Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING: Cancer Research UK.

Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.

BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. FUNDING: Cancer Research UK and Roche.

Prospective evaluation of the International Study Group for Liver Surgery definition of post hepatectomy liver failure after liver resection: an international multicentre study.

BACKGROUND: The International Study Group for Liver Surgery (ISGLS) definition of post hepatectomy liver failure (PHLF) was developed to be consistent, widely applicable, and to include severity stratification. This international multicentre collaborative study aimed to prospectively validate the ISGLS definition of PHLF. METHODS: 11 HPB centres from 7 countries developed a standardised reporting form. Prospectively acquired anonymised data on liver resections performed between 01 July 2010 and 30 June 2011 was collected. A multivariate analysis was undertaken of clinically important variables. RESULTS: Of the 949 patients included, 86 (9%) met PHLF requirements. On multivariate analyses, age ≥70 years, pre-operative chemotherapy, steatosis, resection of >3 segments, vascular reconstruction and intraoperative blood loss >300 ml significantly increased the risk of PHLF. Receiver operator curve (ROC) analysis of INR and serum bilirubin relationship with PHLF demonstrated post-operative day 3 and 5 INR performed equally in predicting PHLF, and day 5 bilirubin was the strongest predictor of PHLF. Combining ISGLS grades B and C groups resulted in a high sensitivity for predicting mortality compared to the 50-50 rule and Peak bilirubin >7 mg/dl. CONCLUSIONS: The ISGLS definition performed well in this prospective validation study, and may be the optimal definition for PHLF in future research to allow for comparability of data.

Proposed standards for reporting outcomes of treating biliary injuries.

BACKGROUND: There is no standard nor widely accepted way of reporting outcomes of treatment of biliary injuries. This hinders comparison of results among approaches and among centers. This paper presents a proposal to standardize terminology and reporting of results of treating biliary injuries. METHODS: The proposal was developed by an international group of surgeons, biliary endoscopists and interventional radiologists. The method is based on the concept of "patency" and is similar to the approach used to create reporting standards for arteriovenous hemodialysis access. RESULTS: The group considered definitions and gradings under the following headings: Definition of Patency, Definition of Index Treatment Periods, Grading of Severity of Biliary Injury, Grading of Patency, Metrics, Comparison of Surgical to Non Surgical Treatments and Presentation of Case Series. CONCLUSIONS: A standard procedure for reporting outcomes of treating biliary injuries has been produced. It is applicable to presenting results of treatment by surgery, endoscopy, and interventional radiology.

Patterns of progression, treatment of progressive disease and post-progression survival in the New EPOC study.

BACKGROUND: The addition of cetuximab (CTX) to perioperative chemotherapy (CT) for operable colorectal liver metastases resulted in a shorter progression-free survival. Details of disease progression are described to further inform the primary study outcome. METHODS: A total of 257 KRAS wild-type patients were randomised to CT alone or CT with CTX. Data regarding sites and treatment of progressive disease were obtained for the 109 (CT n=48, CT and CTX n=61) patients with progressive disease at the cut-off date for analysis of November 2012. RESULTS: The liver was the most frequent site of progression (CT 67% (32/48); CT and CTX 66% (40/61)). A higher proportion of patients in the CT and group had multiple sites of progressive disease (CT 8%, 4/48; CT and CTX 23%, 14/61 P=0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further CT, most frequently irinotecan based. Twenty-two patients, 11 in each arm, received CTX as a further line agent. CONCLUSIONS: Both the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.

Guidelines for Perioperative Care for Liver Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) is a multimodal pathway developed to overcome the deleterious effect of perioperative stress after major surgery. In colorectal surgery, ERAS pathways reduced perioperative morbidity, hospital stay and costs. Similar concept should be applied for liver surgery. This study presents the specific ERAS Society recommendations for liver surgery based on the best available evidence and on expert consensus. METHODS: A systematic review was performed on ERAS for liver surgery by searching EMBASE and Medline. Five independent reviewers selected relevant articles. Quality of randomized trials was assessed according to the Jadad score and CONSORT statement. The level of evidence for each item was determined using the GRADE system. The Delphi method was used to validate the final recommendations. RESULTS: A total of 157 full texts were screened. Thirty-seven articles were included in the systematic review, and 16 of the 23 standard ERAS items were studied specifically for liver surgery. Consensus was reached among experts after 3 rounds. Prophylactic nasogastric intubation and prophylactic abdominal drainage should be omitted. The use of postoperative oral laxatives and minimally invasive surgery results in a quicker bowel recovery and shorter hospital stay. Goal-directed fluid therapy with maintenance of a low intraoperative central venous pressure induces faster recovery. Early oral intake and mobilization are recommended. There is no evidence to prefer epidural to other types of analgesia. CONCLUSIONS: The current ERAS recommendations were elaborated based on the best available evidence and endorsed by the Delphi method. Nevertheless, prospective studies need to confirm the clinical use of the suggested protocol.

