Search

Background and aimsNon-alcoholic fatty liver disease (NAFLD) is a complex trait that has a global prevalence estimated as 25%. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes.MethodsExome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison to healthy non-carriers and wild type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts. The phenotype was assessed using imaging, targeted RNA analysis and molecular expression arrays.ResultsWe identified a rare causal variant in MTTP, c.1691T>C p.I564T (rs745447480) encoding microsomal triglyceride transfer protein (MTP) associated with progressive non-alcoholic fatty liver disease, unrelated to metabolic syndrome. Although other described mutations in MTTP cause abetalipoproteinemia, neither homozygotes nor heterozygotes exhibited characteristic manifestations of this severe disease. HLCs derived from a homozygote donor had lower lipoprotein ApoB secretion, compared to wild type cells. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators and production of reactive oxygen species.ConclusionWe have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia.

Purpose The aim of this study was to compare the prognostic value of established scoring systems with early warning scores in a large cohort of patients with acute pancreatitis. Methods In patients presenting with acute pancreatitis, age, sex, American Society of Anaesthesiologists (ASA) grade, Modified Glasgow Score, Ranson criteria, APACHE II scores and early warning score (EWS) were recorded for the first 72 h following admission. These variables were compared between survivors and non-survivors, between patients with mild/moderate and severe pancreatitis (based on the 2012 Atlanta Classification) and between patients with a favourable or adverse outcome. Results A total of 629 patients were identified. EWS was the best predictor of adverse outcome amongst all of the assessed variables (area under curve (AUC) values 0.81, 0.84 and 0.83 for days 1, 2 and 3, respectively) and was the most accurate predictor of mortality on both days 2 and 3 (AUC values of 0.88 and 0.89, respectively). Multivariable analysis revealed that an EWS ≥2 was independently associated with severity of pancreatitis, adverse outcome and mortality. Conclusion This study confirms the usefulness of EWS in predicting the outcome of acute pancreatitis. It should become the mainstay of risk stratification in patients with acute pancreatitis.

Hepatic metastasectomy remains the only potentially curative treatment for colorectal liver metastases (CRLM). Some of these patients develop indeterminate pulmonary nodules (IPNs). This study aimed to compare outcomes of patients with and without IPN undergoing resection of CRLM to ascertain whether their presence is clinically significant. Cases and controls were identified from a prospectively maintained database of CRLM resections. Patients with staging radiology demonstrating IPNs were included as cases. Controls were matched to the cases by four primary factors: age, type of resection (primary or redo), clinical risk score (CRS) and chemotherapy. The median disease-free survival (DFS) and overall survival (OS) for the cases were 7.0 months (95% CI 4.8–9.2) and 28.6 months (95% CI 21.2–36.0), respectively, and 12.0 months (95% CI 10.7–13.2) and 30.5 months (95% CI 19.4–41.6) for the controls. The 1-, 3- and 5-year survival rates were 92.7, 39.7 and 0.0% for the IPN group, and 92.4, 32.9 and 21.9% for those without. In total, 60.7% of IPN patients progressed to lung metastases, of which 39.3% underwent pulmonary resections. DFS was significantly shorter in the IPN group (p = 0.022), but OS was not significantly different (p = 0.421). The presence of IPN was independently associated with a shortened DFS (p = 0.027), as was a CRS of 3 or greater (p = 0.007). This study suggests that IPN does not significantly affect OS, but may predict earlier disease recurrence. IPN presence alone should not preclude radical resection but could be used to prompt more careful post-operative surveillance to detect lung metastases at a potentially operable stage.

Up to three‐quarters of patients undergoing liver resection for colorectal liver metastases (CRLM) develop intrahepatic recurrence. Repeat hepatic resection appears to provide the optimal chance of cure for these patients. The aim of this study was to analyze short‐ and long‐term outcomes following index and repeat hepatectomy for CRLM. Clinicopathological data were obtained from a prospectively maintained database. Perioperative variables and outcomes were compared using the Chi‐squared test. Variables associated with long‐term survival following index and second hepatectomy were identified by Cox regression analyses. Over the study period, 488 patients underwent hepatic resection for CRLM, with 71 patients undergoing repeat hepatectomy. There was no significant difference in rates of morbidity (P = 0.135), major morbidity (P = 0.638), or mortality (P = 0.623) when index and second hepatectomy were compared. Performance of repeat hepatectomy was independently associated with increased overall and cancer‐specific survival following index hepatectomy. Short disease‐free interval between index and second hepatectomy, number of liver metastases >1, and resection of extrahepatic disease were independently associated with shortened survival following repeat resection. Repeat hepatectomy for recurrent CRLM offers short‐term outcomes equivalent to those of patients undergoing index hepatectomy, while being independently associated with improved long‐term patient survival.

BACKGROUND Clinical risk scores (CRS) within the context of neoadjuvant chemotherapy for colorectal liver metastases (CRLM) has not been validated. The predictive value of clinical risk scoring in patients administered neoadjuvant chemotherapy prior to liver surgery for CRLM is evaluated. METHODS A prospective database over a 15-year period (April 1999 to March 2014) was analysed. We identified two groups: A, neoadjuvant chemotherapy prior to CRLM surgery; and B, no neoadjuvant chemotherapy. RESULTS Overall median survival in groups A and B were 36 (2-137) months and 33 (2-137) months. In group A, nodal status, size, number of metastases and carcinoembryonic antigen levels were not found to be independent predictors of overall survival (OS). However, patients with a shorter disease-free interval of less than 12 months had an increased OS (P = 0.0001). Multivariate analysis of high- and low-risk scores compared against survival in group B (P < 0.05) confirms the applicability of the scoring system in traditional settings. CONCLUSION Traditional CRS are not a prognostic predictive tool when applied to patients receiving neoadjuvant chemotherapy for CRLM. Disease-free interval may be one independent variable for use in future risk score systems specifically developed for the neoadjuvant chemotherapy era.

