An adaptable research platform for ex vivo normothermic machine perfusion of the liver.

PURPOSE: This paper presents an assessment of a low-cost organ perfusion machine designed for use in research settings. The machine is modular and versatile in nature, built on a robotic operating system (ROS2) pipeline allowing for the addition of specific sensors for different research applications. Here we present the system and the development stages to achieve viability of the perfused organ. METHODS: The machine's perfusion efficacy was assessed by monitoring the distribution of perfusate in livers using methylene blue dye. Functionality was evaluated by measuring bile production after 90 min of normothermic perfusion, while viability was examined using aspartate transaminase assays to monitor cell damage throughout the perfusion. Additionally, the output of the pressure, flow, temperature, and oxygen sensors was monitored and recorded to track the health of the organ during perfusion and assess the system's capability of maintaining the quality of data over time. RESULTS: The results show the system is capable of successfully perfusing porcine livers for up to three hours. Functionality and viability assessments show no deterioration of liver cells once normothermic perfusion had occurred and bile production was within normal limits of approximately 26 ml in 90 min showing viability. CONCLUSION: The developed low-cost perfusion system presented here has been shown to keep porcine livers viable and functional ex vivo. Additionally, the system is capable of easily incorporating several sensors into its framework and simultaneously monitor and record them during perfusion. The work promotes further exploration of the system in different research domains.

Evaluation of A Novel Organ Perfusion Research Platform.

This paper presents a novel, low cost, organ perfusion machine designed for use in research. The modular and versatile nature of the system allows for additional sensing equipment to be added or adapted for specific use. Here we introduce the system and present its preliminary evaluation by assessing its ability to maintain a predetermined input pressure. A proportional-integral-derivative (PID) controller was implemented and tested on a porcine liver to maintain input pressure to the hepatic artery and compared to bench tests. The results confirmed the effectiveness of the controller for maintaining input through the hepatic artery (HA) in a timely manner. Clinical Relevance-Machine Perfusion (MP) is proving to be an invaluable adjunct in clinical practice. With its ongoing success in the transplant arena, we propose MP for use in research. A cost-effective, versatile system that can be modified for specific research use to test new pharmacological therapies, imaging techniques or develop simulation training would be beneficial.

Performance of image guided navigation in laparoscopic liver surgery - A systematic review.

BACKGROUND: Compared to open surgery, minimally invasive liver resection has improved short term outcomes. It is however technically more challenging. Navigated image guidance systems (IGS) are being developed to overcome these challenges. The aim of this systematic review is to provide an overview of their current capabilities and limitations. METHODS: Medline, Embase and Cochrane databases were searched using free text terms and corresponding controlled vocabulary. Titles and abstracts of retrieved articles were screened for inclusion criteria. Due to the heterogeneity of the retrieved data it was not possible to conduct a meta-analysis. Therefore results are presented in tabulated and narrative format. RESULTS: Out of 2015 articles, 17 pre-clinical and 33 clinical papers met inclusion criteria. Data from 24 articles that reported on accuracy indicates that in recent years navigation accuracy has been in the range of 8-15 mm. Due to discrepancies in evaluation methods it is difficult to compare accuracy metrics between different systems. Surgeon feedback suggests that current state of the art IGS may be useful as a supplementary navigation tool, especially in small liver lesions that are difficult to locate. They are however not able to reliably localise all relevant anatomical structures. Only one article investigated IGS impact on clinical outcomes. CONCLUSIONS: Further improvements in navigation accuracy are needed to enable reliable visualisation of tumour margins with the precision required for oncological resections. To enhance comparability between different IGS it is crucial to find a consensus on the assessment of navigation accuracy as a minimum reporting standard.

5-Aminolevulinic acid for fluorescence-guided surgery in pancreatic cancer: Cellular transport and fluorescence quantification studies.