A multicentre, prospective, randomized, controlled trial comparing EVARREST™ fibrin sealant patch to standard of care in controlling bleeding following elective hepatectomy: anatomic versus non-anatomic resection.

BACKGROUND: This multicentre, randomized clinical trial assessed the safety and effectiveness of the EVARREST™ Fibrin Sealant Patch (FP) in treating parenchymal bleeding following anatomic and non-anatomic liver resections. METHODS: One hundred and two patients were stratified according to the type of hepatic resection (anatomic/non-anatomic), and randomized (1:1) after identification of an appropriate bleeding site, to FP vs Standard of Care (SoC, manual compression ± topical haemostat). The primary endpoint was haemostasis at 4 min from bleeding site identification with no re-bleeding requiring re-treatment. RESULTS: The FP was superior in achieving haemostasis at 4 min (96%, 48/50) to SoC (46%, 24/52; p < 0.001). Stratification for resection type showed treatment differences for primary endpoint for anatomic (24/25 FP vs 13/23 SoC; p = 0.001) and non-anatomic liver resections (24/25FP vs 11/29 SoC; p < 0.001). Adverse events related to the study procedure were reported in 40/50 patients (80%) in the FP group and 43/52 patients (83%) in the SoC group. One (2%) adverse event (infected intra-abdominal fluid collection) was possibly related to study treatment. CONCLUSION: This clinical trial confirms that the FP is safe and highly effective in controlling parenchymal bleeding following hepatectomy regardless of the type of resection. ClinicalTrials.gov NCT01993888.

Lung ultrasonography as a direct measure of evolving respiratory dysfunction and disease severity in patients with acute pancreatitis.

BACKGROUND: The value of lung ultrasonography in the diagnosis of respiratory dysfunction and severity stratification in patients with acute pancreatitis (AP) was investigated. METHODS: Over a 3-month period, 41 patients (median age: 59.1 years; 21 males) presenting with a diagnosis of potential AP were prospectively recruited. Each participant underwent lung ultrasonography and the number of comet tails was linked with contemporaneous clinical data. Group comparisons, areas under the curve (AUC) and respective measures of diagnostic accuracy were investigated. RESULTS: A greater number of comet tails were evident in patients with respiratory dysfunction (P = 0.021), those with severe disease (P < 0.001) and when contemporaneous and maximum CRP exceeded 100 mg/L (P = 0.048 and P = 0.003 respectively). Receiver-operator characteristic plot area under the curve (AUC) was greater when examining upper lung quadrants, using respiratory dysfunction and AP severity as variables of interest (AUC = 0.783, 95% C.I.: 0.544-0.962, and AUC = 0.996, 95% C.I.: 0.982-1.000, respectively). Examining all lung quadrants except for the lower lateral resulted in greater AUCs for contemporaneous and maximum CRP (AUC = 0.708, 95% C.I.: 0.510-0.883, and AUC = 0.800, 95% C.I.: 0.640-0.929). DISCUSSION: Ultrasonography of non-dependent lung parenchyma can reliably detect evolving respiratory dysfunction in AP. This simple bedside technique shows promise as an adjunct to severity stratification.

Prospective evaluation of the International Study Group for Liver Surgery definition of bile leak after a liver resection and the role of routine operative drainage: an international multicentre study.