Background S100 proteins have been implicated in various aspects of cancer, including epithelial-mesenchymal transitions (EMT), invasion and metastasis, and also in inflammatory disorders. Here we examined the impact of individual members of this family on the invasion of pancreatic ductal adenocarcinoma (PDAC) cells, and their regulation by EMT and inflammation. Methods Invasion of PDAC cells was analysed in zebrafish embryo xenografts and in transwell invasion assays. Expression and regulation of S100 proteins was studied in vitro by immunoblotting, quantitative PCR and immunofluorescence, and in pancreatic lesions by immunohistochemistry. Results Whereas the expression of most S100 proteins is characteristic for epithelial PDAC cell lines, S100A4 and S100A6 are strongly expressed in mesenchymal cells and upregulated by ZEB1. S100A4/A6 and epithelial protein S100A14 respectively promote and represses cell invasion. IL-6/11-STAT3 pathway stimulates expression of most S100 proteins. ZEB1 synergises with IL-6/11-STAT3 to upregulate S100A4/A6, but nullifies the effect of inflammation on S100A14 expression. Conclusion EMT/ZEB1 and IL-6/11-STAT3 signalling act independently and congregate to establish the expression pattern of S100 proteins, which drives invasion. Although ZEB1 regulates expression of S100 family members, these effects are masked by IL-6/11-STAT3 signalling, and S100 proteins cannot be considered as bona fide EMT markers in PDAC.

PURPOSE This study compared 2 methods of palliative stent placement, 6-monthly interval stent changes (RS), or a single-stent policy with no planned stent change (SS). RESULTS A total of 460 patients were identified. There were no significant differences in the proportion of patients requiring unplanned stent changes in the RS or SS group (22.3% vs. 22.8%). Median survival was not significantly different between the RS and SS groups, for both benign disease (96 vs. 92 mo) and malignant disease (9 vs. 6 mo). Patients undergoing unplanned stent changes had the poorest survival and the highest stent change-related complication rate. Patients with a blocked stent episode were more likely to develop further problems with stent patency, within a median interval of 2.5 months. CONCLUSIONS In carefully selected patients, a single stent may be adequate with no planned change of stent. There appears to be a clearly defined subgroup of patients who have recurrent problems with stent patency; these should have their interval exchange brought forward on a 3-monthly basis, or a self-expanding metal stent should be used.

The serine/threonine kinase Nek2 (NIMA‐related kinase 2) regulates centrosome separation and mitotic progression, with overexpression causing inductionofaneuploidyinvitro.Overexpression mayalsoenabletumourprogressionthrougheffects uponAktsignalling, celladhesionmarkersand the Wnt pathway. The objective of this study was to examine Nek2 protein expression in colorectal cancer (CRC). Nek2 protein expression was examined in a panel of CRC cell lines using Western blotting and immunofluorescence microscopy. Nek2 and beta‐catenin expression were examined by immunohistochemistry in a series of resected CRC, as well as their matched lymph node and liver metastases, and correlated with clinicopathological characteristics. Nek2 protein expression in all CRC lines examined was higher than in the immortalised colonocyte line HCEC. Nek2 overexpression was present in 86.4% of resected CRC and was significantly associated with advancing AJCC tumour stage and shortened cancer‐specific survival. Elevated Nek2 expression was maintained within all matched metastases from overexpressing primary tumours. Nek2 overexpression was significantly associated with lower tumour membranous beta‐catenin expression and higher cytoplasmic and nuclear beta‐ catenin accumulation. These data support a role for Nek2 in CRC progression and confirm potential for Nek2 inhibition as a therapeutic avenue in CRC. J. Surg. Oncol. . 2014 Wiley Periodicals, Inc.

Death from sepsis in the intensive care unit (ITU) is frequently preceded by the development of multiple organ failure as a result of uncontrolled inflammation. Treatment with ω-3 has been demonstrated to attenuate the effects of uncontrolled inflammation and may be clinically beneficial.A randomized control trial investigating the effects of parenteral ω-3 was carried out. Consecutive patients diagnosed with sepsis were entered into the study and randomized to receive either parenteral ω-3 or standard medical care only. The primary outcome measure was a reduction in organ dysfunction using the Sequential Organ Failure Assessment (SOFA) score as a surrogate marker. The secondary outcome measures were mortality, length of stay, mean C-reactive protein (CRP), and days free of organ dysfunction/failure.Sixty patients were included in the study. The baseline demographics were matched for the two cohorts. Patients treated with parenteral ω-3 were associated with a significant reduction in new organ dysfunction (Δ-SOFA 2.2 ± 2.2 vs. 1.0 ± 1.5, P = .005 and maximum-SOFA 10.1 ± 4.2 vs. 8.1 ± 3.2, P = .041) and maximum CRP (186.7 ± 78 vs. 141.5 ± 62.6, P = .019). There was no significant reduction in the length of stay between cohorts. Patients treated with ω-3 in the strata of less severe sepsis had a significant reduction in mortality (P = .042).The treatment of critically ill septic patients with parenteral ω-3 is safe. It is associated with a significant reduction in organ dysfunction. It may be associated with a reduction in mortality in patients with less severe sepsis.

Background Pancreatic cystic lesions are an increasing problem and investigation of these cysts can be fraught with difficulty. There is currently no gold standard for diagnosis or surveillance. This review was undertaken to determine the present reliability of the characterisation, assessment of malignant potential and diagnosis of pancreatic cystic lesions using available imaging modalities. Methods A Medline search using the terms ‘pancreatic’, ‘pancreas’, ‘cyst’, ‘cystic’, ‘lesions’, ‘imaging’, ‘PET’. ‘CT’, ‘MRI’ and ‘EUS’ was performed. Publications were screened to include studies examining the performance of CT, MRI, MRCP, EUS and 18-FDG PET in the determination of benign or malignant cysts, cyst morphology and specific diagnoses. Results Nineteen studies were identified that met the inclusion criteria. 18-FDG PET had a sensitivity and specificity of 57.0–94.0% and 65.0–97.0% and an accuracy of 94% in determining benign versus malignant cysts. CT had a sensitivity and specificity of 36.3–71.4% and 63.9–100% in determining benign disease but had an accuracy of making a specific diagnosis of 39.0–44.7%. MRI had a sensitivity and specificity of 91.4–100.0% and 89.7% in assessing main pancreatic duct communication. Conclusion CT is a good quality initial investigation to be used in conjunction with clinical data. MRCP can add useful information regarding MPD communication but should be used judiciously. PET may have a role in equivocal cases to determine malignancy. Further examination of CT-PET in this patient group is warranted.