5-Aminolevulinic acid (ALA) is a potential contrast agent for fluorescence-guided surgery in pancreatic ductal adenocarcinoma (PDAC). However, factors influencing ALA uptake in PDAC have not been adequately assessed. We investigated ALA-induced porphyrin fluorescence in PDAC cell lines CFPAC-1 and PANC-1 and pancreatic ductal cell line H6c7 following incubation with 0.25-1.0 mM ALA for 4-48 h. Fluorescence was assessed qualitatively by microscopy and quantitatively by plate reader and flow cytometry. Haem biosynthesis enzymes and transporters were measured by quantitative polymerase chain reaction (qPCR). CFPAC-1 cells exhibited intense fluorescence under microscopy at low concentrations whereas PANC-1 cells and pancreatic ductal cell line H6c7 showed much lower fluorescence. Quantitative fluorescence studies demonstrated fluorescence saturation in the two PDAC cell lines at 0.5 mM ALA, whereas H6c7 cells showed increasing fluorescence with increasing ALA. Based on the PDAC:H6c7 fluorescence ratio studies, lower ALA concentrations provide better contrast between PDAC and benign pancreatic cells. Studies with qPCR showed upregulation of ALA influx transporter PEPT1 in CFPAC-1, whereas PANC-1 upregulated the efflux transporter ABCG2. We conclude that PEPT1 and ABCG2 expression may be key contributory factors for variability in ALA-induced fluorescence in PDAC.

Comparison of manual and semi-automatic registration in augmented reality image-guided liver surgery: a clinical feasibility study.

BACKGROUND: The laparoscopic approach to liver resection may reduce morbidity and hospital stay. However, uptake has been slow due to concerns about patient safety and oncological radicality. Image guidance systems may improve patient safety by enabling 3D visualisation of critical intra- and extrahepatic structures. Current systems suffer from non-intuitive visualisation and a complicated setup process. A novel image guidance system (SmartLiver), offering augmented reality visualisation and semi-automatic registration has been developed to address these issues. A clinical feasibility study evaluated the performance and usability of SmartLiver with either manual or semi-automatic registration. METHODS: Intraoperative image guidance data were recorded and analysed in patients undergoing laparoscopic liver resection or cancer staging. Stereoscopic surface reconstruction and iterative closest point matching facilitated semi-automatic registration. The primary endpoint was defined as successful registration as determined by the operating surgeon. Secondary endpoints were system usability as assessed by a surgeon questionnaire and comparison of manual vs. semi-automatic registration accuracy. Since SmartLiver is still in development no attempt was made to evaluate its impact on perioperative outcomes. RESULTS: The primary endpoint was achieved in 16 out of 18 patients. Initially semi-automatic registration failed because the IGS could not distinguish the liver surface from surrounding structures. Implementation of a deep learning algorithm enabled the IGS to overcome this issue and facilitate semi-automatic registration. Mean registration accuracy was 10.9 ± 4.2 mm (manual) vs. 13.9 ± 4.4 mm (semi-automatic) (Mean difference - 3 mm; p = 0.158). Surgeon feedback was positive about IGS handling and improved intraoperative orientation but also highlighted the need for a simpler setup process and better integration with laparoscopic ultrasound. CONCLUSION: The technical feasibility of using SmartLiver intraoperatively has been demonstrated. With further improvements semi-automatic registration may enhance user friendliness and workflow of SmartLiver. Manual and semi-automatic registration accuracy were comparable but evaluation on a larger patient cohort is required to confirm these findings.

Evolution of dynamic, biochemical, and morphological parameters in hypothermic machine perfusion of human livers: A proof-of-concept study.

