Background To determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM). Methods We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990-2015). Survival after resection of CCLM from midgut origin (n=238) and hindgut origin (n=487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy. Results Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs. 27%, P<0.001; OS rate at 3 years: 46% vs. 68%, P<0.001). Independent factors associated with minor pathologic response were midgut embryonic origin (odds ratio [OR] 1.55, P=0.010), absence of bevacizumab (OR 1.42, P=0.034), and mutant RAS (OR 1.41, P=0.043). Independent factors associated with worse OS were midgut embryonic origin (hazard ratio [HR] 2.04, P<0.001), carcinoembryonic antigen value ≥5 ng/mL at hepatic resection (HR 1.46, P=0.0021), synchronous CCLM (HR 1.45, P=0.012), and mutant RAS (HR 1.43, P=0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs. 78%, P=0.003). Conclusion Compared to CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status.

TACE is a safe treatment for a highly selected population of HCC patients with PVT. Despite worse survival rates compared to PVB thrombosis, PVT in the MPV should not be considered an absolute contraindication to TACE.

Objective To determine the inflammatory effects of time-dependent exposure to the hypobaric environment of simulated aeromedical evacuation following traumatic brain injury (TBI). Methods Mice were subjected to a blunt TBI or sham injury. Righting reflex response (RRR) time was assessed as an indicator of neurologic recovery. Three or 24 h (Early and Delayed groups, respectively) after TBI, mice were exposed to hypobaric flight conditions (Fly) or ground-level control (No Fly) for 5 h. Arterial blood gas samples were obtained from all groups during simulated flight. Serum and cortical brain samples were analyzed for inflammatory cytokines after flight. Neuron specific enolase (NSE) was measured as a serum biomarker of TBI severity. Results TBI resulted in prolonged RRR time compared with sham injury. After TBI alone, serum levels of interleukin-6 (IL-6) and keratinocyte-derived chemokine (KC) were increased by 6 h post-injury. Simulated flight significantly reduced arterial oxygen saturation levels in the Fly group. Post-injury altitude exposure increased cerebral levels of IL-6 and macrophage inflammatory protein-1α (MIP-1α), as well as serum NSE in the Early but not Delayed Flight group compared to ground-level controls. Conclusions The hypobaric environment of aero-medical evacuation results in significant hypoxia. Early, but not delayed, exposure to a hypobaric environment following TBI increases the neuroinflammatory response to injury and the severity of secondary brain injury. Optimization of the post-injury time to fly using serum cytokine and biomarker levels may reduce the potential secondary cerebral injury induced by aeromedical evacuation.

CXC chemokines mediate hepatic inflammation and injury following ischemia/reperfusion (I/ R). More recently, signaling through CXC chemokine receptor-2 (CXCR2) was shown to delay liver recovery and repair after I/R injury. The chemokine receptor CXCR1 shares ligands with CXCR2, yet nothing is known about its potential role in liver pathology. In the present study, we examined the role of CXCR1 in the injury and recovery responses to I/R using a murine model. CXCR1 expression was undetectable in livers of sham-operated mice. However, after ischemia CXCR1 expression increased 24 hours after reperfusion and was maximal after 96 hours of reperfusion. CXCR1 expression was localized largely to hepatocytes. In order to assess the function of CXCR1, CXCR22/2 mice were treated with the CXCR1/CXCR2 antagonist, repertaxin. Prophylactic treatment with repertaxin had no effect on acute inflammation or liver injury. However, when repertaxin was administered 24 hours postreperfusion there was a significant increase in hepatocellular injury and a delay in recovery compared to control-treated mice. CXCR12/2 mice also demonstrated delayed recovery and regeneration after I/R when compared to wild-type mice. In vitro, hepatocytes from CXCR2 2/2 mice that were stimulated to express CXCR1 showed increased proliferation in response to ligand. Hepatocyte proliferation was decreased in CXCR1 2/2 mice in vivo. Conclusion: This is the first report to show that CXCR1 expression is induced in hepatocytes after injury. Furthermore, the data suggest that CXCR1 has divergent effects from CXCR2 and appears to facilitate repair and regenerative responses after I/R injury. (HEPATOLOGY 2011;53:261-271) I schemia/reperfusion (I/R) of the liver often occurs as a result of liver resection surgery, transplantation, and trauma, and is a primary cause of subsequent liver dysfunction.1-3 The recovery and regeneration of the liver after I/R is associated with the temporal expression of cell cycle control proteins. 4 Recent data from our laboratory has demonstrated that this process is regulated by signaling through CXC chemokine receptor-2 (CXCR2). 5 These studies demonstrated that deletion or pharmacological blockade of CXCR2 increased hepatocyte proliferation and liver regeneration in association with increased activation of the transcription factors, nuclear factor-jB (NF-jB) and signal transducer and activator of transcription-3 (STAT3). Furthermore, we showed that ligands of CXCR2 have direct, dose-dependent effects on hepatocytes to regulate cell death or proliferation. 5The ligands for CXCR2 are comprised of a subclass of CXC chemokines which possess the amino acid sequence Glu-Leu-Arg (ELR motif ) in the amino terminus.6,7 However, CXCR2 is not the only receptor for ELR þ CXC chemokines. In humans, CXC chemokine receptor-1 (CXCR1) also binds many of these ligands and has both overlapping and independent Abbreviations: ALT, alanine amino transferase; BrdU, 5-bromo-2 0 -deoxyuridine; CXCR1, CXC chemokine receptor-1; CXCR2, CXC chemokine receptor-...

Background/Aims-Our previous work suggested an important role for the peptidyl-prolyl isomerase, Pin1, in hepatic NF-κB activation and liver injury during ischemia/reperfusion (I/R). In this study, we sought to determine the function of Pin1 in the injury response to hepatic I/R.