Clinical risk scores (CRS) within the context of neoadjuvant chemotherapy for colorectal liver metastases (CRLM) has not been validated. The predictive value of clinical risk scoring in patients administered neoadjuvant chemotherapy prior to liver surgery for CRLM is evaluated.A prospective database over a 15-year period (April 1999 to March 2014) was analysed. We identified two groups: A, neoadjuvant chemotherapy prior to CRLM surgery; and B, no neoadjuvant chemotherapy.Overall median survival in groups A and B were 36 (2-137) months and 33 (2-137) months. In group A, nodal status, size, number of metastases and carcinoembryonic antigen levels were not found to be independent predictors of overall survival (OS). However, patients with a shorter disease-free interval of less than 12 months had an increased OS (P = 0.0001). Multivariate analysis of high- and low-risk scores compared against survival in group B (P0.05) confirms the applicability of the scoring system in traditional settings.Traditional CRS are not a prognostic predictive tool when applied to patients receiving neoadjuvant chemotherapy for CRLM. Disease-free interval may be one independent variable for use in future risk score systems specifically developed for the neoadjuvant chemotherapy era.

Background: death from sepsis in the intensive therapy unit (ITU) is frequently preceded by the development of multiple organ failure as a result of uncontrolled inflammation. Treatment with omega-3 (n-3) fatty acids (FAs), principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been demonstrated to attenuate the effects of uncontrolled inflammation and may be clinically beneficial in reducing mortality from organ dysfunction. Fish oil (FO) is a source of EPA and DHA. Methods: a randomized trial investigating the effects of parenteral (intravenous) nutrition providing FO (0.092 g EPA+DHA/kg body weight/day) was conducted. Sixty consecutive ITU patients diagnosed with sepsis were randomised to receive either once daily parenteral FO and standard medical care or standard medical care only. Results: forty one patients (21 received fish oil; 20 controls) consented to blood sampling and blood was taken on days 0, 1, 2, 3, 5, 7, 10 and 13; because of deaths, patient discharge and withdrawal of consent, the number of blood samples available for analysis diminished with time. FA composition of plasma phosphatidylcholine (PC), plasma non-esterified FAs (NEFAs) and peripheral blood mononuclear cells (PBMCs) was determined by gas chromatography. EPA and DHA were rapidly in corporated into all 3 lipid pools investigated. There was a reduction in the arachidonic acid (AA) to EPA+DHA ratio in plasma PC and NEFAs. Fewer patients died in the FO group (13.3% (n=4)) compared with the control group (26.7% (n=8)) but this difference was not significant. A reduction in the AA/(EPA+DHA) ratio in PBMCs and plasma PC was associated with significantly improved survival. Plasma PC, plasma NEFA and PBMC FA profiles are rapidly altered by FO infusion in critically ill septic patients. Conclusion: the provision of high dose n-3 FAs resulted in a rapid and significant increase in EPA and DHA and a reduction in AA/(EPA+DHA) ratio. This latter reduction is associated with improved survival

Introduction The United Kingdom’s Department of Health has identified reducing delays in patient discharge as a key aim for Health Service development. Laparoscopic cholecystectomy and laparoscopic inguinal hernia repair may be safely performed on a short stay basis, but day case rates remain low, with delays in discharge identified as a major contributing factor. Nurse-led discharge has been widely advocated to speed patient discharge across varied specialities, but objective evidence to support its use is lacking. This study aimed to assess the effectiveness of nurse-led discharge following laparoscopic surgery. Methods A retrospective comparison of doctor-led and nurse-led discharge following laparoscopic surgery was performed by analysis of two consecutive 4-month periods, prior to and following the introduction of nurse-led discharge by a laparoscopic nurse specialist. Outcomes assessed included time to discharge, reasons for delayed discharge, hospital readmissions and primary care episodes following discharge. Results A total of 128 patients were included in the study, with each discharge group containing 64 patients. Patients in the nurse-led discharge group were significantly more likely to be discharged on the day of surgery than patients in the doctor-led discharge group (17.2% vs. 4.7%; P = 0.023), with a highly significant difference in same day discharge rates noted among patients operated on during morning theatre lists (44.0% vs. 10.7%; P = 0.006). There was no significant difference between the discharge groups in readmission rates or in the number of patients seeking primary care attention following discharge. Conclusions Nurse-led discharge may speed discharge following laparoscopic surgery with no apparent detriment to patient care.

EWS is frequently used to monitor acute admissions requiring emergency surgery. This study examined preoperative early warning scoring (EWS) and its ability to predict mortality and critical care admission. Postoperative EWS was also evaluated as a predictor of mortality.Preoperative EWS, age, physiologic and operative severity (POSSUM) scores, ASA grade, and serology were compared in 280 patients undergoing emergency surgery.Two hundred eighty patients were identified with a mortality of 15%. Among the physiological scoring systems, ASA grade and POSSUM scores were the best predictors of mortality (AUC values of 0.81). EWS, APACHE II, and age were the next best predictors (AUC values of 0.70). Postoperative APACHE II and EWS both predicted mortality. EWS on day 2 postoperatively was the best overall predictor of mortality of all the variables studied (AUC value of 0.83). Survival between patients with "improving or stable" EWS and those with "deteriorating or failing to improve" EWS was also found to be significantly different (P0.001). In addition, both EWS on admission and EWS 1 h preoperatively were found to predict critical care requirement postoperatively (AUC value of 0.78).EWS can predict the need for critical care admission and mortality following emergency surgery. In particular, the progression of EWS preoperatively, that is, whether scores improve or deteriorate, is a highly significant factor in predicting survival following emergency surgery. These findings support the use of EWS in monitoring the acute surgical patient.