INTRODUCTION: Hypothermic machine perfusion (HMP) is increasingly investigated as a means to assess liver quality, but data on viability markers is inconsistent and the effects of different perfusion routes and oxygenation on perfusion biomarkers are unclear. METHODS: This is a single-centre, randomised, multi-arm, parallel study using discarded human livers for evaluation of HMP using arterial, oxygen-supplemented venous and non-oxygen-supplemented venous perfusion. The study included 2 stages: in the first stage, 25 livers were randomised into static cold storage (n = 7), hepatic artery HMP (n = 10), and non-oxygen-supplemented portal vein HMP (n = 8). In the second stage, 20 livers were randomised into oxygen-supplemented and non-oxygen-supplemented portal vein HMP (n = 11 and 9, respectively). Changes in dynamic, biochemical, and morphologic parameters during 4-hour preservation were compared between perfusion groups, and between potentially transplantable and non-transplantable livers. RESULTS: During arterial perfusion, resistance was higher and flow was lower than venous perfusion (p = 0.001 and 0.01, respectively); this was associated with higher perfusate markers during arterial perfusion (p>0.05). Supplementary oxygen did not cause a significant alteration in the studied parameters. Morphology was similar between static and dynamic preservation groups. Perfusate markers were 2 fold higher in non-transplantable livers (p>0.05). CONCLUSIONS: Arterial only perfusion might not be adequate for graft perfusion. Hepatocellular injury markers are accessible and easy to perform and could offer insight into graft quality, but large randomised trials are needed to identify reliable quality assessment biomarkers.

Alterations in coagulation following major liver resection.

The international normalised ratio is frequently raised in patients who have undergone major liver resection, and is assumed to represent a potential bleeding risk. However, these patients have an increased risk of venous thromboembolic events, despite conventional coagulation tests indicating hypocoagulability. This prospective, observational study of patients undergoing major hepatic resection analysed the serial changes in coagulation in the early postoperative period. Thrombin generation parameters and viscoelastic tests of coagulation (thromboelastometry) remained within normal ranges throughout the study period. Levels of the procoagulant factors II, V, VII and X initially fell, but V and X returned to or exceeded normal range by postoperative day five. Levels of factor VIII and Von Willebrand factor were significantly elevated from postoperative day one (p < 0.01). Levels of the anticoagulants, protein C and antithrombin remained significantly depressed on postoperative day five (p = 0.01). Overall, the imbalance between pro- and anticoagulant factors suggested a prothrombotic environment in the early postoperative period.

A diaphragmatic retroperitoneal cyst.

Diaphragmatic lesions are usually congenital bronchogenic cysts. A patient with a known diaphragmatic cyst presented with new onset right upper quadrant pain. Repeat imaging showed enlargement of the cyst, the CA19-9 cancer marker was raised at 312 iu/ml (normal: <27 iu/ml) and positron emission tomography combined with computed tomography showed focally increased uptake in the cystic wall. In view of symptoms and risk of neoplasia, the lesion was excised. Histology showed a benign epidermoid cyst. Features falsely suggesting neoplasia have been reported previously with benign splenic cysts but not with a benign diaphragmatic epidermoid cyst.

Outcome after surgical resection for duodenal adenocarcinoma in the UK.

BACKGROUND: Factors influencing long-term outcome after surgical resection for duodenal adenocarcinoma are unclear. METHODS: A prospectively created database was reviewed for patients undergoing surgery for duodenal adenocarcinoma in six UK hepatopancreaticobiliary centres from 2000 to 2013. Factors influencing overall survival and disease-free survival (DFS) were identified by regression analysis. RESULTS: Resection with curative intent was performed in 150 (84·3 per cent) of 178 patients. The postoperative morbidity rate for these patients was 40·0 per cent and the in-hospital mortality rate was 3·3 per cent. Patients who underwent resection had a better median survival than those who had a palliative surgical procedure (84 versus 8 months; P < 0·001). The 1-, 3- and 5-year overall survival rates for patients who underwent resection were 83·9, 66·7 and 51·2 per cent respectively. Median DFS was 53 months, and 1- and 3-year DFS rates were 80·8 and 56·5 per cent respectively. Multivariable analysis revealed that node status (hazard ratio 1·73, 95 per cent c.i. 1·07 to 2·79; P = 0·006) and lymphovascular invasion (hazard ratio 3·49, 1·83 to 6·64; P = 0·003) were associated with overall survival. CONCLUSION: Resection of duodenal adenocarcinoma in specialist centres is associated with good long-term survival. Lymphovascular invasion and nodal metastases are independent prognostic indicators.

