Safe Cholecystectomy Multi-society Practice Guideline and State of the Art Consensus Conference on Prevention of Bile Duct Injury During Cholecystectomy.

BACKGROUND: BDI is the most common serious complication of laparoscopic cholecystectomy. To address this problem, a multi-society consensus conference was held to develop evidenced-based recommendations for safe cholecystectomy and prevention of BDI. METHODS: Literature reviews were conducted for 18 key questions across 6 broad topics around cholecystectomy directed by a steering group and subject experts from 5 surgical societies (Society of Gastrointestinal and Endoscopic Surgeons, Americas Hepato-Pancreato-Biliary Association, International Hepato-Pancreato-Biliary Association, Society for Surgery of the Alimentary Tract, and European Association for Endoscopic Surgery). Evidence-based recommendations were formulated using the grading of recommendations assessment, development, and evaluation methodology. When evidence-based recommendations could not be made, expert opinion was documented. A number of recommendations for future research were also documented. Recommendations were presented at a consensus meeting in October 2018 and were voted on by an international panel of 25 experts with greater than 80% agreement considered consensus. RESULTS: Consensus was reached on 17 of 18 questions by the guideline development group and expert panel with high concordance from audience participation. Most recommendations were conditional due to low certainty of evidence. Strong recommendations were made for (1) use of intraoperative biliary imaging for uncertainty of anatomy or suspicion of biliary injury; and (2) referral of patients with confirmed or suspected BDI to an experienced surgeon/multispecialty hepatobiliary team. CONCLUSIONS: These consensus recommendations should provide guidance to surgeons, training programs, hospitals, and professional societies for strategies that have the potential to reduce BDIs and positively impact patient outcomes. Development of clinical and educational research initiatives based on these recommendations may drive further improvement in the quality of surgical care for patients undergoing cholecystectomy.

Safe cholecystectomy multi-society practice guideline and state-of-the-art consensus conference on prevention of bile duct injury during cholecystectomy.

BACKGROUND: Bile duct injury (BDI) is the most common serious complication of laparoscopic cholecystectomy. To address this problem, a multi-society consensus conference was held to develop evidenced-based recommendations for safe cholecystectomy and prevention of BDI. METHODS: Literature reviews were conducted for 18 key questions across six broad topics around cholecystectomy directed by a steering group and subject experts from five surgical societies (SAGES, AHPBA IHPBA, SSAT, and EAES). Evidence-based recommendations were formulated using the GRADE methodology. When evidence-based recommendations could not be made, expert opinion was documented. A number of recommendations for future research were also documented. Recommendations were presented at a consensus meeting in October 2018 and were voted on by an international panel of 25 experts with greater than 80% agreement considered consensus. RESULTS: Consensus was reached on 17 of 18 questions by the Guideline Development Group (GDG) and expert panel with high concordance from audience participation. Most recommendations were conditional due to low certainty of evidence. Strong recommendations were made for (1) use of intraoperative biliary imaging for uncertainty of anatomy or suspicion of biliary injury; and (2) referral of patients with confirmed or suspected BDI to an experienced surgeon/multispecialty hepatobiliary team. CONCLUSION: These consensus recommendations should provide guidance to surgeons, training programs, hospitals, and professional societies for strategies that have the potential to reduce BDIs and positively impact patient outcomes. Development of clinical and educational research initiatives based on these recommendations may drive further improvement in the quality of surgical care for patients undergoing cholecystectomy.

Pancreatic grade 3 neuroendocrine tumors behave similarly to neuroendocrine carcinomas following resection: a multi-center, international appraisal of the WHO 2010 and WHO 2017 staging schema for pancreatic neuroendocrine lesions.

