaccinated women. Methods We tested enrollment sera from participants in the control arm of the Costa Rica Vaccine Trial (n = 488) for HPV16 and HPV18 using GST-L1, VLP-ELISA, and two assays that measure neutralizing antibodies (cLIA and SEAP-NA). With statistical adjustment for sampling, we compared GST-L1 serostatus to established HPV seropositivity correlates and incident cervical HPV infection using odds ratios. We further compared GST-L1 to VLP-ELISA using pair-wise agreement statistics and by defining alternate assay cutoffs. Results Odds of HPV16 GST-L1 seropositivity increased with enrollment age (OR = 1.20 per year, 95%CI 1.03-1.40) and lifetime number of sexual partners (OR = 2.06 per partner, 95%CI 1.49-2.83), with similar results for HPV18. GST-L1 seropositivity did not indicate protection from incident infection over 4 years of follow-up (HPV16 adjusted OR = 1.72, 95%CI 0.95-3.13; HPV18 adjusted OR = 0.38, 95%CI 0.12-1.23). Seroprevalence by GST-L1 (HPV16 and HPV18, respectively) was 5.0% and 5.2%, compared to 19.4% and 23.8% by VLP-ELISA, giving positive agreement of 39.2% and 20.8%. Lowering GST-L1 seropositivity cutoffs improved GST-L1/VLP-ELISA positive agreement to 68.6% (HPV16) and 61.5% (HPV18). Conclusions Our data support GST-L1 as a marker of cumulative HPV infection, but not immune protection. At lower seropositivity cutoffs, GST-L1 better approximates VLP-ELISA.

Background Some patients diagnosed with early-stage lung cancer and treated according to standard care survive for only a short period of time, while others survive for years for reasons that are not well understood. Associations between markers of inflammation and survival from lung cancer have been observed. Materials and methods Here, we investigate whether circulating levels of 77 inflammatory markers are associated with long versus short survival in stage I and II lung cancer. Patients who had survived either 156 weeks (3 years) (long survivors, LS) were selected from a retrospective population-based study. Logistic regression was used to calculate adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The false discovery rate was calculated to adjust for multiple testing. Results A total of 157 LS and 84 SS were included in this analysis. Thirteen markers had adjusted OR on the order of 2- to 5-fold when comparing the upper and lower quartiles with regard to the odds of short survival versus long. Chemokine CCL15 [chemokine (C-C motif) ligand 15] was the most significant marker associated with increased odds of short survival (ORs = 4.93; 95% CI 1.90–12.8; q-value: 0.042). Smoking and chronic obstructive pulmonary disease were not associated with marker levels. Conclusions Our results provide some evidence that deregulation of inflammatory responses may play a role in the survival of early-stage lung cancer. These findings will require confirmation in future studies.

Background: Two HPV serological assays, the competitive Luminex immunoassay (cLIA), and an enzyme-linked immunoassay (ELISA) against HPV16 have been used to define HPV-naïve subcohorts within large HPV vaccination trials. Some of the variation in estimated vaccine efficacies may be due to the differences in these assays used to define the HPV-naïve subgroups. To guide the interpretation of published results, we compared these assays. Methods: Replicate enrollment sera from a stratified sample of 388 unvaccinated women from the control arm of the Costa Rica HPV 16/18 Vaccine Trial were measured for antibodies against HPV16 using cLIA and ELISA. Agreement between the assays was estimated using standard and alternative assay cutoffs. Results: Using laboratory-determined seropositivity cutoffs, sampling-adjusted HPV16 seropositivity was 24.8% by ELISA and 7.2% by cLIA. Comparing cLIA and ELISA antibody levels based on the standard cutoffs, overall agreement was 53% (positive-agreement = 49%). The poor agreement was mainly driven by the higher sensitivity of the ELISA than cLIA, resulting in 30% of the ELISA-positive sample that were cLIA-negative (none of the ELISA-negatives were cLIA-positive). Increasing ELISA cutoff to 54 ELISA units (EU)/mL (the level which maximized agreement with cLIA; ELISA standard cutoff is 8 EU/mL) resulted in higher agreement (overall agreement = 91%; positive agreement = 78%). Conclusions: ELISA and cLIA are different from each other based on the laboratory-determined cutoff. Increasing ELISA cutoff increased agreement with cLIA, which could facilitate comparisons among studies that use different assays. Impact: Keeping cLIA at the laboratory-determined cutoff but altering ELISA cutoff for seropositivity might facilitate vaccine efficacy comparisons in the naïve cohorts defined by cLIA. Cancer Epidemiol Biomarkers Prev; 21(9); 1547–54. ©2012 AACR.

