Altered ANG/TIE gene expression in advanced ovarian cancer is not accompanied by disproportionate body water accumulation relative to perioperative fluid balance

Vollständiger Abstract

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Abstract Abdominal cytoreductive surgery due to advanced-stage ovarian cancer (OC) often requires extensive fluid administration to stabilize hemodynamic conditions. Recently, systemic changes in the expression profile of Angiopoietin (ANG)/TIE axis genes have been demonstrated in those patients, raising the question whether they exhibit an inherent clinical phenotype associated with vascular dysfunction and leakage that may explain the significant perioperative fluid demands. Abdominal muscle tissue gene expression analysis as well as pre- and postoperative whole-body bioelectrical impedance analysis (BIA) in patients with OC ( n = 20) and in control subjects ( n = 16) were performed, and Total Body Water (TBW), Extracellular Water (ECW) and the ECW/TBW ratio were calculated. Intraoperative management comprised advanced hemodynamic monitoring and goal-directed therapy. Data are given as median values with interquartile range (IQR). Postoperative fluid balance normalized to duration of surgery was greater in OC group (11.2 (IQR 9.8–13.2) vs. 8.3 mL/min (6.3–10.8) in controls, p = 0.01), as was the maximum body weight-adjusted norepinephrine administration rate ( p < 0.001), whereas the intraoperative fluid administration rate did not differ between groups ( p = 0.29). Gene expression analysis revealed significantly increased ANG-2/1 and ANG-2/TIE2 expression ratios in peripheral muscle tissue from OC patients ( p < 0.01), while additional markers of angiogenesis, endothelial activation, adhesion, and vascular barrier integrity showed no significant intergroup differences. ANG-2/1 gene expression ratio was significantly associated with postoperative fluid balance in the whole cohort ( r = 0.54, p < 0.001). There were no pre- or postoperative intergroup differences in TBW, ECW and in the ECW/TBW ratio. However, intraoperative percentage increase in BIA parameters was significantly more pronounced in the OC group, compared to controls (TBW: 12.3 (9.9–14.6) vs. 8.1% (5.2–9.0), p < 0.001; ECW: 21.7 (17.1–25.9) vs. 15.5% (11.0–18.1), p < 0.001; ECW/TBW: 8.7 (7.7–10.4) vs. 6.9% (5.1–8.5), p = 0.006). Importantly, the relationships between perioperative fluid balance and changes in TBW, ECW and ECW/TBW ratio did not differ between groups (group × fluid balance interactions: p = 0.614, p = 0.511, and p = 0.545, respectively). In contrast, these BIA-derived changes increased progressively with longer duration of surgery in OC patients but not in controls, resulting in significant group × duration of surgery interactions ( p = 0.030, p = 0.018, and p = 0.037, respectively). Patients with advanced-stage OC exhibited altered ANG/TIE gene-expression profiles, greater vasopressor requirements, and a distinct time-dependent pattern of perioperative body-water accumulation during cytoreductive surgery. However, BIA did not demonstrate a disproportionate increase in body water relative to positive fluid balance compared with controls. Thus, the observed alterations in ANG/TIE gene expression were not accompanied by a detectable systemic vascular leakage phenotype using BIA.