Cost-effectiveness of early laparoscopic cholecystectomy for mild acute gallstone pancreatitis.

BACKGROUND: A recent Cochrane review suggested that laparoscopic cholecystectomy carried out early following mild gallstone pancreatitis was safe. This study compared the cost-effectiveness of laparoscopic cholecystectomy performed within 3 days of admission, during the same admission but after more than 3 days, or electively in a subsequent admission. METHODS: A model-based cost-utility analysis was performed estimating mean costs and quality-adjusted life-years (QALYs) per patient in the UK National Health Service with a 1-year time horizon. A decision tree model was constructed and populated with probabilities, outcomes and cost data from published sources for mild gallstone pancreatitis, including one-way and probabilistic sensitivity analyses. RESULTS: The costs of laparoscopic cholecystectomy performed within 3 days of admission, beyond 3 days but in the same admission, and electively in a subsequent admission were € 2748, € 3543 and € 3752 respectively; the QALYs were 0.888, 0.888 and 0.884 respectively. Early laparoscopic cholecystectomy had a 91 per cent probability of being cost-effective at the maximum willingness to pay for a QALY commonly used in the UK. It is acknowledged that many hospitals do not have access to magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography, especially at weekends, and that implementing a 3-day target is unrealistic without allocating new resources that could erode the cost-effectiveness. CONCLUSION: Performing laparoscopic cholecystectomy for mild gallstone pancreatitis within 3 days of admission is cost-effective, but may not be feasible without significant resource allocation. After 3 days there is little financial advantage to same-admission operation.

Meta-analysis of randomized clinical trials on safety and efficacy of biliary drainage before surgery for obstructive jaundice.

BACKGROUND: This meta-analysis aimed to investigate whether preoperative biliary drainage (PBD) is beneficial to patients with obstructive jaundice. METHODS: Data from randomized clinical trials related to safety and effectiveness of PBD versus no PBD were extracted by two independent reviewers. Risk ratios, rate ratios or mean differences were calculated with 95 per cent confidence intervals (c.i.), based on intention-to-treat analysis, whenever possible. RESULTS: Six trials (four using percutaneous transhepatic biliary drainage and two using endoscopic sphincterotomy) including 520 patients with malignant or benign obstructive jaundice comparing PBD (265 patients) with no PBD (255) were included in this review. All trials had a high risk of bias. There was no significant difference in mortality (risk ratio 1.12, 95 per cent c.i. 0.73 to 1.71; P = 0.60) between the two groups. Overall serious morbidity (grade III or IV, Clavien-Dindo classification) was higher in the PBD group (599 complications per 1000 patients) than in the direct surgery group (361 complications per 1000 patients) (rate ratio 1.66, 95 per cent c.i. 1.28 to 2.16; P < 0.001). Quality of life was not reported in any of the trials. There was no significant difference in length of hospital stay between the two groups: mean difference 4.87 (95 per cent c.i. -1.28 to 11.02) days (P = 0.12). CONCLUSION: PBD in patients undergoing surgery for obstructive jaundice is associated with similar mortality but increased serious morbidity compared with no PBD. Therefore, PBD should not be used routinely.

31-Phosphorus magnetic resonance spectroscopy for dynamic assessment of adenosine triphosphate levels in pancreas preserved by the two-layer method.

