Hyperlactatemia in patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest: Risk factors and its effects on the outcome.

INTRODUCTION: To determine the risk factors of hyperlactatemia in pulmonary endarterectomy (PEA) surgery and assess whether elevated blood lactate levels are associated with adverse outcomes. METHODS: In this retrospective observational study, a total of 111 consecutive patients who underwent PEA for chronic thromboembolic pulmonary hypertension at the XXX Hospital between December 2016 and January 2022 were included. We retrospectively evaluated arterial blood samples analyzed intraoperatively. The pre- and intraoperative risk factors for hyperlactatemia and the postoperative outcomes were recorded. RESULTS: Lactate levels gradually increased during surgery. The optimal cut-off lactate level for major postoperative complications, calculated using receiver operating characteristic analysis, was 7.0 mmol/L. Deep hypothermic circulatory arrest (DHCA) duration, nadir hematocrit, and preoperative pulmonary vascular resistance were risk factors for lactate levels >7 mmol/L. Moreover, the intraoperative peak lactate level during PEA under DHCA was found to be a statistically significant predictor of major complications being associated with longer mechanical ventilation time (r = 0.294; p = .003) and intensive care unit length of stay (r = 0.327; p = .001). CONCLUSIONS: Deep hypothermic circulatory arrest duration, nadir hematocrit, and preoperative pulmonary vascular resistance were associated with hyperlactatemia. Increased lactate levels were independent predictors of longer mechanical ventilation time, intensive care unit length of stay, and major complications.

CT-707, a Novel FAK Inhibitor, Synergizes with Cabozantinib to Suppress Hepatocellular Carcinoma by Blocking Cabozantinib-Induced FAK Activation.

Hepatocellular carcinoma is among the leading causes of cancer-related deaths worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met inhibitor, cabozantinib, and a novel FAK inhibitor, CT-707, exerted synergistic antitumor effects against hepatocellular carcinoma in vitro and in vivo Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the antitumor activity of cabozantinib. The simultaneous exposure to CT-707 effectively inhibited the activation of FAK that was induced by cabozantinib, which contributes to the synergistic effect of the combination. Furthermore, cabozantinib increased the mRNA and protein levels of integrin α5, which is a canonical upstream of FAK, and the introduction of cilengitide to block integrin function could abrogate FAK activation by cabozantinib, indicating that cabozantinib upregulated the phosphorylation of FAK in an integrin-dependent manner. Similar synergy was also observed on PHA-665752, another selective MET inhibitor, indicating that this observation might be a common characteristic of MET-targeting strategies. Our findings not only favor the development of the novel FAK inhibitor CT-707 as a therapeutic agent against hepatocellular carcinoma but also provide a new strategy of combining MET and FAK inhibitors to potentiate the anticancer activities of these two types of agents for treating hepatocellular carcinoma patients. Mol Cancer Ther; 15(12); 2916-25. ©2016 AACR.