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.

This study found four circulating ILs that were associated with gallstones. Future studies are needed to validate the findings and evaluate the common pathway or mechanism in the development of gallbladder diseases associated with these cytokine signatures.

No abstract

Purpose We examined inflammation as a mediator of associations between bacterial infection markers and gallbladder cancer (GBC). Methods Bacterial response proteins [lipopolysaccharide (LPS), soluble CD14 (sCD14), and LPS-binding protein (LBP)] were measured in 40 GBC cases and 126 gallstone controls with data on 63 serum inflammation markers. The relationships of LPS, LBP, and sCD14 with GBC were examined by logistic regression, which also was used to evaluate whether these associations are influenced by systemic inflammation as measured by a combinatorial inflammation score. Results The third versus the first tertiles of sCD14 and of LBP were associated with an increased GBC risk [Odds Ratio (95% Confidence Interval): 5.41 (2.00–16.75) for sCD14, and 6.49 (2.24–23.79) for LBP]. sCD14 and LBP were strongly associated with inflammation score (above versus below the median), which itself was associated with a >21-fold increased risk of GBC for the third vs. first tertiles. Associations between GBC and sCD14 and LBP were markedly attenuated when the inflammation score was included in the model. While LPS was not associated with GBC or inflammation, only 35% of cases and 22% of controls had detectable levels. Conclusions These findings suggest that these LPS-pathway proteins are associated with GBC via inflammation-related pathways.

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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Telomerase reverse transcriptase (TERT) is one of two essential components of telomerase, an enzyme complex that generates and maintains telomeres. Telomerase is expressed mainly in embryonic and adult stem cells. Telomere biology has recently been implicated in the pathogenesis of a variety of diseases, and mutations in telomerase components result in a predisposition to solid malignancies. More recent findings show that TERT is not only expressed in late stage primary tumor cells and metastatic cells, but also expressed in incipient cancer stem cells and/or tumor-initiating cells, indicating that TERT has essential roles at every stage of tumorigenesis. However, the clinical benefit of a TERT (hTERT)-targeting vaccine, given as a single agent or in combination with chemotherapeutic agents, has been limited in patients with advanced cancer, possibly due to insufficient epitope coverage as well as tumor-induced immune suppression. Thus, targeting TERT in tumor-initiating cells in early stage lesions may be more effective in preventing cancer development and progression. To develop cancer preventive TERT vaccines, novel immunogenic epitopes must be first identified and evaluated in a relevant preclinical model of tumorigenesis. The goal of this project is to identify the epitopes of mouse TERT (mTERT) with high immunogenicity via epitope mapping using two approaches. The first one consists in washing off the MHC I-bound mTERT peptides (Mild Acid Elution; MAE) from the cell surface of mTERT-overexpressing cells (SPON-10-mTERT cells generated from spontaneous lung tumors developed in an A/J mouse), followed by mass spectrometry analysis. The initial mass spec analysis showed one 14-mer peptide from MAE with 22 PSMs, with a good XCorr score compared to peptide from PBS elution control with only 1 PSMs, with lower XCorr score. The second approach is to inject overlapping mTERT peptides covering the whole protein sequence in mice, and then splenocytes from these mice will be stimulated in vitro using mTERT peptide library to determine immunogenic peptides. Both approaches are in progress to identify potential mTERT epitopes. Funded by NCI Contract No. HHSN261200800001E Citation Format: Yurong Song, Jason Marshall, Sudipto Das, Thorkell Andresson, Amanda Corbel, Shizuko Sei, Robert H. Shoemaker, Ligia Pinto. Epitope mapping of mTERT for vaccine development [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 LB-173.

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.