Contemporary Management of Median Arcuate Ligament in Liver Transplantation.

Median arcuate ligament (MAL) can impair arterial inflow during orthotopic liver transplantation (OLT). Furthermore, approaches to ensure optimal vascular inflow in the presence of MAL is not standardized. Methods: We undertook a systematic review according to the Cochrane systematic review protocol and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We analyzed the incidence of MAL, investigations, treatment options, and potential complications associated with MAL intervention in patients undergoing OLT. After the exclusion criteria were implemented, the dataset from the final 21 manuscripts yielded 117 patients who underwent a liver transplant in the presence of MAL. Results: The incidence of MAL in patients undergoing OLT is between 1.6% and 12%. In 63.2% of cases, an open approach for MAL intervention was undertaken. Hepatic artery thrombosis developed in 17% (7) patients without MAL intervention versus 2.6% (2) after MAL intervention. Seven grafts (5.9%) were lost after OLT in patients with MAL. Three (3.9%) patients developed arterial stenosis post-MAL intervention. Conclusions: We propose an algorithm for intraoperative assessment and management of liver transplant arterial inflow in the presence of MAL based on the hepatic artery flow changes with respiration, following clamping of the recipient gastroduodenal artery. In the presence of a 30%-50% flow variation on respiration, the arterial inflow should be established preserving additional inflow from the recipient gastroduodenal artery. Consider an open MAL release if the flow remains insufficient. A poor arterial flow with no variation with respiration and lack of evidence of aortoiliac atherosclerosis indicates the need for arterial jump graft.

From Haphazard to a Sustainable Normothermic Regional Perfusion Service: A Blueprint for the Introduction of Novel Perfusion Technologies.

Normothermic Regional Perfusion (NRP) has shown encouraging clinical results. However, translation from an experimental to routine procedure poses several challenges. Herein we describe a model that led to the implementation of NRP into standard clinical practice in our centre following an iterative process of refinement incorporating training, staffing and operative techniques. Using this approach we achieved a four-fold increase in trained surgical staff and a 6-fold increase in competent senior organ preservation practitioners in 12 months, covering 93% of the retrieval calls. We now routinely provide NRP throughout the UK and attended 186 NRP retrievals from which 225 kidneys, 26 pancreases and 61 livers have been transplanted, including 5 that were initially declined by all UK transplant centres. The 61 DCD(NRP) liver transplants undertaken exhibited no primary non-function or ischaemic cholangiopathy with up to 8 years of follow-up. This approach also enabled successful implementation of ex situ normothermic liver perfusion which together with NRP contributed 37.5% of liver transplant activity in 2021. Perfusion technologies (in situ and ex situ) are now supported by a team of Advanced Perfusion and Organ Preservation Specialists. The introduction of novel perfusion technologies into routine clinical practice presents significant challenges but can be greatly facilitated by developing a specific role of Advanced Perfusion and Organ Preservation Specialist supported by a robust education, training and recruitment programme.

Current Evidence in the Management of Premalignant Cystic Lesions of the Pancreas in Patients Undergoing Liver Transplantation.

ABSTRACT: Incidental premalignant pancreatic cystic lesions (pPCLs) are increasingly being detected in patients undergoing orthotopic liver transplantation (OLT). The impact of chronic immunosuppression upon pPCLs may elevate risk of progression to pancreatic cancer. This systematic review assesses prevalence, outcome, and management of pPCLs in patients undergoing OLT. Systematic literature searches were performed in accordance with Cochrane review guidelines. Data on 658 patients were identified from 13 articles. Median age was 59 years with a prevalence of 6.2%. Most studies focused on branch-duct intraductal papillary mucinous neoplasms. Average cyst size at diagnosis was 10.3 mm. Six patients (0.9%) underwent pancreatic resection, post-OLT, for suspected "worrisome features" on imaging. One death was due to pancreatic-related cancer, post-OLT. Based on the review, the authors suggest the following: (1) patients with pPCLs undergoing OLT, without "worrisome features," should be followed conservatively; (2) presence of pPCLs alone should not preclude eligibility for OLT, nor should chronic immunosuppression be altered; (3) follow-up should parallel standard approach applied in immunocompetent patients, as development of "worrisome features" of cancer is rare and does not appear to be hastened by immunosuppression; (4) resection is recommended for surgically fit patients without portal hypertension that develop "worrisome features."

Liver Transplantation in Locally Unresectable, Undifferentiated Embryonal Cell Sarcoma.