Background: Although endoscopic treatment of jaundice is increasingly used in the palliation of unresectable malignant disease, surgical bypass still has a role to play in this setting. This study aimed to reappraise the short-term and long-term results of combined biliary/gastric bypass (hepaticojejunostomy and gastrojejunostomy) as palliation for unresectable malignant disease. Methods: All patients undergoing simultaneous biliary and gastric bypass procedures for unresectable malignant disease between August 2000 and January 2006 were identified and outcomes reviewed. Results: One hundred and two patients underwent open surgical biliary drainage procedures for palliation of malignant disease. Underlying malignant disease included pancreatic carcinoma (n = 88), duodenal adenocarcinoma (n = 6) and distal cholangiocarcinoma (n = 3). Thirty-one of the patients underwent a planned palliative bypass procedure, the remainder being carried out after unresectable disease was identified at laparotomy. Postoperative mortality and morbidity rates were higher in the group undergoing planned bypass. During follow up, two patients developed recurrent jaundice that required transhepatic stenting and two patients developed late gastric outlet obstruction requiring refashioning of the gastrojejunostomy. Conclusion: Combined surgical biliary and gastric bypass achieved effective palliation of jaundice and gastric outlet obstruction until death in >95% of patients in this series. It remains first-line therapy in patients identified as having unresectable disease at laparotomy.

Pancreatic resection is associated with a significant morbidity. Efforts to reduce hospital stay and enhance recovery have seen the introduction of minimally invasive surgical techniques. This article reviews the current published literature on the safety and efficacy of minimally invasive surgery of the pancreas. An electronic search of the PubMed and Embase databases was performed from 1996 to May 2008 to identify all relevant publications; studies meeting predefined inclusion criteria were retrieved and analyzed using a standardized protocol. Data on the safety and efficacy of minimally invasive surgery of the pancreas were recorded and analyzed. Of 565 abstracts reviewed, 39 studies were identified as eligible for inclusion. There were 37 case series and two case control studies. Compared with open pancreatic surgery, minimally invasive pancreatic resection is similar in terms of morbidity and mortality. Blood loss and length of stay are decreased. Laparoscopic distal pancreatic resection and enucleation of insulinoma appear to be safe procedures with reduced hospital stay, though morbidity remains significant. The evidence for laparoscopic pancreaticoduodenectomy is in its infancy, but the authors feel it is unlikely that many centers will achieve sufficient case load to make the introduction of minimally invasive resection feasible.

The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, with the incidence in United Kingdom (UK) now exceeding 1000 cases per year. It is an aggressive malignancy typified by unresponsiveness to the existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though post-operative disease recurrence is common, with 5-year survival rates of less than 25% following resection. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date, p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.

Background/Aims: Due to enhanced imaging modalities, pancreatic cysts are being increasingly detected, often as an incidental finding. They comprise a wide range of differing underl

Aims With a progressively ageing population, increasing numbers of elderly patients will present with colorectal metastases and be referred for surgical resection. The aim of this study was to assess the safety of hepatic resection in patients over 70 years of age by comparing outcomes with those of a younger cohort of patients. Methods Forty-nine patients over 70 years of age who underwent hepatic resection of colorectal liver metastases were compared to 142 patients less than 70 years of age in terms of pre-, peri- and post-operative results, as well as long-term survival. Results Major resections were performed in 61% of the elderly group and 68% of the younger group. The two groups were comparable in terms of operative duration, transfusion rate, length of HDU stay and post-operative hospital stay. The elderly group had a non-significant increase in post-operative morbidity. The 30-day and 60-day/inpatient mortality rates were similar between the two groups (elderly 0% and 4%; younger 2% and 3%). Long-term disease-free survival was similar between elderly and younger patients. Conclusion This study confirms that an aggressive surgical policy towards colorectal metastases in elderly patients is associated with low peri-operative morbidity and mortality, as well as good long-term outcomes.

Background and Objectives Reactivation of the Notch signalling pathway occurs in a range of human malignancies. Previous research suggests that Notch3 is expressed in pancreatic adenocarcinomas, but neither cellular location nor association with clinical parameters has been described. The relationship between Notch3, clinical endpoints, and other proteins with potential to interact with Notch was therefore examined. Methods An immunohistochemical study was performed on human pancreatic adenocarcinoma (n = 23) and normal pancreas (n = 12), to assess expression of Notch3, cyclin D1, pAkt, STAT3 and pSTAT3. Immunohistochemical data were then correlated with clinicopathological characteristics. Results Notch3 was significantly overexpressed in the cytoplasm of 73.9% of tumours. Nuclear expression was not observed in normal pancreatic ductal tissue, but was noted in 43.5% of tumours. No tumour expressing nuclear Notch3 was resectable. There were significant correlations between expression and intracellular location of Notch3 and each of STAT3, pSTAT3 and pAkt, but not cyclin D1. Conclusion The presence of Notch3 in tumour nuclei is likely to represent functional activation of the protein, and is clearly linked to a more aggressive tumour phenotype. The correlation with STAT3, pSTAT3 and pAkt expression has not previously been described and the concurrent intracellular localisation of these proteins suggests a functional relationship between them. J. Surg. Oncol. 2008;97:63–68. © 2007 Wiley-Liss, Inc.