Cold preservation injury influences islet graft function. Reliable tools for real-time assessment of pancreas viability before islet isolation are lacking. Phosphorus magnetic resonance spectroscopy ((31)P-MRS) was used immediately after organ harvest to study rat pancreases at 4 °C to 6 °C in five randomized preservation groups: Marshall's solution, static two-layer method (TLM), continuous TLM with oxygen perfused at 0.5 L/min, and static TLM or continuous TLM both the latter following 30 minutes of warm ischemia (WI). (31)P spectra were analyzed for phosphomonoesters, inorganic phosphate (Pi) and α-, ß-and γ-nucleotide triphosphate. Intergroup rates of change of [γ-adenosine triphosphate (ATP)]/[Pi] and [ß-ATP]/[Pi] throughout preservation period were significantly different. For continuous TLM there was an increase relative to baseline (0.043 (SD0.033) h(-1) and 0.029 (0.029) h(-1), respectively) but a decrease for both static TLM (-0.023 (0.016) h(-1) and 0.015 (0.026), P < .001 and < .05, respectively) and Marshall's (-0.049 (0.025) h(-1) and -0.036 (0.019) h(-1), respectively, both P < .001) with respect to continuous TLM. Rate of decrease was similar for the Marshall's and static TLM groups. [γ-ATP]/[Pi] and [ß-ATP]/[Pi] increased with WI continuous TLM (0.008 [0.009] h(-1) and 0.007 [0.008] hr(-1), respectively) but decreased for WI static TLM (-0.018 (0.008) h(-1) and -0.014 (0.004) hr(-1), respectively, P < .001). (31)P-MRS is an effective tool for noninvasive assessment of pancreas bioenergetics. Continuous TLM preserves cellular bioenergetics and is superior to current non-perfluorocar bone based solutions for pancreas preservation.

Systematic review and meta-analysis of intraoperative versus preoperative endoscopic sphincterotomy in patients with gallbladder and suspected common bile duct stones.

BACKGROUND: Most patients with gallbladder and common bile duct stones are treated by preoperative endoscopic sphincterotomy (POES) followed by laparoscopic cholecystectomy. Recently, intraoperative endoscopic sphincterotomy (IOES) during laparoscopic cholecystectomy has been suggested as an alternative treatment. METHODS: Data from randomized clinical trials related to safety and effectiveness of IOES versus POES were extracted by two independent reviewers. Risk ratios (RRs) or mean differences were calculated with 95 per cent confidence intervals based on intention-to-treat analysis whenever possible. RESULTS: Four trials with 532 patients comparing IOES with POES were included. There were no deaths. There was no significant difference in rates of ampullary cannulation (RR 1·01, 0·97 to 1·04; P = 0·70) or stone clearance by ES (RR 0·99, 0·96 to 1·02; P = 0·58) between the groups. The proportion of patients with at least one post-ES complication, including pancreatitis, bleeding, perforation, cholangitis, cholecystitis or gastric ulcer, was significantly lower in the IOES group (RR 0·37, 0·18 to 0·78; P = 0·009). There was no significant difference in morbidity after laparoscopic cholecystectomy or requirement for open operation between the groups. Mean hospital stay was 3 days shorter in the IOES group: mean difference - 2·83 (-3·66 to - 2·00) days (P < 0·001). CONCLUSION: In patients with gallbladder and common bile duct stones, IOES is as effective and safe as POES and results in a significantly shorter hospital stay.

Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy.

BACKGROUND & AIMS: Transient elastography is a non-invasive method, for the assessment of hepatic fibrosis, developed as an alternative to liver biopsy. We studied the performance of elastography for diagnosis of fibrosis using meta-analysis. METHODS: MEDLINE, EMBASE, SCI, Cochrane Library, conference abstracts books, and article references were searched. We included studies using biopsy as a reference standard, with the data necessary to calculate the true and false positive, true and false negative diagnostic results of elastography for a fibrosis stage, and with a 3-month maximum interval between tests. The quality of the studies was rated with the QUADAS tool. RESULTS: We identified 40 eligible studies. Summary sensitivity and specificity was 0.79 (95% CI 0.74-0.82) and 0.78 (95% CI 0.72-0.83) for F2 stage and 0.83 (95% CI 0.79-0.86) and 0.89 (95% CI 0.87-0.91) for cirrhosis. After an elastography result at/over the threshold value for F2 or cirrhosis ("positive" result), the corresponding post-test probability for their presence (if pre-test probability was 50%) was 78%, and 88% respectively, while, if values were below these thresholds ("negative" result), the post-test probability was 21% and 16%, respectively. No optimal stiffness cut-offs for individual fibrosis stages were validated in independent cohorts and cut-offs had a wide range and overlap within and between stages. CONCLUSIONS: Elastography theoretically has good sensitivity and specificity for cirrhosis (and less for lesser degrees of fibrosis); however, it should be cautiously applied to everyday clinical practice because there is no validation of the stiffness cut-offs for the various stages. Such validation is required before elastography is considered sufficiently accurate for non-invasive staging of fibrosis.