PURPOSE.:TRAIL/Apo-2L is cytotoxic against numerous prostate tumor cell lines; however, some lines are more resistant than others. Identification of an agent that increases prostate tumor cell sensitivity to TRAIL/Apo-2L would prove valuable for TRAIL/Apo-2L-mediated tumor therapy. Thus, we examined the effect of combining five clinically approved chemotherapeutic agents with TRAIL/Apo-2L for treating prostate tumor cells.Four human prostate tumor cell lines were initially tested for TRAIL/Apo-2L sensitivity. Subsequent studies examined whether the TRAIL/Apo-2L-induced killing of DU-145 cells was augmented in the presence of the chemotherapeutic molecules, as measured by annexin V-FITC/propidium iodide staining. Furthermore, caspase 8 activation and BID cleavage were examined by immunoblotting. RT-PCR and flow cytometry were performed to monitor TRAIL-R1 and TRAIL-R2 levels after chemotherapeutic treatment.DU-145 cells were the least responsive of the prostate tumor cell lines tested to TRAIL/Apo-2L-induced death. Surprisingly, only topotecan, a topoisomerase I inhibitor, when used in combination with rTRAIL/Apo-2L led to significant apoptosis of DU-145 cells, as measured by caspase 8 activation, BID cleavage, and annexin V-FITC/PI staining. Topotecan alone had little to no toxicity on the DU-145 cells. Furthermore, the increase in TRAIL/Apo-2L sensitivity following topotecan treatment correlated with increased expression of TRAIL-R1 and TRAIL-R2 and decreased intracellular levels of the antiapoptotic protein survivin.Our results define a promising direction for alternative therapies against androgen-independent prostate cancers. The sensitivity of DU-145 cells to TRAIL/Apo-2L was dramatically increased when combined with topotecan, suggesting that low-dose topotecan treatment to upregulate TRAIL-R1 and TRAIL-R2 and downregulate survivin, followed by TRAIL/Apo-2L administration, may be a viable therapy for treating cancer of the prostate.

Background: Few epidemiologic studies have investigated the role of inflammation in lung cancer etiology. We have carried out 2 independent studies nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial to assess associations between circulating inflammation markers and lung cancer risk, after carefully controlling for smoking. In the discovery study, we showed associations between 11 circulating inflammation markers (CRP, SAA, sTNFRII, IL-1RA, IL-7, TGF-A, ENA 78/CXCL5, MIG/CXCL9, BCA-1/CXCL13, TARC/CCL17 and MDC/CCL22) and prospective lung cancer risk (Shiels, JNCI 2013). To assess the reproducibility of these associations, we have carried out a large, independent replication study. Methods: We designed a replication case-control study nested within the PLCO in 526 lung cancer cases and 625 controls, matched by gender, age, smoking (status, pack-years and time since quit), study visit and years of blood draw and exit. Serum levels of 51 inflammation markers were measured using Luminex bead-based assays. We combined the data from the discovery and replication studies (1052 cases and 1217 controls) and created study-specific marker categories. Conditional logistic regression was used to estimate odds ratios (ORs) overall and stratified by latency and histology in the pooled dataset. Results: In our prior study, 11 inflammation markers were associated with lung cancer risk with ORs ranging from 1.41 to 2.27. Of these 11 markers, C-reactive protein (CRP), serum amyloid A (SAA), soluble tumor necrosis factor receptor 2 (sTNFRII) and monokine induced by gamma interferon (MIG/CXCL9) were associated with prospective lung cancer risk in the replication study with ORs ranging from 1.70 to 2.09 (p-trend across quartiles3 years) (all p-interactions>0.2). Further, each marker was associated with both lung adenocarcinoma and squamous cell carcinoma (all p-trends Conclusions: With results from two independent case-control studies, we have confirmed that pre-diagnostic circulating levels of two acute phase proteins (CRP and SAA), a receptor for a pro-inflammatory cytokine (sTNFRII), and a chemokine (MIG/CXCL9) are each associated with prospective lung cancer risk, after carefully controlling for cigarette smoking. These results provide evidence implicating inflammation in the development of lung cancer. Citation Format: Meredith S. Shiels, Hormuzd A. Katki, Allan Hildesheim, Ruth M. Pfeiffer, Eric A. Engels, Marcus C. Williams, Troy J. Kemp, Neil E. Caporaso, Ligia A. Pinto, Anil K. Chaturvedi. Circulating inflammation markers and subsequent lung cancer risk: A discovery and replication study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2920. doi:10.1158/1538-7445.AM2014-2920