Pancreatic cancer has a poor prognosis. The use of drugs or natural agents which inhibit or slow down tumour growth therefore has important potential in the development of future therapies.A literature search of the PubMed and ISI Web of Science databases was undertaken to review the current data available on the alterations in signalling pathways found in pancreatic carcinogenesis, in order to identify sites that could be targeted by chemopreventive agents. Several agents of particular relevance to pancreatic cancer were identified, and their possible mechanisms of action reviewed.Chemopreventive agents such as non-steroidal anti-inflammatory drugs, green tea constituents, and antioxidants have been shown to target various steps in intracellular signalling pathways, particularly those controlling cell proliferation and survival. Work on cell lines and animal models has shown that some of these agents may be able to modulate the growth of pancreatic tumours. Initial clinical trials of some chemopreventives in pancreatic cancer have been undertaken, and have yielded mixed results, prompting the need for further studies.As the molecular pathology of pancreatic cancer becomes better understood, sites of action of chemopreventive substances have been uncovered. Several agents have shown promising results by their ability to inhibit pancreatic carcinogenesis in laboratory studies. If these effects can be successfully translated into human studies then these agents may prove to be valuable adjuvant therapies in the future.

The Early Warning Score (EWS) is a widely used general scoring system to monitor patient progress with a varying score of 0-20 in critically unwell patients. This study evaluated the EWS system compared with other established scoring systems in patients with acute pancreatitis. EWS scores were compared with APACHE scores, Imrie scores, computed tomography grading scores, and Ranson criteria for 110 admissions with acute pancreatitis. A favorable outcome was considered to be survival without intensive therapy unit admission or surgery. Nonsurvivors, necrosectomy, and critical care admission were considered adverse outcomes. EWS was the best predictor of adverse outcome in the first 24 hours of admission (receiver operating curve, 0.768). The most accurate predictor of mortality overall was EWS on day 3 of admission (receiver operating curve, 0.920). EWS correlated with duration of intensive therapy unit stay and number of ventilated days (P < 0.05) and selected those who went on to develop pancreas-specific complications such as pseudocyst or ascites. EWS of 3 or above is an indicator of adverse outcome in patients with acute pancreatitis. EWS can accurately and reliably select both patients with severe acute pancreatitis and those at risk of local complications.

Progression of malignancy is associated with invasion into surrounding normal tissues and spread, via blood vessels and lymphatic channels, to distant sites (metastasis). Metastases are responsible for 90% of cancer-related death, with opportunities for resection exceptional and long-term control with other treatment modalities uncommon. Altered expression of adhesion molecules, including cadherins and intergrins, permits cellular detachment from the primary tumour mass, through changes in adhesion specificity and direct signalling to intracellular pathways (‘inside-out’ signalling). Tumour and conscripted host cells produce matrix-degrading proteases that disrupt the architecture of surrounding tissue and release matrix-bound growth factors that support invasion. Migrating malignant cells must gain entry into the bloodstream or lymphatic vessels (intravasation), survive transport in the circulation and exit at secondary sites (extravasation). Recent studies have confirmed the importance of post-extravasation interactions between tumour cells and the new environment, including resistance to host apoptotic stimuli, to successful metastatic colonization. An important factor in cancer growth, invasion and metastasis is the recruitment of new blood vessels from the existing vasculature (angiogenesis). Tumour and host cell-derived pro-angiogenic factors bind to receptors on nearby blood vessels and induce the activation, proliferation and migration of endothelial cells towards the tumour. Angiogenesis is also crucial to metastatic growth at secondary sites. This contribution reviews current knowledge regarding the processes of angiogenesis, invasion and metastasis. Elucidation of the mechanisms underpinning these processes is imperative to allow accurate staging of patients and to permit the identification of novel therapeutic targets.

Summary Background Bacterial colonisation of indwelling medical devices by coagulase-negative staphylococci is a prevalent risk in intensive-care units. Factors determining biofilm formation and progression to catheter-related infection are incompletely understood. We postulated that administration of inotropic agents via indwelling intravenous catheters may stimulate growth and formation of biofilms by Staphylococcus epidermidis . Methods Inocula representing physiologically relevant infecting doses of S epidermidis were incubated in a minimum medium supplemented with fresh human plasma in the presence or absence of pharmacological concentrations of norepinephrine or dobutamine. Biofilm formation on polystyrene and medical-grade silicone was examined. After incubation, cultures were assessed for growth and formation of biofilms by colony counting and scanning electronmicroscopy. The production of exopolysaccharide, a major constituent of S epidermidis biofilms, was also assessed by use of immunofluorescence microscopy. Findings Incubation of S epidermidis with catecholamine inotropes in the presence of human plasma resulted in a significant increase in growth compared with control on both polystyrene and silicone surfaces, with pronounced increases in biofilm formation as visualised by scanning electronmicroscopy. Experiments with transferrin labelled with radioactive iron showed the ability of catecholamine inotropes to facilitate acquisition of iron by S epidermidis . Immunofluorescence microscopy revealed extensive exopolysaccharide production associated with S epidermidis biofilms. Interpretation The ability of catecholamine inotropic drugs to stimulate bacterial proliferation and biofilm formation may be an aetiological factor in the development of intravascular catheter colonisation and catheter-related infection. The removal of iron from transferrin for subsequent use by S epidermidis is a possible mechanism by which catecholamine inotropes stimulate bacterial growth as biofilms.

A range of prognostic cellular indices of the systemic inflammatory response, namely the neutrophil–lymphocyte ratio (NLR), derived NLR (dNLR), platelet–lymphocyte ratio (PLR), lymphocyte–monocyte ratio (LMR), combination of platelet count and neutrophil–lymphocyte ratio (COP–NLR) and prognostic nutritional index (PNI), have been developed and found to have prognostic utility across varied malignancies. The current study is the first to examine the prognostic value of these six inflammatory scores in patients with resectable colorectal liver metastases (CRLM). Data from 302 consecutive patients undergoing surgery for resectable CRLM were evaluated. The prognostic influence of clinicopathological variables and the inflammatory scores NLR, dNLR, PLR, LMR, COP–NLR and PNI upon overall survival (OS) and cancer-specific survival (CSS) were determined by log-rank analysis and univariate and multivariate Cox regression analyses. High preoperative NLR was the only inflammatory variable independently associated with shortened OS (HR 1.769, 95 % CI 1.302–2.403, P < 0.001) or CSS (HR 1.927, 95 % CI 1.398–2.655, P < 0.001) following metastasectomy. When NLR was replaced by dNLR in analyses, high dNLR was independently associated with shortened OS (HR 1.932, 95 % CI 1.356–2.754, P < 0.001) and CSS (HR 1.807, 95 % CI 1.209–2.702, P = 0.004). The inflammatory scores PLR, LMR, COP–NLR and PNI demonstrated no independent association with either overall or cancer-specific survival in the study population. Our findings support high preoperative NLR and dNLR as independent prognostic factors for poor outcome in patients undergoing CRLM resection, with prognostic value superior to other cellular-based systemic inflammatory scores.