BACKGROUND: The International Study Group for Liver Surgery (ISGLS) proposed a definition for bile leak after liver surgery. A multicentre international prospective study was designed to evaluate this definition. METHODS: Data collected prospectively from 949 consecutive patients on specific datasheets from 11 international centres were collated centrally. RESULTS: Bile leak occurred in 69 (7.3%) of patients, with 31 (3.3%), 32 (3.4%) and 6 (0.6%) classified as grade A, B and C, respectively. The grading system of severity correlated with the Dindo complication classification system (P < 0.001). Hospital length of stay was increased when bile leak occurred, from a median of 7 to 15 days (P < 0.001), as was intensive care stay (P < 0.001), and both correlated with increased severity grading of bile leak (P < 0.001). 96% of bile leaks occurred in patients with intra-operative drains. Drain placement did not prevent subsequent intervention in the bile leak group with a 5-15 times greater risk of intervention required in this group (P < 0.001). CONCLUSION: The ISGLS definition of bile leak after liver surgery appears robust and intra-operative drain usage did not prevent the need for subsequent drain placement.

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial.

BACKGROUND: Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of oxaliplatin and fluorouracil chemotherapy. The addition of cetuximab to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype. We aimed to assess the benefit of addition of cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis. METHODS: Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour (one or more of: ≥ 4 metastases, N2 disease, or poor differentiation of primary tumour), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m(2) intravenously over 2 h and fluorouracil bolus 400 mg/m(2) intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m(2) repeated every 2 weeks (regimen one) or oxaliplatin 130 mg/m(2) intravenously over 2 h and oral capecitabine 1000 mg/m(2) twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m(2) intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given as an intravenous dose of 500 mg/m(2) every 2 weeks with regimen one and three or a loading dose of 400 mg/m(2) followed by a weekly infusion of 250 mg/m(2) with regimen two. The primary endpoint was progression-free survival. This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria. This trial is registered, ISRCTN22944367. FINDINGS: 128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with cetuximab between Feb 26, 2007, and Nov 1, 2012. 117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis. The median follow-up was 21.1 months (95% CI 12.6-33.8) in the chemotherapy alone group and 19.8 months (12.2-28.7) in the chemotherapy plus cetuximab group. With an overall median follow-up of 20.7 months (95% CI 17.9-25.6) and 123 (58%) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus cetuximab group than in the chemotherapy alone group (14.1 months [95% CI 11.8-15.9] vs 20.5 months [95% CI 16.8-26.7], hazard ratio 1.48, 95% CI 1.04-2.12, p=0.030). The most common grade 3 or 4 adverse events were low neutrophil count (15 [11%] preoperatively in the chemotherapy alone group vs six [4%] in the chemotherapy plus cetuximab group; four [4%] vs eight [8%] postoperatively), embolic events (six [4%] vs eight [6%] preoperatively; two [2%] vs three [3%] postoperatively), peripheral neuropathy (six [4%] vs one [1%] preoperatively; two [2%] vs four [4%] postoperatively), nausea or vomiting (four [3%] vs six [4%] preoperatively; four [4%] vs two [2%] postoperatively), and skin rash (two [1%] vs 21 [15%] preoperatively; 0 vs eight [8%] postoperatively). There were three deaths in the chemotherapy plus cetuximab group (one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism) and one in the chemotherapy alone group (heart failure) that might have been treatment related. INTERPRETATION: Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended.

Early organ dysfunction affects long-term survival in acute pancreatitis patients.

BACKGROUND: The effect of early organ dysfunction on long-term survival in acute pancreatitis (AP) patients is unknown. OBJECTIVE: The aim of this study was to ascertain whether early organ dysfunction impacts on long-term survival after an episode of AP. METHODS: A retrospective analysis was performed using survival data sourced from a prospectively maintained database of patients with AP admitted to the Royal Infirmary of Edinburgh during a 5-year period commencing January 2000. A multiple organ dysfunction syndrome (MODS) score of ≥ 2 during the first week of admission was used to define early organ dysfunction. After accounting for in-hospital deaths, long-term survival probabilities were estimated using the Kaplan-Meier test. The prognostic significance of patient characteristics was assessed by univariate and multivariate analyses using Cox's proportional hazards methods. RESULTS: A total of 694 patients were studied (median follow-up: 8.8 years). Patients with early organ dysfunction (MODS group) were found to have died prematurely [mean survival: 10.0 years, 95% confidence interval (CI) 9.4-10.6 years] in comparison with the non-MODS group (mean survival: 11.6 years, 95% CI 11.2-11.9 years) (log-rank test, P = 0.001) after the exclusion of in-hospital deaths. Multivariate analysis confirmed MODS as an independent predictor of long-term survival [hazard ratio (HR): 1.528, 95% CI 1.72-2.176; P = 0.019] along with age (HR: 1.062; P < 0.001), alcohol-related aetiology (HR: 2.027; P = 0.001) and idiopathic aetiology (HR: 1.548; P = 0.048). CONCLUSIONS: Early organ dysfunction in AP is an independent predictor of long-term survival even when in-hospital deaths are accounted for. Negative predictors also include age, and idiopathic and alcohol-related aetiologies.