BACKGROUND: In 2017, the WHO updated their 2010 classification of pancreatic neuroendocrine tumors, introducing a well-differentiated, highly proliferative grade 3 tumor, distinct from neuroendocrine carcinomas. The aim of this study was to investigate the clinical significance of this update in a large cohort of resected tumors. METHODS: Using a multicenter, international dataset of patients with pancreatic neuroendocrine lesions, patients were classified both according to the WHO 2010 and 2017 schema. Multivariable survival analyses were performed, and the models were evaluated for discrimination ability and goodness of fit. RESULTS: Excluding patients with a known germline MEN1 mutation and incomplete data, 544 patients were analyzed. The performance of the WHO 2010 and 2017 models was similar, however surgically resected grade 3 tumors behaved very similarly to neuroendocrine carcinomas. CONCLUSION: The addition of a grade 3 NET classification may be of limited utility in surgically resected patients, as these lesions have similar postoperative survival compared to carcinomas. While the addition may allow for a more granular evaluation of novel treatment strategies, surgical intervention for high grade tumors should be considered judiciously.

Pre-, peri- and post-operative factors for the development of pancreatic fistula after pancreatic surgery.

BACKGROUND: The most hazardous complication to pancreatic surgery is the development of a post-operative pancreatic fistula (POPF). Appropriate understanding of the underlying pathophysiology, risk factors and perioperative mechanisms may allow for better management and use of preventive measures. METHODS: Systematic literature search using the English PubMed literature up to April 2019, with emphasis on the past 5 years. RESULTS: Several risk scores have been developed but none are perfect in predicting POPF risk. A conceptual framework of factors that contribute to the pathophysiology of pancreatic fistulae is still developing but incomplete. Recognized factors include those related to the patient, the pathology and the perioperative care. Interventions such as use of drains, stents and various drugs to mediate risk is still debated. Emerging data suggest that both the microbiome and the inflammation in the post-operative phase may play important roles in risk for POPF. Available risk scores allow for stratification of risk and mitigation strategies tailored to reduce this. However, accurate estimation of risk remains a challenge and mechanisms are only partially understood. CONCLUSIONS: The pathophysiology of POPF remains poorly understood. Current models only partially explain risks or associated mechanisms. Novel areas of investigation need to be explored for better prediction.

Minimally invasive and endoscopic versus open necrosectomy for necrotising pancreatitis: a pooled analysis of individual data for 1980 patients.

OBJECTIVE: Minimally invasive surgical necrosectomy and endoscopic necrosectomy, compared with open necrosectomy, might improve outcomes in necrotising pancreatitis, especially in critically ill patients. Evidence from large comparative studies is lacking. DESIGN: We combined original and newly collected data from 15 published and unpublished patient cohorts (51 hospitals; 8 countries) on pancreatic necrosectomy for necrotising pancreatitis. Death rates were compared in patients undergoing open necrosectomy versus minimally invasive surgical or endoscopic necrosectomy. To adjust for confounding and to study effect modification by clinical severity, we performed two types of analyses: logistic multivariable regression and propensity score matching with stratification according to predicted risk of death at baseline (low: <5%; intermediate: ≥5% to <15%; high: ≥15% to <35%; and very high: ≥35%). RESULTS: Among 1980 patients with necrotising pancreatitis, 1167 underwent open necrosectomy and 813 underwent minimally invasive surgical (n=467) or endoscopic (n=346) necrosectomy. There was a lower risk of death for minimally invasive surgical necrosectomy (OR, 0.53; 95% CI 0.34 to 0.84; p=0.006) and endoscopic necrosectomy (OR, 0.20; 95% CI 0.06 to 0.63; p=0.006). After propensity score matching with risk stratification, minimally invasive surgical necrosectomy remained associated with a lower risk of death than open necrosectomy in the very high-risk group (42/111 vs 59/111; risk ratio, 0.70; 95% CI 0.52 to 0.95; p=0.02). Endoscopic necrosectomy was associated with a lower risk of death than open necrosectomy in the high-risk group (3/40 vs 12/40; risk ratio, 0.27; 95% CI 0.08 to 0.88; p=0.03) and in the very high-risk group (12/57 vs 28/57; risk ratio, 0.43; 95% CI 0.24 to 0.77; p=0.005). CONCLUSION: In high-risk patients with necrotising pancreatitis, minimally invasive surgical and endoscopic necrosectomy are associated with reduced death rates compared with open necrosectomy.

Clinical update on management of pancreatic trauma.