Trauma is well recognized to result in the immediate and sustained release of stress-related neurochemicals such as the catecholamine norepinephrine. Past work has shown that in addition to their ability to function as neurotransmitters, catecholamines can also directly stimulate the growth of a number of pathogenic bacteria. The development of trauma-associated sepsis has often been linked to the ability of otherwise normal commensal bacteria to invade and penetrate the gut mucosal barrier. Therefore, the aim of our study was to examine whether catecholamines could also stimulate the growth of commensal Escherichia coli strains of the type present in the intestinal tract at the time of a traumatic event. Herein we report that the growth of a range of non-pathogenic isolates of E. coli of human and environmental origin was significantly increased in the presence of catecholamines. A primary mechanism by which catecholamines increase bacterial growth was shown to be iron removal from lactoferrin and transferrin and subsequent acquisition by bacteria. The 3,4-dihydroxybenzoyl (catechol) structure of the catecholamines was further demonstrated to be critical to iron acquisition. The synthetic catecholamine inotropes dobutamine and isoprenaline, as well as norepinephrine metabolites that retained the catechol structure were also active, whereas norepinephrine metabolites in which the catechol moiety had been modified were not. A role for catecholamine-mediated bacterial iron supply in the pathophysiology of gut-derived sepsis due to trauma is proposed.

The serine/threonine kinase Nek2 (NIMA-related kinase 2) regulates centrosome separation and mitotic progression, with overexpression causing induction of aneuploidy in vitro. Overexpression may also enable tumour progression through effects upon Akt signalling, cell adhesion markers and the Wnt pathway. The objective of this study was to examine Nek2 protein expression in colorectal cancer (CRC). Nek2 protein expression was examined in a panel of CRC cell lines using Western blotting and immunofluorescence microscopy. Nek2 and beta-catenin expression were examined by immunohistochemistry in a series of resected CRC, as well as their matched lymph node and liver metastases, and correlated with clinicopathological characteristics. Nek2 protein expression in all CRC lines examined was higher than in the immortalised colonocyte line HCEC. Nek2 overexpression was present in 86.4% of resected CRC and was significantly associated with advancing AJCC tumour stage and shortened cancer-specific survival. Elevated Nek2 expression was maintained within all matched metastases from overexpressing primary tumours. Nek2 overexpression was significantly associated with lower tumour membranous beta-catenin expression and higher cytoplasmic and nuclear beta-catenin accumulation. These data support a role for Nek2 in CRC progression and confirm potential for Nek2 inhibition as a therapeutic avenue in CRC.

Drugs commonly used in intensive care settings were assayed for their ability to affect the growth of Staphylococcus epidermidis in a minimal salts medium containing 30% serum. Of 28 compounds tested, the inotropic catecholamines adrenaline, dobutamine, dopamine, isoprenaline and noradrenaline significantly stimulated bacterial growth. These drugs, but not structurally similar compounds lacking a dihydroxybenzoyl moiety (such as tyramine, phenylephrine and salbutamol), were able to remove iron from iron-saturated transferrin and to supply transferrin-bound 55Fe to S. epidermidis cells. Similar results were observed with a range of coagulase-negative staphylococci associated with line infections, but not with Staphylococcus aureus (including MRSA).

Duplication of the gallbladder is a rare congenital abnormality. Pre-operative diagnosis is challenging and, with the almost universal use of laparoscopic cholecystectomy, the scope for missing the second intrahepatic gallbladder is increased. Here we report the use of CT cholangiography to define ductal anatomy successfully in a patient with gallbladder duplication.

In general, a surgical day case is a patient admitted for investigation or operation on a planned non-resident basis who requires facilities for recovery [1]. For these patients the proposed limit of their hospital stay is 23 hours or less [1,2]. In reality, many day surgery units (DSUs) do not operate over a 23-hour period, hence, patients requiring a hospital stay longer than planned will need transfer to a main surgical ward. The Department of Health in the UK has set a target of 75% of elective surgery to be performed as day cases, and it has been recommended that the unplanned admission rate should be less than 3% for these cases [1]. Identifying the predisposing factors contributing to unplanned admissions is vital in order to reduce costs and pressure on acute hospital beds.

A case of cholecystobronchial fistula secondary to adenomyomatosis of the gallbladder is described. A cholecystobronchial fistula is a very unusual cause of fistulation between the bronchial and biliary tree. This is only the fifth reported case in the English language literature.

60] in VOG (p = NS). Duration of surgical procedure was 349141 minutes [150e820], 375161 minutes [90e800] and 315153 minutes [115e745] in YG, OG and VOG, respectively (p = NS). Intraoperative blood transfusions were 245510 mL [0e3300], 262506 mL [0e2500] and 168327 mL [0e1200] in YG, OG and VOG, respectively (p = NS). Postoperative hospital stay was 10.384.17 days [6e33], 11.217.79 days [6e68] and 10.246.29 days [4e 32] respectively (p = NS). Postoperative complications were 13.13%, 19.56% and 17.24% in YG, OG and VOG respectively (p = NS). Two patients died, one in OG and one in VOG groups, respectively (p = NS). Conclusions: Advanced age should not be considered a deterrent for liver resection in patients with CRLM.