Influence of zinc and zinc chelator on HT-29 colorectal cell line.

Trace elements are involved in many key pathways involving cell cycle control. The influence of zinc and zinc chelator (TPEN) on transcription levels of the main zinc transporters (ZnT1 and ZIP1) in the HT-29 colorectal cell line has not been reported. Proliferation of HT-29 cells was measured using the methylene blue assay after exposure to zinc (two concentrations), TPEN (two concentrations), or a combination of zinc and TPEN (simultaneously and sequentially) for 4 h, 8 h, and 24 h. The transcription levels of ZnT1, ZIP1, vascular endothelial growth factor (VEGF), and caspase-3 were determined using reverse transcriptase real-time polymerase chain reaction (RT-PCR) after exposure of cells to zinc and TPEN. The zinc content in the substrate (medium used for culture) was determined using atomic absorption spectrometry. TPEN decreased cellular proliferation causing complete cell death by 8 h. Zinc had a protective effect against short periods of exposure to TPEN. There was no correlation between the transcripts of main zinc transporters and the zinc content in the substrate. The zinc content in the substrate remained constant after varying periods of cell culture. TPEN decreased the transcript levels of caspase-3 and VEGF, which are surrogate markers for apoptosis and angiogenesis. Zinc chelation of HT-29 cells causes cell death. Zinc appears to be protective for short periods of exposure to TPEN but has no protective effect on prolonged exposure. HT-29 cells are not able to counteract the effect of intracellular chelation of zinc by altering zinc transport. Further research into the mechanisms of these findings is necessary and may lead to novel therapeutic options.

Biochemical indicators of in-hospital complications following pancreatic surgery.

Early recognition of complications following pancreatic surgery could reduce morbidity and mortality. White cell counts (WCCs), platelets (PLTs), C-reactive protein (CRP) and albumin (ALB) are commonly used as guides in clinical decision making. However, the evidence to support their role as early indicators of complications is unclear. A retrospective cohort analysis of consecutive pancreatic surgical procedures between 2004 and 2008 was performed. Operative procedures, inflammatory markers--WCCs, PLTs, CRP, and ALB--preoperatively and on postoperative days (PODs) 1, 3, 5, 7, 9, 12, and 15, and clinical outcomes were recorded. WCC > 11 x 10(9)/L on POD5 was significantly associated with complications [odds ratio (OR), 2.60; P = 0.0067]. ALB < 28 g/L on POD7 was significantly associated with a postoperative complication (OR, 2.94; P = 0.0031). WCC > 12.2 x 10(9)/L and ALB < or = 28 g/L on POD7 were more likely to be associated with a complication (OR, 4.86; P = 0.0002). Postoperative WCC and ALB levels may be useful as aids to the early diagnosis of complications following pancreatic surgery.

Cost-utility and value-of-information analysis of early versus delayed laparoscopic cholecystectomy for acute cholecystitis.

BACKGROUND: : A recent systematic review found early laparoscopic cholecystectomy (ELC) to be safe and to shorten total hospital stay compared with delayed laparoscopic cholecystectomy (DLC) for acute cholecystitis. The cost-effectiveness of ELC versus DLC for acute cholecystitis is unknown. METHODS: : A decision tree model estimating and comparing costs to the UK National Health Service (NHS) and quality-adjusted life years (QALYs) gained following a policy of either ELC or DLC was developed with a time horizon of 1 year. Uncertainty was investigated with probabilistic sensitivity analysis, and value-of-information analysis estimated the likely return from further investment in research in this area. RESULTS: : ELC is less costly (approximately - pound820 per patient) and results in better quality of life (+0.05 QALYs per patient) than DLC. Given a willingness-to-pay threshold of pound20 000 per QALY gained, there is a 70.9 per cent probability that ELC is cost effective compared with DLC. Full implementation of ELC could save the NHS pound8.5 million per annum. CONCLUSION: : The results of this decision analytic modelling study suggest that on average ELC is less expensive and results in better quality of life than DLC. Future research should focus on quality-of-life measures alone.