BACKGROUND: Pancreatic injury is rare and optimal diagnosis and management is still debated. The aim of this study was to review the existing data and consensus on management of pancreatic trauma. METHODS: Systematic literature review until May 2018. RESULTS: Pancreas injury is reported in 0.2-0.3% of all trauma patients. Severity is scored by the organ injury scale (OIS), with new scores including physiology needing validation. Diagnosis is difficult, clinical signs subtle, and imaging by ultrasound (US) and computed tomography (CT) non-specific with <60% sensitivity for pancreatic duct injury. MRCP and ERCP have superior sensitivity (90-100%) for detecting ductal disruption. Early ERCP with stent is a feasible approach for initial management of all branch-duct and most main-duct injuries. Distal pancreatectomy (±splenectomy) may be required for a transected gland distal to the major vessels. Early peripancreatic fluid collections are common in ductal injuries and one-fifth may develop pseudocysts, of which two-thirds can be managed conservatively. Non-operative management has a high success rate (50-75%), even in high-grade injuries, but associated with morbidity. Mortality is related to associated injuries. CONCLUSION: Pancreatic injuries are rare and can often be managed non-operatively, supported by percutaneous drainage and ductal stenting. Distal pancreatectomy is the most common operative procedure.

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.

Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference.

OBJECTIVES: Liver metastasis from a neuroendocrine tumour (NET) represents a significant clinical entity. A multidisciplinary group of experts was convened to develop state-of-the-art recommendations for its management. METHODS: Peer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed and the findings presented to a jury of peers. The therapies reviewed included transarterial embolization (TAE), transarterial chemoembolization (TACE) and radioembolization (RE). Two systems were used to evaluate the level of evidence in each publication: (i) the US National Cancer Institute (NCI) system, and (ii) the GRADE system. RESULTS: Eighteen publications were reviewed. These comprised 11 reports on TAE or TACE and seven on RE. Four questions posed to the panel were answered and recommendations offered. CONCLUSIONS: Studies of moderate quality support the use of TAE, TACE and RE in hepatic metastases of NETs. The quality and strength of the reports available do not allow any modality to be determined as superior in terms of imaging response, symptomatic response or impact on survival. Radioembolization may have advantages over TAE and TACE because it causes fewer side-effects and requires fewer treatments. Based on current European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines, RE can be substituted for TAE or TACE in patients with either liver-only disease or those with limited extrahepatic metastases.

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 present on scans 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 = 0.013), those with severe disease (P = 0.001) and when contemporaneous and maximum in-patient C-reactive protein (CRP) exceeded 150 mg/l (P = 0.018 and P = 0.049, 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 = 0.803, 95% CI: 0.583-1.000, and AUC = 0.996, 95% CI: 0.983-1.000, respectively). Examining all lung quadrants resulted in greater AUCs for contemporaneous and maximum CRP (AUC = 0.764, 95% CI: 0.555-0.972, and AUC = 0.704, 95% CI: 0.510-0.898). 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.

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.

Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial.

BACKGROUND: Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. METHODS: This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m(2) (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. FINDINGS: Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6-9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68-1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0-83·4) in the perioperative chemotherapy group and 54·3 months (41·9-79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6-58·3) in the perioperative chemotherapy group versus 47·8% (40·3-55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. INTERPRETATION: We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. FUNDING: Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

Individual patient data meta-analysis of organ failure in acute pancreatitis: protocol of the PANCREA II study.

CONTEXT: Organ failure is a major determinant of mortality in patients with acute pancreatitis. These patients usually require admission to high dependency or intensive care units and consume considerable health care resources. Given a low incidence rate of organ failure and a lack of large non-interventional studies in the field of acute pancreatitis, the characteristics of organ failure that influence outcomes of patients with acute pancreatitis remain largely unknown. Therefore, the Pancreatitis Across Nations Clinical Research and Education Alliance (PANCREA) aims to conduct a meta-analysis of individual patient data from prospective non-interventional studies to determine the influence of timing, duration, sequence, and combination of different organ failures on mortality in patients with acute pancreatitis. METHODS: Pancreatologists currently active with acute pancreatitis clinical research will be invited to contribute. To be eligible for inclusion patients will have to meet the criteria of acute pancreatitis, develop at least one organ failure during the first week of hospitalization, and not be enrolled into an intervention study. Raw data will then be collated and checked. Individual patient data analysis based on a logistic regression model with adjustment for confounding variables will be done. For all analyses, corresponding 95% confidence intervals and P values will be reported. CONCLUSION: This collaborative individual patient data meta-analysis will answer important clinical questions regarding patients with acute pancreatitis that develop organ failure. Information derived from this study will be used to optimize routine clinical management and improve care strategies. It can also help validate outcome definitions, allow comparability of results and form a more accurate basis for patient allocation in further clinical studies.

Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial 40983).

OBJECTIVE: In EORTC study 40983, perioperative FOLFOX increased progression-free survival (PFS) compared with surgery alone for patients with initially 1 to 4 resectable liver metastases from colorectal cancer (CRC). We conducted an exploratory retrospective analysis to identify baseline factors possibly predictive for a benefit of perioperative FOLFOX on PFS. METHODS: The analysis was based on 237 events from 342 eligible patients. Cox proportional hazards regression models with a significance level of 0.1 were used to build up univariate and multivariate models. RESULTS: After adjustment for identified prognostic factors, moderately (5.1-30 ng/mL) and highly (>30 ng/mL) elevated carcinoembryonic antigen (CEA) serum levels were both predictive for the benefit of perioperative chemotherapy (interaction P = 0.07; hazard ratio [HR] = 0.58 and HR = 0.52 for treatment benefit). For patients with moderately or highly elevated CEA (>5 ng/mL), the 3-year PFS was 35% with perioperative chemotherapy compared to 20% with surgery alone. Performance status (PS) 0 and BMI lower than 30 were also predictive for the benefit of perioperative chemotherapy (interaction P = 0.04 and P = 0.02). However, the number of patients with PS 1 and BMI 30 or higher were limited. The benefit of perioperative therapy was not influenced by the number of metastatic lesions (1 vs 2-4, interaction HR = 0.98). CONCLUSIONS: Perioperative FOLFOX seems to benefit in particular patients with resectable liver metastases from CRC when CEA is elevated and when PS is unaffected, regardless of the number of metastatic lesions.ClinicalTrials.gov number NCT00006479.

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.

Clinical features and postoperative survival in patients with sporadic versus multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: An international cohort study.

BACKGROUND: The optimal surgical management of pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 is controversial. This study sought to compare clinicopathologic characteristics and outcomes of multiple endocrine neoplasia type 1-associated and sporadic pancreatic neuroendocrine tumors from a large multi-national database. METHODS: A multi-institutional, international database of patients with surgically resected pancreatic neuroendocrine tumors was analyzed. The cohort was divided into 2 groups: those with multiple endocrine neoplasia type 1 versus those with sporadic disease. Clinicopathologic comparisons were made. Overall and disease-free survival were analyzed. Propensity score matching was used to reduce bias. RESULTS: Of 651 patients included, 45 (6.9%) had multiple endocrine neoplasia type 1 and 606 sporadic pancreatic neuroendocrine tumors. Multiple endocrine neoplasia type 1-associated pancreatic neuroendocrine tumors were more common in younger patients and associated with multifocal disease at the time of surgery and higher T-stage. Lymph node involvement and the presence of metastasis were similar. Total pancreatectomy rate was 5-fold higher in the multiple endocrine neoplasia type 1 cohort. Median survival did not differ (disease-free survival 126 months multiple endocrine neoplasia type 1 vs 198 months sporadic, P > .5). After matching, survival remained similar (overall survival not reached in either cohort, disease-free survival 126 months multiple endocrine neoplasia type 1 vs 198 months sporadic, P > .5). Equivalence in overall survival and disease-free survival persisted even when patients who underwent subtotal and total pancreatectomy were excluded. CONCLUSION: Multiple endocrine neoplasia type 1-associated pancreatic neuroendocrine tumors are more common in younger patients and are associated with multifocality and higher T-stage. Survival for patients with multiple endocrine neoplasia type 1-associated pancreatic neuroendocrine tumors is comparable to those with sporadic pancreatic neuroendocrine tumors, even in the absence of radical pancreatectomy. Consideration should be given to parenchymal-sparing surgery to preserve pancreatic function.