OBJECTIVE To ascertain the best management options for patients presenting with gallbladder polyps. DESIGN Retrospective case-note analysis. SETTING Tertiary referral teaching hospital practice. PATIENTS Patients with ultrasonography-detected gallbladder polyps. INTERVENTIONS Ultrasonography surveillance or surgery. MAIN OUTCOME MEASURES Demographic data and size and number of polyps were recorded as well as size increase and histological findings. Detection rates for potentially neoplastic and frankly neoplastic polyps were recorded and compared with complication rates from cholecystectomy. Cost-effectiveness of ultrasonography surveillance was examined. RESULTS Nine hundred eighty-six patients were identified and 467 patients underwent further follow-up. Only 6.6% of polyps exhibited an increase in size over the surveillance period. Polyps that subsequently progressed in size on surveillance had a significantly greater diameter at first presentation than those polyps that remained static (7 mm vs 5 mm, respectively) (P lt; .05). Only 3.7% of resected polyps had malignant or potentially malignant histology. Size greater than 10 mm and increase in size during surveillance predicted neoplastic potential. CONCLUSIONS A surveillance with or without selective surgery policy could potentially detect and prevent 5.4 gallbladder cancers per 1000 individuals per year with a cost saving of more than £130 000 (US $201 676) per year. Cancer prevention benefits would exceed the risk ratios from cholecystectomy complications. Polyps greater than 10 mm should be resected; those between 5 and 10 mm should be under ultrasonography surveillance.

The role of laparoscopy in staging periampullary malignancies is to detect small-volume metastatic disease not visible on preoperative imaging. Owing to improvements in preoperative imaging, some centers no longer undertake routine laparoscopic staging, whereas others still find it a useful pre-exploration tool.This study investigated the diagnostic yield of staging laparoscopies in 137 consecutive potentially resectable patients with periampullary malignancies. Serology on presentation, tumor size on computed tomography and proinflammatory markers such as C-reactive protein, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and Glasgow Prognostic Score were also examined to see if they were able to identify patients more likely to benefit from staging laparoscopy.Laparoscopy identified occult disease in 16.1% of the patients. Only tumor diameter on cross-sectional imaging was related to an increase in diagnostic yield on staging laparoscopy. Area-under-curve values for tumor size and occult disease at laparoscopy were 0.8, with P = 0.0001.Staging laparoscopy is a useful adjunct to computed tomography in staging periampullary cancers. Tumor size (especially45 mm) is the only preoperative marker predictive of unexpected occult disease and may be used to select high-risk patients for laparoscopic staging.

Background Postoperative complications are associated with a poor long-term prognosis after resection of colorectal liver metastases via an undetermined mechanism. The preoperative systemic inflammatory response, itself a predictor of poor survival, was recently shown to independently predict postoperative infectious complications after primary colorectal cancer resection. Objective To examine the association of postoperative infectious complications with preoperative systemic inflammation and survival in patients undergoing resection of colorectal liver metastases. Design Retrospective study based on a prospectively updated database. Setting A United Kingdom tertiary referral hepatobiliary unit. Patients A total of 202 consecutive patients with colorectal liver metastases undergoing hepatectomy between January 1, 2000, and April 30, 2006. Main Outcome Measures Multivariable analyses were performed to correlate preoperative and operative variables with postoperative complications and to correlate complications with long-term survival after metastasectomy. Results Ninety-day mortality and morbidity were 2.0% and 25.7%, respectively. The preoperative systemic inflammatory response independently predicted the development of infectious complications ( P = .009) and major infectious complications ( P = .005) after hepatectomy, along with performance of trisectionectomy. Infectious complications were associated with poor long-term survival after metastasectomy but lost independent significance when systemic inflammatory variables were included in multivariable analyses. Conclusions The preoperative systemic inflammatory response independently predicts the development of infectious complications after colorectal liver metastases resection. Although infectious complications are associated with adverse long-term prognosis after hepatectomy, they lacked independent prognostic value when systemic inflammatory variables were also considered, suggesting that much of their prognostic value arises from their association with the preoperative systemic inflammatory response.

Serological proinflammatory markers such as C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have been associated with reduced survival for many different types of cancer. This study determined the prognostic value of the preoperative value of these markers in patients with resectable pancreatic adenocarcinoma. Consecutive patients who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma were entered into our database from 2001 to the present day. CRP, NLR, and PLR at the time of presentation were recorded as well as overall and disease-free survival. Seventy-four patients were identified. Overall median survival was 35.0 months and median disease-free survival was 27.0 months. Follow-up ranged from 1 to 125.8 months. Preoperative NLR was significantly greater in those patients who developed recurrence in the follow-up period (4.5 vs. 3.1). CRP and PLR were not found to differ significantly between the two groups. Kaplan-Meier survival analysis of patients with NLR > 5 demonstrated a disease-free survival of 12 months compared with 52 months for those patients with NLR < 5 (p

The United Kingdom's Department of Health has identified reducing delays in patient discharge as a key aim for Health Service development. Laparoscopic cholecystectomy and laparoscopic inguinal hernia repair may be safely performed on a short stay basis, but day case rates remain low, with delays in discharge identified as a major contributing factor. Nurse-led discharge has been widely advocated to speed patient discharge across varied specialities, but objective evidence to support its use is lacking. This study aimed to assess the effectiveness of nurse-led discharge following laparoscopic surgery.A retrospective comparison of doctor-led and nurse-led discharge following laparoscopic surgery was performed by analysis of two consecutive 4-month periods, prior to and following the introduction of nurse-led discharge by a laparoscopic nurse specialist. Outcomes assessed included time to discharge, reasons for delayed discharge, hospital readmissions and primary care episodes following discharge.A total of 128 patients were included in the study, with each discharge group containing 64 patients. Patients in the nurse-led discharge group were significantly more likely to be discharged on the day of surgery than patients in the doctor-led discharge group (17.2% vs. 4.7%; P = 0.023), with a highly significant difference in same day discharge rates noted among patients operated on during morning theatre lists (44.0% vs. 10.7%; P = 0.006). There was no significant difference between the discharge groups in readmission rates or in the number of patients seeking primary care attention following discharge.Nurse-led discharge may speed discharge following laparoscopic surgery with no apparent detriment to patient care.