Distance learning improves attainment of professional milestones in the early years of surgical training.

OBJECTIVES: To assess the impact of a surgical sciences e-learning programme in supporting the academic development of surgical trainees during their preparation for professional examination. BACKGROUND: In 2007, a 3-year online part-time Master of Surgical Sciences (MSc) degree programme was launched, utilizing an innovative platform with virtual case scenarios based on common surgical conditions addressed by the curriculum relating to the Membership Examination of the Royal Colleges of Surgeons (MRCS). Multiple-choice questions with feedback and discussion boards facilitated by expert clinical tutors provided formative assessment. Summative assessment comprised written examination at the end of each of the first 2 years (equivalent to MRCS level), culminating in submission of a research dissertation in year 3 toward an MSc. METHODS: Students' age, gender, and level at entry to the programme were documented. Anonymized student feedback from 2008 to 2012 was examined using online questionnaires, and performance in the MSc programme was compared to MRCS examination outcomes for students who had consented to release of their results. RESULTS: A total of 517 surgical trainees from 40 countries were recruited over the 6-year period, and 116 MSc students have graduated to date. Of 368 students, 279 (76%) were foundation doctors (interns) and had not commenced formal surgical training on enrolling in the MSc programme. However, level at entry did not influence performance (P > 0.05 across all 3 years). Average pass rates since the programme launched, for those students completing all of the required assessments, were 84% ± 11% in year 1, 85% ± 10% in year 2, and 88% ± 7% in year 3 of the MSc programme. MSc students had significantly higher MRCS pass rates than nonenrolled trainees (67% vs 51%, P < 0.01, n = 352). There was a significant correlation between MRCS examination performance and overall performance in the MSc (R = 58%; P < 0.01, n = 37). Of 248 respondents, 202 (81%) considered that the MSc would improve their chances of gaining a surgical training post, and 224 (90%) would recommend the programme to their peers. CONCLUSIONS: The online MSc programme supports academic development of trainees in the early years of surgical training, is well received by students, and is associated with improved success in their professional examination.

Increasing survival of hepatocellular carcinoma patients in Scotland: a review of national cancer registry data.

OBJECTIVES: This study describes changes in the survival of patients with hepatocellular carcinoma (HCC) registered with the Scottish Cancer Registry between 1985 and 2008. METHODS: Data on patients diagnosed with HCC were extracted from the Scottish Cancer Registry, along with linked data on treatment and risk factors for liver disease. One-, 3- and 5-year relative survival rates were calculated for each time period and a Cox regression model was used to assess the impact of prior admissions on survival. RESULTS: The incidence of HCC increased between 1985 and 2008. The proportion of patients with prior alcohol-related admissions rose over the time period studied from 16.0% to 27.1%. Five-year relative survival increased in women between 1985-1989 and 2005-2007 from 0.5% [95% confidence interval (CI) 0.0-3.7] to 10.6% (95% CI 5.2-18.1). In men, 5-year relative survival increased from 0.4% (95% CI 0.2-2.2) to 4.4% (95% CI 1.5-9.9). Regression analysis showed that older age, history of alcohol-related admissions and deprivation were associated with lower survival, and hospitalization for viral hepatitis was associated with higher survival. CONCLUSIONS: Against the background of an increasing incidence of HCC in Scotland, survival times have increased substantially.

A phase III, randomized, controlled, superiority trial evaluating the fibrin pad versus standard of care in controlling parenchymal bleeding during elective hepatic surgery.

