Stephen J. Wigmore

The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection

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.

Negative Regulation of Soluble Flt-1 and Soluble Endoglin Release by Heme Oxygenase-1

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-&ggr;– and tumor necrosis factor-&agr;–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.

Association between early systemic inflammatory response, severity of multiorgan dysfunction and death in acute pancreatitis.

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.

The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer.

Cachexia is common in patients with pancreatic cancer and has been associated with persistent activation of the hepatic acute phase response and increased energy expenditure. Fatty acids have been shown to have anticachectic effects in animal models and to reduce inflammatory mediators in healthy subjects and patients with chronic inflammatory disease. Eighteen patients with unresectable pancreatic cancer received dietary supplementation orally with fish oil capsules (1 g each) containing eicosapentaenoic acid 18% and docosahexaenoic acid 12%. Anthropometric measurement, body composition analysis, and measurement of resting energy expenditure and serum C-reactive protein were performed before and after supplementation with a median of 12 g/day of fish oil. Patients had a median weight loss of 2.9 kg/month (IQR 2-4.6) prior to supplementation. At a median of 3 months after commencement of fish oil supplementation, patients had a median weight gain of 0.3 kg/month (IQR 0-0.5) (p < 0.002). Changes in weight were accompanied by a temporary but significant reduction in acute phase protein production (p < 0.002) and by stabilisation of resting energy expenditure. This study suggests a component fish oil, perhaps EPA, merits further investigation in the treatment of cancer cachexia.

Acute-phase protein response and survival duration of patients with pancreatic cancer

Background. Current methods to predict survival duration of patients with pancreatic cancer are limited. The aim of this study was to determine whether certain nutritional indices and the acute‐phase protein response are prognostic factors independent of disease stage for patients with unresectable pancreatic cancer.

Systemic inflammation, cachexia and prognosis in patients with cancer

Purpose of reviewCachexia 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. Recent findingsPro-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. SummaryPro-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.

Changes in nutritional status associated with unresectable pancreatic cancer.

Weight loss is common in patients with pancreatic cancer; however, the nature and progress of their nutritional depletion are not well documented. In this study, pre-illness weight and duration of weight loss were recorded in 20 patients with histologically confirmed unresectable cancer of the pancreas. Patients then underwent nutritional analysis at monthly intervals until death. The median period of assessment was 27 weeks (interquartile range 22.5-38.0 weeks). At the time of diagnosis, all patients had lost weight [median 14.2% (10.0-20.0%) of pre-illness stable weight], and this weight loss was progressive, increasing to a median of 24.5% by the time of the last assessment (P =0.0004). Body mass index was significantly reduced from a pre-illness median value of 24.9 kg m-2 (22.4-27.4 kg m-2) to 20.7 kg m-2 (19.5-23.6 kg m-2) at the time of diagnosis and further to 17.7 kg m-2 (16.6-23.1 kg m-2) just before death (P =0.0003). Further evidence of tissue depletion was evident from the significant reductions in lean body mass [43.4 kg (36.9-53.0 kg) to 40.1 kg (33.5-50.7 kg) P =0.008] and fat mass [12.5 kg (8.9-17.8 kg) to 9.6 kg (6.3-15.1 kg) P =0.03). This study confirms that the majority of patients with unresectable pancreatic cancer have already undergone significant weight loss by the time of diagnosis and that the natural history of this process is one of inexorable progression. These results highlight the need for selective non-toxic therapeutic intervention to attenuate cachexia and indicate that such interventions should be instituted early in the course of the disease.

Management of biliary tract complications after orthotopic liver transplantation.

Abstract:  Introduction:  Despite improved survival, biliary complications remain a significant cause of morbidity following orthotopic liver transplantation. The aim of this study was to review the incidence, treatment and optimum management pathway of biliary complications at the Scottish Liver Transplant Unit.

A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss.

SummaryThe use of megestrol acetate in the treatment of weight loss in gastrointestinal cancer patients has been disappointing. The aim of the present study was to compare the combination of megestrol acetate and placebo with megestrol acetate and ibuprofen in the treatment of weight loss in such patients. At baseline, 4–6 weeks and 12 weeks, patients underwent measurements of anthropometry, concentrations of albumin and C-reactive protein and assessment of appetite, performance status and quality of life using EuroQol-EQ-5D and EORTC QLQ-C30. Thirty-eight and 35 patients (median weight loss 18%) were randomized to megestrol acetate/placebo or megestrol acetate/ibuprofen, respectively, for 12 weeks. Forty-six (63%) of patients failed to complete the 12-week assessment. Of those evaluable at 12 weeks, there was a decrease in weight (median 2.8 kg) in the megestrol acetate/placebo group compared with an increase (median 2.3 kg) in the megestrol acetate/ibuprofen group (P < 0.001). There was also an improvement in the EuroQol-EQ-5D quality of life scores of the latter group (P < 0.05). The combination of megestrol acetate/ibuprofen appeared to reverse weight loss and appeared to improve quality of life in patients with advanced gastrointestinal cancer. Further trials of this novel regimen in weight-losing patients with hormone-insensitive cancers are warranted.

Meta-analysis of the value of somatostatin and its analogues in reducing complications associated with pancreatic surgery

The role of somatostatin and its analogues in reducing complications after pancreatic resection is controversial. This is a meta‐analysis of the evidence of benefit.