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  • br Among pro inflammatory cytokines there has traditionally been specific

    2022-09-07


    Among pro-inflammatory cytokines, there has traditionally been specific interest in interleukin-6 (IL-6) as a biomarker for PDAC-induced cachexia. Early studies in a murine model of cachexia demonstrated a positive correlation with weight loss and increased serum IL-6 levels [7]. The abrogation of cachexia in mice with an IL-6 antibody has suggested that IL-6 may be a primary mediator of cachexia. Similarly, IL-6 levels have been reported to be elevated in the sera of subjects with PDAC-induced cachexia compared to patients without cachexia [8,9]. However, other studies have failed to find an association between circulating IL-6 and cachexia, and importantly, many studies demonstrating an association between IL-6 and cachexia have not considered differ-ences in tumor and cancer stage as potential confounding variables [10]. We and others have reported that increased serum levels of IL-6 in treatment-naïve subjects with PDAC are associated with dis-ease progression and decreased survival [11e13], but whether cachexia is associated with increased circulating IL-6 independent of these factors has not been assessed. Therefore, in the current study we sought to determine if elevated IL-6 levels in subjects with PDAC-induced cachexia is related to weight loss or simply reflective of an advanced cancer stage.  Factors associated with increased circulating IL-6 levels
    We initiated our analysis of IL-6 using a multiplex platform. Results showed that only 43/136 (31.4%) subjects had levels of Kainic acid IL-6 above the detection threshold, so data were dichoto-mized as detectable or undetectable. Detectable plasma IL-6 levels were associated with increased primary tumor size, the presence of metastases, as well as higher serum CA-19-9, AST, and absolute neutrophil counts (Table 2). Importantly, detectable plasma IL-6 levels using multiplex were not associated with the degree of weight loss (relative or absolute) at diagnosis or usual adult BMI. Comparisons remained unchanged when performing a sensitivity analysis excluding those in the surgery cohort receiving therapy prior to surgery, with the exception that differences in serum AST and absolute neutrophil counts were no longer statistically different (data not shown).
    To confirm these findings, we performed a similar analysis using a high-sensitivity ELISA detection method. Using this platform, all subjects had measurable IL-6 and were dichotomized as greater than or less than the median value (2.28 pg/mL). Subjects with high IL-6 were heavier overall, including higher usual adult BMI and BMI at diagnosis. Importantly, high IL-6 was associated with the pres-ence of metastases (Table 2). Even though subjects with high IL-6 had greater absolute weight loss at the time of diagnosis, the rates of cachexia and relative weight loss were not different be-tween the groups.
    Next, a multivariable logistic regression model was fit to assess the relationship between increased plasma IL-6 and clinical factors of interest. By multiplex, the presence of detectable plasma IL-6 levels was most strongly associated with the presence of metas-tases (OR 8.25, 95% CI 3.09e21.95, p < 0.001) (Table 3, Model 1). Although detectable plasma IL-6 was also associated with higher BMI and baseline neutrophil counts, the associated effect sizes were negligible. Similarly, the presence of metastases was strongly associated with increased IL-6 values by ELISA (OR 3.44, 95% CI 1.41e8.41, p ¼ 0.007). Otherwise, female sex, usual body weight, and AST levels were statistically significant, but had small effect sizes (Table 3, Model 2). Sensitivity analyses were performed for both models excluding subjects from cohort A (potentially resect-able subjects) with previous chemotherapy exposure, and showed similar results, including effect sizes (data not shown).