INTRODUCTION: Haemostasis after liver resection may be difficult to achieve as a result of the presence of challenging bleeding, the anatomic landscape of the liver and the quality of tissue making up the hepatic parenchyma. The fibrin pad (FP) is a topical absorbable haemostat designed to be effective in a variety of tissues and across multiple bleeding intensities. This is the first clinical trial to evaluate the hemostat's safety and effectiveness in controlling bleeding during elective hepatic resection. METHODS: This prospective, randomized, controlled superiority trial enrolled 104 subjects undergoing elective hepatectomy in 5 countries. After parenchymal transection, subjects with an appropriately defined target bleeding site (TBS) were stratified according to the type of hepatic parenchyma and immediately randomized 1:1: FP versus Standard of Care (SoC). SoC comprised manual compression with the use of an approved topical absorbable haemostat. The primary endpoint was haemostasis at 4 min from identification of the TBS, with no re-bleeding requiring re-treatment prior to abdominal closure. Results were stratified for both normal and abnormal (steatosis or cirrhosis) hepatic parenchyma. All subjects were followed for 60 days post-operatively. RESULTS: The intent-to-treat (ITT) analysis showed an overall treatment difference of 53.0% (P < 0.001), 82.5% (33/40 FP) versus 29.5% (13/44 SoC) in achieving haemostasis at 4 min with no re-bleeding requiring treatment up to wound closure. The per protocol analysis showed an overall treatment difference of 65.7% (P < 0.001), with 33/35 successes (94.3%) in the FP group and 12/42 in the SoC group (28.6%). The stratification results showed treatment differences between the normal parenchyma group, 63.6% (95.8% FP versus 32.3% SoC P < 0.001) and a larger difference of 72.7% in the abnormal parenchyma group (90.9% FP versus 18.2% SoC P = 0.0003). Post-operative intra-abdominal fluid collections were less frequent in the FP group (3.4% FP versus 13.3% SoC P = 0.059). There was no difference in the safety profile between the FP or SoC groups. CONCLUSIONS: The FP is safe and effective when used as an adjunct to achieve haemostasis during hepatic surgery. The success rate of achieving haemostasis with a FP remained high compared with the SOC group, especially in steatotic or cirrhotic liver tissue where the control success rates diminish. In addition, FP treatment of hepatic parenchymal surfaces may reduce the risk of post-operative biliary and fluid collections.

Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis.

Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1ß to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.

Randomized clinical trial of local infiltration plus patient-controlled opiate analgesia vs. epidural analgesia following liver resection surgery.

OBJECTIVES: Epidural analgesia is recommended for the provision of analgesia following major abdominal surgery. Continuous local anaesthetic wound infiltration may be an effective alternative. A prospective randomized trial was undertaken to compare these two methods following open liver resection. The primary outcome was length of time required to fulfil criteria for discharge from hospital. METHODS: Patients undergoing open liver resection were randomized to receive either epidural (EP group) or local anaesthetic wound infiltration plus patient-controlled opiate analgesia (WI group) for the first 2 days postoperatively. All other care followed a standardized enhanced recovery protocol. Time to fulfil discharge criteria, pain scores, physical activity measurements and complications were recorded. RESULTS: Between August 2009 and July 2010, 65 patients were randomized to EP (n = 32) or WI (n = 33). The mean time required to fulfil discharge criteria was 4.5 days (range: 2.5-63.5 days) in the WI group and 6.0 days (range: 3.0-42.5 days) in the EP group (P = 0.044). During the first 48 h following surgery, pain scores were significantly lower in the EP group both at rest and on movement. Resting pain scores within both groups were rated as mild (range: 0-3). There was no significant difference between the groups in time to first mobilization or overall complication rate (48.5% in the WI group vs. 58.1% in the EP group; P = 0.443). CONCLUSIONS: Local anaesthetic wound infiltration combined with patient-controlled opiate analgesia reduces the length of time required to fulfil criteria for discharge from hospital compared with epidural analgesia following open liver resection. Epidural analgesia provides superior analgesia, but does not confer benefits in terms of faster mobilization or recovery.

Factors in perioperative care that determine blood loss in liver surgery.

OBJECTIVES: Excessive blood loss during liver surgery contributes to postoperative morbidity and mortality and the minimizing of blood loss improves outcomes. This study examines pre- and intraoperative factors contributing to blood loss and identifies areas for improvement. METHODS: All patients who underwent elective hepatic resection between June 2007 and June 2009 were identified. Detailed information on the pre- and perioperative clinical course was analysed. Univariate and multivariate analyses were used to identify factors associated with intraoperative blood loss. RESULTS: A total of 175 patients were studied, of whom 95 (54%) underwent resection of three or more segments. Median blood loss was 782 ml. Greater blood loss occurred during major resections and prolonged surgery and was associated with an increase in postoperative complications (P= 0.026). Peak central venous pressure (CVP) of >10 cm H(2)O was associated with increased blood loss (P= 0.01). Although no differences in case mix were identified, blood loss varied significantly among anaesthetists, as did intraoperative volumes of i.v. fluids and transfusion practices. CONCLUSIONS: This study confirms a relationship between CVP and blood loss in hepatic resection. Intraoperative CVP values were higher than those described in other studies. There was variation in the intraoperative management of patients. Collaboration between surgical and anaesthesia teams is required to minimize blood loss and the standardization of intraoperative anaesthesia practice may improve outcomes following liver surgery.

