Inflammatory response and oxidative stress during liver resection

<div><p>Background</p><p>Postoperative complications are still a major concern after liver resection (LR). Systemic inflammation and deregulated reactive oxygen species during major abdominal surgery may impair outcome after hepatectomy.</p><p>Methods</p><p>Patients undergoing LR were included in this study (n = 40). Oxidative stress (OS) was measured peri- and post-operatively as static oxidation-reduction potential markers (sORP) and antioxidant capacity ORP (cORP) by using the RedoxSYS Diagnostic system. Furthermore, Th1- and Th2-specific cytokines were assessed.</p><p>Results</p><p>Whereas there was no significant change in systemic sORP during LR and in the early postoperative course, there was a substantial decrease of cORP immediately post-surgery, and on postoperative days 1 and 3 (p<0.001). OS response was tightly regulated, as there was a significant correlation between sORP and cORP (p<0.0001; R²:0.457). An increase of OS (sORP) after LR of more than 3 mV was predictive for severe postoperative complications (53.8% vs. 12.5; p = 0.017). There was a significantly higher IL-2 (p = 0.006) and IL-5 (p = 0.001) increase during hepatectomy in patients who developed a severe morbidity.</p><p>Conclusion</p><p>Antioxidant capacity remained stable during LR but dropped during the post-surgical period, suggesting a consumption of antioxidants to maintain OS within healthy range. Severe postoperative complications were associated with a pronounced inflammatory response during surgery.</p></div

Oxidative stress (OS) during liver resection.

<p><b>(A)</b> OS measured as static oxidative reduction potential (sORP) remains relatively stable during and after liver resection. <b>(B)</b> However, capacity oxidative reduction potential (cORP) significantly decreases after surgery and on postoperative day 1 and 3 (p<0.001). <b>(C, D)</b> Both, OS and capacity in the in- and outflow of the liver (portal vein, hepatic vein) remained virtually unchanged before and after liver resection, respectively. <b>(E)</b> OS is tightly regulated, as there was a significant correlation between sORP and cORP measured systemically (p<0.0001; R²: 0.458). Data are expressed as means with standard error of the mean (SEM) and comparison was performed by using a paired t-test (A, B) or an unpaired t-test (C, D). Correlation was calculated by using the Pearson-test (D). n.s. non significant, *** p<0.001, **** p<0.0001.</p

Cytokines during liver resection.

<p>Classical Th1 (A, B) and TH2 cytokines (C, D) were measured perioperatively. Even though there was a trend towards higher values of IL-2 (A), INF-y (B), IL-4 (C), IL-5 (D) and GM-CSF (F) perioperatively, the observed differences did not reach statistical significance. (E) Patients with severe post-operative complication had significantly higher levels of IL-6, measured POD3 (24.6 (3.1) pg/ml vs. (53.7 (13.8) pg/ml; p = 0.004). Data are expressed as means with standard error of the mean (SEM) and comparison was performed by using an unpaired t-test.** p <0.01.</p

Patient characteristics and postoperative outcome.

<p>Patient characteristics and postoperative outcome.</p

Change in OS is associated with severe post-operative complication.

<p>(A) Mean sORP increase during LR was higher in patients who developed a severe post-operative complication compared to patients with no/minor post-operative complication (0.6 (3.6) mV vs. 7.4 (8.1) mV; p = 0.386). (B) Measuring the increase of OS after LR revealed a significantly increased response in patients with severe morbidity compared to patients without (-5.3 (3.3) mV vs. 10.5 (7.3) mV; p = 0.028). Data are expressed as means with standard error of the mean (SEM) and comparison was performed by using an unpaired t-test.* p<0.05.</p

Inflammatory response during and after liver resection.

<p><b>(A)</b> Mean interleukin-2 (IL-2) increase during surgery was more pronounced in patients, who developed severe postoperative complication (-5.1 (2.2) pg/ml vs. 9.8 (6.1) pg/ml; p = 0.006). <b>(B)</b> Similar to that, there was a trend towards an increased interferon-gamma (INF-y) response (p = 0.085). <b>(C, D)</b> Whereas there was only a trend towards a higher IL-4 increase during liver resection, an higher interleukin-5 (IL-5) increase during hepatectomy was predictive for severe postoperative complication (-2 (0.7) pg/ml vs. 3.2 (1.7) pg/ml; p = 0.001). <b>(E)</b> There was no significant difference regarding perioperative IL-6 increase. <b>(F)</b> Perioperative increase in granulocyte macrophage colony-stimulating factor (GM-CSF) was higher in patients with major complication compared to patients without, however the observed difference did not reach statistical significance. Data are expressed as means with standard error of the mean (SEM) and comparison was performed by using an unpaired t-test.** p<0.01.</p

Additional file 4: Table S3. of Development and verification of the PAM50-based Prosigna breast cancer gene signature assay

Accuracy estimates (ICC, Slopes, and R-squared) for all genes between nCounter and qRT-PCR. (DOC 57 kb

Additional file 11: Figure S6. of Development and verification of the PAM50-based Prosigna breast cancer gene signature assay

Distribution of the ROR scores for ABCSG8 and transATAC patient tumor samples. The limits of the boxes represent the first and third quartile and the whiskers represent +/−1.58 IQR/sqrt(n) for each of the three subtypes shown. The horizontal dashed lines illustrate the ROR cutoffs for low/intermediate and intermediate/high risk for N0 patients. Individual points are jittered for illustration purposes. (PDF 83 kb

Additional file 2: Table S2. of Development and verification of the PAM50-based Prosigna breast cancer gene signature assay

Description of FFPE breast cancer patient samples used for training and verifying the Prosigna Algorithm. (DOCX 30 kb

Additional file 10: Table S5. of Development and verification of the PAM50-based Prosigna breast cancer gene signature assay

Genes used to calculate the Prosigna proliferation score. (DOC 28 kb