Meta-analysis of randomized controlled trials on the safety and effectiveness of early versus delayed laparoscopic cholecystectomy for acute cholecystitis.

BACKGROUND: : In many countries laparoscopic cholecystectomy for acute cholecystitis is mainly performed after the acute episode has settled because of the anticipated increased risk of morbidity and higher conversion rate from laparoscopic to open cholecystectomy. METHODS: : A systematic review was performed with meta-analysis of randomized clinical trials of early laparoscopic cholecystectomy (ELC; performed within 1 week of onset of symptoms) versus delayed laparoscopic cholecystectomy (performed at least 6 weeks after symptoms settled) for acute cholecystitis. Trials were identified from The Cochrane Library trials register, Medline, Embase, Science Citation Index Expanded and reference lists. Risk ratio (RR) or mean difference was calculated with 95 per cent confidence intervals (c.i.) based on intention-to-treat analysis. RESULTS: : Five trials with 451 patients were included. There was no significant difference between the two groups in terms of bile duct injury (RR 0.64 (95 per cent c.i. 0.15 to 2.65)) or conversion to open cholecystectomy (RR 0.88 (95 per cent c.i. 0.62 to 1.25)). The total hospital stay was shorter by 4 days for ELC (mean difference -4.12 (95 per cent c.i. -5.22 to -3.03) days). CONCLUSION: : ELC during acute cholecystitis appears safe and shortens the total hospital stay.

Assessment of risk of bias in randomized clinical trials in surgery.

BACKGROUND: Meta-analysis of randomized clinical trials (RCTs) with low risk of bias is considered the highest level of evidence available for evaluating an intervention. Bias in RCTs may overestimate or underestimate the true effectiveness of an intervention. METHODS: The causes of bias in surgical trials as described by The Cochrane Collaboration, and the methods that can be used to avoid them, are reviewed. RESULTS: Blinding is difficult in many surgical trials but careful trial design can reduce the bias risk due to lack of blinding. It is possible to conduct surgical trials with low risk of bias by using appropriate trial design. CONCLUSION: The risk of providing a treatment based on a biased effect estimate must be balanced against the difficulty of conducting trials with very low risk of bias. Better understanding of the risk of bias may result in improved trials with a closer estimate of the true effectiveness of an intervention.

Effect of portal vein embolisation on the growth rate of colorectal liver metastases.

Portal vein embolisation (PVE) is used to increase the remnant liver volume before major liver resection for colorectal metastases. The resection rate after PVE is 60-70%, mainly limited by disease progression. The effect of PVE on tumour growth rate has not been investigated. The objective of this study was to compare the growth characteristics of resected colorectal liver metastases in patients undergoing pre-operative PVE with those of matched controls who had not undergone PVE. There were 22 patients who had undergone preoperative PVE and 20 matched controls. Tumour growth rate was calculated by the change in tumour volume (CT/MRI volumetric assessment) from diagnosis to resection. Resected histological specimens were examined by two histopathologists independently for cell differentiation, percentage tumour cell necrosis and mitotic rate. Immunochemical staining with Ki67 was carried out using the MIB-1 monoclonal antibody and quantified using a Glasgow cell-counting graticule. The groups were comparable in demographics, stage of primary disease, volume of liver metastases at presentation and chemotherapy received. The tumour growth rate calculated from imaging was more rapid in the PVE group compared with that in controls (control: 0.05+/-0.25 ml day(-1), PVE: 0.36+/-0.68 ml day(-1), P=0.06). Histology showed no difference in the degree of differentiation, extent of necrosis or apoptosis between the two groups. However, mitotic rate was higher post PVE, as was the proliferation index Ki67 (P=0.04). This study has confirmed that tumour growth rate increased following PVE and that this is related to increased tumour cell division.