Background: We and other investigators have recently reported associations between elevated serum concentrations of selected immune markers and subsequent risk of non-Hodgkin lymphoma (NHL). While these findings support a role for subtle immunologic effects in lymphomagenesis, the relatively short length of follow-up after phlebotomy in these studies (10-13 years) limits the ability to rule out reverse causation as an explanation for these findings. To clarify the temporal nature of these associations, we conducted a nested case-control study investigating serum levels of six immune markers and NHL diagnosed up to 23 years after phlebotomy within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a cohort with banked fasting serum from 29,133 male Finnish smokers. Methods: We selected 272 first-primary NHL cases diagnosed 2+ years after phlebotomy, identified through linkage with the Finnish Cancer Registry, and 325 controls individually matched to cases on baseline age, phlebotomy date, and number of previous specimen thaws. Serum from these individuals were tested for soluble CD23 (sCD23), sCD27, sCD30, B cell attracting chemokine-1 (BCA-1), soluble tumor necrosis factor receptor-2 (sTNFR-2), and soluble vascular endothelial growth factor receptor-2. Odds ratios (OR) and 95% confidence intervals (CI) relating categories of analyte concentration to NHL risk were computed through conditional logistic regression with adjustment for cigarette pack-years. Polytomous regression models were also fit to compute ORs for the two most common NHL histologic subtypes, chronic lymphocytic leukemia (CLL) and diffuse large B cell lymphoma (DLBCL). Results: We observed NHL associations with elevated pre-diagnostic concentrations of the B cell activation markers sCD23 (highest analyte category vs. lowest: OR 2.4, 95% CI 1.5-3.8, Ptrend = 0.0005) and sCD30 (OR 3.3, 95% CI 1.9-5.5, Ptrend < 0.0001). The associations with sCD23 and sCD30 were apparent for cases diagnosed as far as 15-23 years after blood collection (OR 5.1, 95% CI 1.8-14.6, Ptrend = 0.002 and OR 3.7, 95% CI 1.5-9.3, Ptrend = 0.01 respectively). In subtype-specific analyses, both sCD23 and sCD30 were significantly associated with DLBCL, both overall and in later follow-up periods. sCD23 was significantly associated with CLL, particularly for earlier follow-up periods, while sCD30 was not. Associations with NHL were observed for sCD27, BCA-1, and sTNFR-2 but became weaker or null for cases diagnosed >8 years post-phlebotomy. Conclusions: Our study provides strong evidence that elevated serum sCD23 and sCD30 are associated with future risk of NHL many years after blood collection. Our findings for these B cell activation markers suggest that B cell activation is an important mechanism in NHL development in the general population. Citation Format: Mark P. Purdue, Qing Lan, Troy J. Kemp, Allan Hildesheim, Stephanie J. Weinstein, Demetrius Albanes, Ligia A. Pinto, Nathaniel Rothman. Serum sCD23 and sCD30 associated with non-Hodgkin lymphoma risk as far as 15 to 23 years after blood collection. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5073. doi:10.1158/1538-7445.AM2014-5073

Background: Based on bone marrow (BM) biopsies, increased angiogenesis has been reported in multiple myeloma (MM) and smoldering multiple myeloma (SMM) patients compared with individuals with monoclonal gammopathy of undetermined significance (MGUS). In this prospective clinical trial open for MGUS, SMM and MM patients, we conducted BM biopsies and used immunohistochemistry to define microvessel density (MVD) in every patient; results were compared to results obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and multiplex ELISA-based serum angiogenic cytokine assays. Patients and Methods: We included 10 MGUS, 10 SMM and 10 MM patients. We performed DCE-MRI of entire lumbosacral spine to compare exchange rate constants (contrast agent transit from the extravascular compartment to the intravascular compartment, Kep; movement of contrast agent from plasma to extravascular extracellular space, Ktrans) with bone marrow biopsies immunostained with CD34 as measures of MVD, and serum angiogenic markers By ELISA to include EGF, Ang2, GCSF, BMP9, endoglin, Leptin, Follistatin, IL8, HGF, HBEGF, PLGF, VEGFC, VEGFD, FGF2, VEGFA. The association among continous parameters was determined by Spearman rank correlation. Trends in continuous parameters according to ordered categorical parameter were determined by Jonckheere-Terpstra test for trend. The parameters between two groups were compared using an exact Wilcoxon rank sum test. Results: Both MVD and Kep increased along the myeloma spectrum (MGUS < SMM < MM). MVD and Kep were strongly correlated (r=0.93 and p=0.002). Ktrans was weakly to moderately well correlated with MVD (r=0.43 p=0.03). Higher Kep values were seen in MM/SMM vs. MGUS patients (median 7.1 vs. 3.9; p=0.08). Similarly, higher MVD values were seen in MM/SMM patients versus MGUS (median 20 vs. 15; p=0.01). As regards serum angiogenic markers, levels of HGF (r=0.45; p=0.02), Ang2(r=0.37 and p=0.06), and VEGFD (r=-0.35 and p=0.07), correlated with Kep. The levels of Ang2 (p=0.02), GCSF (p=0.06), follistatin (p=0.06), HGF (p=0.01), and VEGFA (p=0.02), were elevated in MM/SMM patients in comparison to MGUS. Other angiogenic cytokines did not correlate with MVD or Kep. Conclusions: MVD and Kep (measured by DCE-MRI) were highly statistically correlated. MVD increased along the disease spectrum from MGUS to SMM to MM (p=0.008). Some, but not all, angiogenic biomarkers detected in peripheral blood were associated with increased vascularity in the bone marrow. Citation Format: Manisha Bhutani, Esther Mena, Irina Maric, Esther Tan, Neha Korde, Alexandra R. Berg, Alex R. Minter, Brendan M. Weiss, Liza Lindenberg, Baris Turkbey, Omer Aras, Seth Steinberg, Troy Kemp, Katherine R. Calvo, Peter L. Choyke, Karen Kurdziel, Ola Landgren. Role of bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 369. doi:10.1158/1538-7445.AM2013-369