Implementation of an enhanced recovery programme following pancreaticoduodenectomy.

OBJECTIVES: The aim of this prospective study was to investigate the implementation of an enhanced recovery after surgery (ERAS) programme following pancreaticoduodenectomy (PD). METHODS: Patients undergoing PD were managed according to an ERAS protocol. Outcome measures included postoperative mortality, morbidity, hospitalization and 30-day readmission rate. Key protocol targets were: nasogastric tube (NGT) removal [postoperative day (PoD) 1]; resumption of oral fluids (PoD 1); urinary catheter removal (PoD 3); high-dependency unit (HDU) discharge (PoD 3); tolerating diet (PoD 4); drain removal (PoD 5), and hospital discharge (PoD 6). RESULTS: Data were collected for 50 patients (24 male; median age 67 years). Rates of mortality, morbidity and readmission were 4%, 46% and 4%, respectively. The median length of postoperative hospitalization was 10 days. The proportions of patients achieving key targets were: 78% for NGT removal; 82% for resumption of oral fluids; 48% for urinary catheter removal; 82% for HDU discharge; 86% for tolerating diet; 84% for meeting mobility targets, and 72% for drain removal. One patient was discharged by PoD 6, eight patients by PoD 7, 15 patients by PoD 8 and 26 patients (52%) by PoD 10. Discharge was delayed in 16 patients for social or transport-related reasons. CONCLUSIONS: The ERAS protocol was implemented safely. Achieving certain targets was challenging. Non-medical causes remain a significant factor in delayed discharge following PD.

Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study.

PURPOSE: The BILCAP study described a modest benefit for capecitabine as adjuvant therapy for curatively resected biliary tract cancer (BTC), and capecitabine has become the standard of care. We present the long-term data and novel exploratory subgroup analyses. METHODS: This randomized, controlled, multicenter, phase III study recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer after resection with curative intent and an Eastern Cooperative Oncology Group performance status of < 2. Patients were randomly assigned 1:1 to receive oral capecitabine (1,250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation. The primary outcome was overall survival (OS). This study is registered with EudraCT 2005-003318-13. RESULTS: Between March 15, 2006, and December 4, 2014, 447 patients were enrolled; 223 patients with BTC resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. At the data cutoff of January 21, 2021, the median follow-up for all patients was 106 months (95% CI, 98 to 108). In the intention-to-treat analysis, the median OS was 49.6 months (95% CI, 35.1 to 59.1) in the capecitabine group compared with 36.1 months (95% CI, 29.7 to 44.2) in the observation group (adjusted hazard ratio 0.84; 95% CI, 0.67 to 1.06). In a protocol-specified sensitivity analysis, adjusting for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59 to 0.94). We further describe the prognostic impact of R status, grade, nodal status, and sex. CONCLUSION: This long-term analysis supports the previous analysis, suggesting that capecitabine can improve OS in patients with resected BTC when used as adjuvant chemotherapy after surgery and should be considered as the standard of care.

Study on the feasibility of provision of distance learning programmes in surgery to Malawi.

Medical educational opportunities and resources are considerably limited in the developing world. The expansion of computing and Internet access means that there exists a potential to provide education to students through distance learning programmes. This study investigated the feasibility of providing distance learning course in surgery in Malawi. The study investigated the user requirements, technical requirements and Internet connections in two teaching hospitals in Malawi. In addition the appropriateness of current course material from the Edinburgh Surgical Sciences Qualification to Malawi trainees was assessed. The study found a high degree of interest from Malawian trainees in distance learning. The provision of basic science modules such as anatomy and physiology and the ability to access journals were considered highly desirable. The current ESSQ course would require extensive re-modelling to make it suitable to an African trainee's requirements. Internet speeds remain slow and access is currently expensive. There is considerable interest in distance learning programmes in Malawi but access to them is limited partly because of slow and expensive Internet access. Understanding the needs of trainees in countries such as Malawi will allow better direction of educational aid and resources to support surgical training.