Background: Mortality in patients with acute pancreatitis is associated with the number of failing organs and the severity and reversibility of organ dysfunction. The aim of this study was to assess the significance of early systemic inflammatory response syndrome (SIRS) in the development of multiorgan dysfunction syndrome (MODS) and death from acute pancreatitis. Methods: Data for all patients with a diagnosis of acute pancreatitis between January 2000 and December 2004 were reviewed. Serum C‐reactive protein (CRP), Acute Physiology And Chronic Health Evaluation (APACHE) II scores and presence of SIRS were recorded on admission and at 48 h. Marshall organ dysfunction scores were calculated during the first week of presentation. Presence of SIRS and raised serum CRP levels on admission and at 48 h were correlated with the cumulative organ dysfunction scores in the first week. Results: A total of 759 patients with acute pancreatitis were identified, of whom 45 (5·9 per cent) died during the index admission. SIRS was identified in 162 patients on admission and was persistent in 138 at 48 h. The median (range) cumulative Marshall score in patients with persistent SIRS was significantly higher than that in patients in whom SIRS resolved and in those with no SIRS (4 (0–12), 3 (0–7) and 0 (0–9) respectively; P < 0·001). Thirty‐five patients (25·4 per cent) with persistent SIRS died from acute pancreatitis, compared with six patients (8 per cent) with transient SIRS and four (0·7 per cent) without SIRS (P < 0·001). No correlation was observed between CRP level on admission and Marshall score (P = 0·810); however, there was a close correlation between CRP level at 48 h and Marshall score (P < 0·001). Conclusion: Persistent SIRS is associated with MODS and death in patients with acute pancreatitis and is an early indicator of the likely severity of acute pancreatitis. Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Background and aims: Major liver resection incurs a risk of postoperative liver dysfunction and infection and there is a lack of objective evidence relating residual liver volume to these complications. Patients and methods: Liver volumetry was performed on computer models derived from computed tomography (CT) angioportograms of 104 patients with normal synthetic liver function scheduled for liver resection. Relative residual liver volume (%RLV) was calculated as the relation of residual to total functional liver volume and related to postoperative hepatic dysfunction and infection. Receiver operator characteristic curve analysis was undertaken to determine the critical %RLV predicting severe hepatic dysfunction and infection. Univariate analysis and multivariate logistic regression analysis were performed to delineate perioperative predictors of severe hepatic dysfunction and infection. Results: The incidence of severe hepatic dysfunction and infection following liver resection increased significantly with smaller %RLV. A critical %RLV of 26.6% was identified as associated with severe hepatic dysfunction (p<0.0001). Additionally, body mass index (BMI), operating time, and intraoperative blood loss were significant prognostic indicators for severe hepatic dysfunction. It was not possible to predict the individual risk of postoperative infection precisely by %RLV. However, in patients undergoing major liver resection, infection was significantly more common in those who developed postoperative severe hepatic dysfunction compared with those who did not (p = 0.030). Conclusions: The likelihood of severe hepatic dysfunction following liver resection can be predicted by a small %RLV and a high BMI whereas postoperative infection is more related to liver dysfunction than precise residual liver volume. Understanding the relationship between liver volume and synthetic and immune function is the key to improving the safety of major liver resection.

Background— Preeclampsia is characterized clinically by hypertension and proteinuria. Soluble Flt-1 (sFlt-1; also known as soluble vascular endothelial growth factor receptor-1 [VEGFR-1]) and soluble endoglin (sEng) are elevated in preeclampsia, and their administration to pregnant rats elicits preeclampsia-like symptoms. Heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO) exert protective effects against oxidative stimuli. Thus, we hypothesized that HO-1 upregulation may offer protection against preeclampsia by inhibiting sFlt-1 and sEng release. Methods and Results— Preeclamptic villous explants secreted high levels of sFlt-1 and sEng. Adenoviral overexpression of HO-1 in endothelial cells inhibited VEGF-mediated sFlt-1 release and interferon-γ– and tumor necrosis factor-α–induced sEng release, whereas HO-1 inhibition potentiated sFlt-1 and sEng production from endothelial cells and placental villous explants. Consistent with these findings, mice lacking HO-1 produced higher levels of sFlt-1 and sEng compared with wild-type mice. Using selective ligands (VEGF-E and placental growth factor) and a receptor-specific inhibitor (SU-1498), we demonstrated that VEGF-induced sFlt-1 release was VEGFR-2 dependent. Furthermore, CO–releasing molecule-2 (CORM-2) or CO decreased sFlt-1 release and inhibited VEGFR-2 phosphorylation. Treatment of endothelial cells with statins upregulated HO-1 and inhibited the release of sFlt-1, whereas vitamins C and E had no effect. Conclusions— The present study demonstrates that the HO-1/CO pathway inhibits sFlt-1 and sEng release, providing compelling evidence for a protective role of HO-1 in pregnancy, and identifies HO-1 as a novel target for the treatment of preeclampsia.

Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.

Cachexia remains an important cause of morbidity and mortality among cancer patients. The mechanisms underlying this syndrome remain unclear and are almost certainly multifactorial. Evidence from animal models suggests a compelling link between cachexia and inflammation, and a variety of pro-inflammatory cytokines play an integral role. This review summarizes current thinking relating to inflammation, cachexia and prognosis in cancer patients, with particular emphasis on studies relating to recent therapeutic advances. Pro-inflammatory cytokines induce the acute phase protein response, a key marker of systemic inflammation. Recent evidence has also implicated other tumour-derived mediators, such as proteolysis-inducing factor and parathyroid hormone-related peptide. In addition, systemic inflammation has been found in association with many malignancies, and has been correlated with weight loss, hypermetabolism, anorexia, and adverse prognosis. Treatments such as fish oil, monoclonal antibodies, and non-steroidal anti-inflammatory drugs, have all been utilized to attenuate systemic inflammation and influence weight loss. Recent clinical studies have suggested that eicosapentaenoic acid and cyclo-oxygenase 2 inhibitors promote weight gain and downregulate the acute phase protein response. Pro-inflammatory processes are clearly implicated in the hypermetabolism and weight loss associated with cancer-associated cachexia. In addition, the presence of systemic inflammation is now clearly linked with adverse prognosis in patients with cancer, which cannot be fully explained by the association with weight loss. Systemic inflammation remains an important area for novel therapeutic targets in combating cachexia, and eicosapentaenoic acid and cyclo-oxygenase 2 inhibitors appear to be efficacious in the armory against cachexia.