Background: Ovarian cancer is linked to pro-inflammatory mechanisms through its association with increased lifetime number of ovulations, pelvic inflammatory disease, endometriosis, and exposure to talc and asbestos. Exposures that directly reduce inflammation, such as non-steroidal anti-inflammatory drugs and factors that may reduce exposure to irritants, including tubal ligation and hysterectomy, have been shown to reduce ovarian cancer risk. However, limited data are available linking ovarian cancer to measurements of circulating inflammatory markers. Methods: To evaluate whether circulating levels of cytokines and other immune markers are associated with ovarian cancer risk, we conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Four Luminex based multi-plex panels were used to measure circulating levels of 60 inflammation-related biomarkers in all 150 incident ovarian cancer cases with pre-diagnostic serum samples available and 149 controls matched on age at baseline, race, date and time of day of sample collection. Serum samples were collected between 2 and 13 years before cancer diagnosis. We limited analysis to the 24 markers with at least 67% of values above the lower limit of detection and categorized the markers based on the tertile (n=2 markers) or quartile (n=22 markers) distribution in controls. Coefficients of variation for these 24 markers ranged from 1% to 13%. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression in unadjusted models and with further adjustment for parity, oral contraceptive use, menopausal hormone therapy use, cigarette smoking and body mass index. Results: In preliminary analyses, elevated serum levels of IL-8 were associated with increased risk of ovarian cancer [Q4 vs. Q1: adjusted OR 2.62 95% CI (1.15-5.95)]. Elevated serum levels of CRP and TNF-alpha were marginally associated with an increased risk [CRP Q4 vs. Q1: 2.11 (0.97-4.59); TNF-alpha Q4 vs. Q1: 2.27 (0.98-5.28)]. In analyses restricted to serous ovarian cancer, the associations with IL-8 and CRP were strengthened [IL-8 Q4 vs. Q1: 3.47 (1.04-11.55); CRP Q4 vs. Q1: 5.62 (1.54-20.56)]. Elevated IL-8, CRP and TNF-alpha levels were statistically significantly related to increased ovarian cancer risk in analysis restricted to specimens collected at least 5 years before diagnosis. Conclusions: Our preliminary results suggest a positive association between IL-8, CRP and TNF-alpha and increased ovarian cancer risk. Our findings confirm an increased risk of ovarian cancer reported for CRP. Associations between IL-8 and TNF-alpha with ovarian cancer risk have not been previously reported, but both markers have been shown to be involved in ovarian function, specifically follicle rupture and repair, and are detectable in tumor tissue from ovarian cancer patients. These findings suggest that increased inflammation is etiologically important in ovarian carcinogenesis, and argue for additional research to confirm and extend these findings. Citation Format: Britton Trabert, Ligia Pinto, Patricia Hartge, Troy Kemp, Amanda Black, Mark E. Sherman, Louise A. Brinton, Ruth Pfeiffer, Anil Chaturvedi, Allan Hildesheim, Nicolas Wentzensen. Prediagnostic serum levels of inflammation markers and risk of ovarian cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: Preliminary results. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 22.