In order to maximise patient care, assessment of the adequacy of the service provision by the Clinical Nurse Specialist (CNS) must be regularly undertaken. This study attempted to determine whether CNSs were providing an adequate service via retrospective and prospective audit. The results of a comprehensive audit of the work of the CNS within a tertiary referral Hepatobiliary Unit are presented. The audit involved postal and telephone questionnaires as well as prospective collection of data. The majority of responses from patients were positive, with many finding the CNS a useful and well-utilised contact. Overall, the CNSs performed well in each of their designated tasks; however, areas were still identified which could be further improved. Audit is essential in providing feedback to the CNS and to identify areas which require improvement. The CNS has evolved to meet a clinical gap in patient care, and as a result, the role of a CNS is frequently nebulous or poorly defined. This renders evaluation of the CNS problematic and fraught with difficulties. However, a thorough assessment can still be made using carefully constructed audit looking at each task of the CNS.

In patients in whom attempted endoscopic stenting of malignant biliary obstruction fails, combined percutaneous–endoscopic stenting and percutaneous stenting using expandable metallic endoprostheses offer alternative approaches to biliary drainage. Despite the popularity of the percutaneous route, there is no available evidence to support its superiority over combined stenting in this patient group. The objective of this study was to present the short- and long-term results of a large series of combined percutaneous–endoscopic stenting procedures and identify factors associated with adverse outcome. Data were retrospectively collected on patients undergoing combined percutaneous–endoscopic biliary stenting for malignant biliary obstruction between January 2002 and December 2006. Short- and long-term outcomes were recorded, and pre-procedure variables correlated with adverse outcome. Combined biliary stenting was technically successful in 102 (96.2%) of 106 patients. Procedure-associated mortality rate was 0%. In-hospital morbidity and mortality rates were 24.5% and 16.7%, respectively, with the majority of deaths resulting from biliary sepsis. Median survival was 100 days, with a 13.7% stent occlusion rate. On multivariable analysis, baseline American Society of Anaesthesiologists (ASA) grade, decreasing serum albumin and increasing leucocyte count were independently associated with in-hospital mortality following combined stenting. Combined biliary stenting is associated with short- and long-term outcomes equal to those reported in recent series of percutaneous transhepatic stenting. Randomised control trials, including cost-effectiveness analyses, are required to further compare these techniques. Outcomes following combined stenting may be further improved by early recognition and treatment of sepsis and scrupulous management of co-morbid disease.

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and the incidence is rising. Surgery, including transplantation resection, is currently the most effective treatment for HCC; however, recurrence rates are high and long-term survival is poor. Identifying novel chemopreventive and chemotherapeutic agents and targeting them to patients at high risk of developing HCC or following curative treatment may go some way towards improving prognosis. This review examines current knowledge regarding the chemopreventive and chemotherapeutic potential of phytochemicals in heptocarcinogenesis. Both in-vitro and animal studies demonstrate that several phytochemicals, including curcumin, resveratrol, green tea catechins, oltipraz and silibinin, possess promising chemopreventive and chemotherapeutic properties. Despite this, very few clinical trials have been performed. Problems regarding validation of biomarkers, agent delivery, side effects and patient selection are barriers that need to be overcome to determine the potential of such agents in clinical practice.

Objectives Early Warning Scores (EWS) is a widely used scoring system monitoring patient progress, which we have previously shown to predict outcome from acute pancreatitis. This study examined EWS from a larger group of patients to confirm if this predictive value held true. Methods The EWS scores were compared with the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, modified organ dysfunction scores, Imrie scores, computed tomography grading scores, and Ranson criteria for 181 admissions with acute pancreatitis. The accuracy of EWS in predicting outcome was determined by receiver operator characteristics. Results A total of 181 patients were identified with acute pancreatitis. On day 1 of admission, APACHE II scores were the most accurate predictor of mortality with an area under curve (AUC) values of 0.876, closely followed by EWS (AUC, 0.827). By day 2 and 3 after admission, the EWS was the most accurate predictor of mortality (AUC, 0.910 and 0.934, respectively). The APACHE II was the second most accurate scoring system at 48 and 72 hours (AUC, 0.892 and 0.911, respectively). Conclusions The EWSs on days 2 and 3 after admission are sensitive and specific in predicting mortality from acute pancreatitis. It is as accurate as the APACHE II scores and easier to implement in daily practice.

Introduction Early warning scores (EWS) is a physiological scoring system measured hourly. This study determined how progression of EWS affected outcome in acute pancreatitis. Methods The single worst EWS score for each 24 h period following admission was recorded for 110 patients with acute pancreatitis. Scores falling below 3 were defined as improving; scores which remained at 3 or rising were considered deteriorating. Results Deteriorating EWS values were associated with a greatly increased risk of mortality (p Conclusion Deteriorating EWS values within the 48 h from admission are associated with adverse outcome or death in acute pancreatitis. Measuring progression of EWS over 72 h from admission can further improve accuracy of this monitoring system for acute pancreatitis.

Background. There is no consensus regarding the optimum surgical approach to gallbladder cancer. This study reviews the management of gallbladder cancer in a single unit. Methods. Retrospective study of 73 consecutive patients diagnosed with gallbladder cancer. Twenty-three patients underwent surgery with curative intent (surgical group), 28 patients underwent exploratory surgery but had inoperable disease (surgically inoperable group) and 22 patients had inoperable disease radiologically (radiologically inoperable group). Within the surgical group, nine patients (cholecystectomy group) were diagnosed with gallbladder cancer after routine cholecystectomy. Results. The inoperable groups had significantly higher bilirubin and alkaline phosphatase (ALP) than the surgical group (p=0.02 and p68, white cell count (WCC)>7.6×109/L, platelet>345×109/L, bilirubin>16 mol/L, ALP >124 iu/L and sodium =137mmol/L were markers of inoperability. Age, haemoglobin and neutrophil:lymphocyte ratio (NLR) were predictors for survival following surgery (p=0.04, p=0.01 and p