Liver resection for colorectal metastases in presence of extrahepatic disease: results from an international multi-institutional analysis.

BACKGROUND: Hepatic resection for colorectal liver metastasis (CLM) with concomitant extrahepatic disease (EHD) is a controversial topic. We sought to evaluate the long-term outcome of patients undergoing liver resection for CLM in presence of EHD and identify factors associated with prognosis. METHODS: From 1996 to 2007, a total of 1629 patients who underwent resection of CLM were identified from an international multi-institutional database. One hundred seventy-one patients (10.4%) underwent resection of EHD. Clinicopathologic and outcome data were collected and analyzed by univariate and multivariate analyses. RESULTS: Median number of treated CLM was 2 (range, 1-18); most patients had solitary EHD (n = 114; 66.6%) a single anatomic site of EHD (n = 153; 89.4%). The 5-year survival for patients with EHD was 26% compared with 58% for those without EHD (P < 0.001). Recurrence was common (84%). Among patients with EHD, R1 margin status, multiple EHD sites, and location of EHD were associated with worse survival (all P < 0.05). Patients with multiple EHD sites or aortocaval lymph node metastasis had a 5-year survival of 14% and 7%, respectively. When survival was stratified by the total number of metastases treated, the presence of EHD still had a prognostic impact, but the relative impact of EHD diminished as the total number of metastases treated increased. CONCLUSION: Concurrent resection of hepatic and EHD in well-selected patients may provide the possibility of long-term survival. The risk of recurrence, however, remains high, and a worse outcome is associated with both number of metastases and location of EHD.

Portal venous endothelium in developing human liver contains haematopoietic and epithelial progenitor cells.

Future treatments for chronic liver disease are likely to involve manipulation of liver progenitor cells (LPCs). In the human, data characterising the regenerative response is limited and the origin of adult LPCs is unknown. However, these remain critical factors in the design of cell-based liver therapies. The developing human liver provides an ideal model to study cell lineage derivation from progenitors and to understand how foetal haematopoiesis and liver development might explain the nature of the adult LPC population. In 1st trimester human liver, portal venous endothelium (PVE) expressed adult LPC markers and markers of haematopoietic progenitor cells (HPCs) shared with haemogenic endothelium found in the embryonic dorsal aorta. Sorted PVE cells were able to generate hepatoblast-like cells co-expressing CK18 and CK19 in addition to Dlk/pref-1, E-cadherin, albumin and fibrinogen in vitro. Furthermore, PVE cells could initiate haematopoiesis. These data suggest that PVE shares phenotypical and functional similarities both with adult LPCs and embryonic haemogenic endothelium. This indicates that a temporal relationship might exist between progenitor cells in foetal liver development and adult liver regeneration, which may involve progeny of PVE.

Detailed fluid resuscitation profiles in patients with severe acute pancreatitis.

BACKGROUND AND AIM: Appropriate and timely initial fluid resuscitation in acute pancreatitis (AP) is critical. The aim of this retrospective study was to evaluate fluid therapy on an hour-by-hour basis in relation to standard indices of adequate resuscitation during AP. METHODS: Emergency room shock charts, fluid balance sheets and intensive care (ICU) charts for all patients with AP admitted to ICU in a large acute hospital were examined. Vital signs, clinical course and fluid administered during the first 72 h after admission were tabulated against urine output, central venous pressure (CVP) and inotrope/vasopressor therapy. RESULTS: Sixty-three consecutive patients with AP were initially evaluated. Inter-hospital transfers with established organ dysfunction (n= 11) or where records had insufficient detail (n= 22) were excluded. In the remaining 30 patients, in-hospital death occurred in 7. The cumulative volume of crystalloid given was significantly less at 48 h in patients who died in hospital (3331 ± 800 ml vs. survivors, 7287 ± 544 ml; P < 0.001). Non-survivors had a higher CVP, and received more inotropes/vasopressors. CONCLUSION: In severe AP-associated organ failure, fluid resuscitation profiles differ between survivors and non-survivors. CVP alone as a crude indicator of adequate resuscitation may be unreliable, potentially leading to the use of inotropes/vasopressors in the inadequately filled patient.