BACKGROUND: Undifferentiated embryonal cell sarcoma (UESL) of the liver is the third most common malignant liver disease of childhood presenting as a rapidly enlarging intraabdominal mass. This systematic review explores the practicality of liver transplantation as a viable option in the treatment armamentarium for locally advanced undifferentiated embryonal cell sarcoma. METHODS: A systematic review of the literature was performed using Medline and Embase, from inception of databases to December 31, 2018. Keywords and MeSH headings used were embryonal sarcoma, mesenchymal sarcoma, and liver transplant. Reviews and manuscripts with incomplete data were excluded. RESULTS: Twenty-eight patients had orthotopic liver transplantation (OLT) as a curative treatment option. The median age at presentation was 8 and 27 years in the pediatric and adult population, respectively, with a similar male to female ratio. A majority of the patients presented with abdominal pain, palpable mass, and a normal alpha-feto-protein. The median tumor size was 15 cm mainly affecting the right lobe (62%) of the liver. Eighty-two percent of the patients underwent primary OLT and 5 patients had salvage OLT. One death (3.6%) was due to initial misdiagnosis and management for hepatoblastoma. Recurrence was noted in 7.1% of the population. The median follow-up was noted to be 28.5 months. The documented survival rate post-liver transplant for UESL was 96%. CONCLUSIONS: Based on available data and the very positive results therein, liver transplantation is a practical and justifiable use of a scarce resource as a treatment option for locally unresectable, undifferentiated embryonal cell sarcoma. The authors propose (accepting existence of different proposals) neoadjuvant therapy before curative resection, and if not achievable, then liver transplantation followed by adjuvant chemotherapy is an option for suitable candidates. For recurrent tumors after surgical resection, adjuvant therapy with salvage liver transplantation is an option.

Twenty-four hour infusion of human recombinant activated protein C (Xigris) early in severe acute pancreatitis: The XIG-AP 1 trial.

OBJECTIVE: Patients with severe acute pancreatitis were excluded from major trials of human recombinant activated protein C (Xigris) because of concern about pancreatic haemorrhage although these individuals have an intense systemic inflammatory response that may benefit from treatment. The object of this study was to provide initial safety data evaluating Xigris in severe acute pancreatitis. DESIGN: Prospective clinical trial recruiting between November 2009 and October 2011. Patients received human recombinant activated protein C (Xigris) for 24 h by intravenous infusion (24 µg/kg/h) in addition to standard clinical care. A matched historical control group treated within the same hospital unit were used to compare outcomes. Of 166 consecutive admitted patients, 43 met the screening criteria for severe acute pancreatitis and 19 were recruited, all contributing to the analyses. RESULTS: Compared to historical controls, there were fewer bleeding events in the Xigris group although the finding did not reach significance (Xigris 0% vs. Control 21%, p = 0.13), similarly further intervention appeared less frequent (11% vs. 47%, p = 0.07) in the treatment group. Length of stay was shorter for patients receiving Xigris (19 vs. 41 days, p = 0.03) as was inotrope use (5% vs. 32%, p = 0.02); mortality and incidence of infections in both groups were similar. Biomarker protein C increased while IL-6 decreased following infusion. CONCLUSIONS: A 24-hr infusion of Xigris appears safe when used in patients with severe acute pancreatitis. TRIAL REGISTRATION: Eudract Number 2007-003635-23.

Management and diagnosis of gallbladder polyps: a systematic review.

PURPOSE: Recommendation for management of gallbladder polyps (GBPs) >1 cm is cholecystectomy. No consensus exists on management of GBPs <1 cm. This systematic review examines current evidence on management of GBPs. METHODS: MEDLINE, EMBASE and Cochrane library databases were searched from January 1991 to June 2013 using specified terms. A predefined protocol for data extraction was used to retrieve specified end points. RESULTS: Literature search yielded 43 manuscripts with a dataset of 11,685 patients with GBPs. M:F ratio was 1.3:1. Average age (range) was 49 years (32-83). Patients with malignant GBPs had an average (range) age of 58 (50-66) years with M:F ratio of 0.78:1. Cholesterol polyps constituted 60.5% of GBPs followed by adenomas (15.2%) and cancer (11.6%). Malignant GBPs ≥1 cm, <1 cm and <5 mm constituted 8.5, 1.2 and 0% of GBPs, respectively. Majority of patients requiring surgical intervention had laparoscopic cholecystectomy. CONCLUSIONS: Presently employed policy of cholecystectomy for GBPs >1 cm is appropriate. For GBPs <1 cm, the authors propose (accepting existence of differing proposals) the following: 1. Surveillance may not be needed for GBPs <5 mm. 2. For GBPs between 5 and 10 mm, two scans at six monthly intervals is suggested and after that, tailor surveillance to age, growth and ethnicity. In the non-Asian population, if GBP remains the same size or number, discontinuation of surveillance may be considered. In the Asian population, if GBPs remain the same, yearly surveillance is continued for a suggested period of 3 years. 3. Discontinue surveillance if GBPs is/are smaller/ disappeared. Cholecystectomy is advised where size increases to >10 mm.

Administration of human recombinant activated protein C is not associated with pancreatic parenchymal haemorrhage in L-arginine-induced experimental acute pancreatitis.

CONTEXT: Microvascular thrombosis is a critical event in severe acute pancreatitis. Human recombinant activated protein C (Xigris®, Eli Lilly, Indianapolis, IN, USA) modulates the interplay between pro-inflammatory and pro-coagulant pathways and maintains microvascular patency. However, the anticoagulant properties of Xigris® may precipitate bleeding from the inflamed pancreas. OBJECTIVE: This study tests the hypothesis that Xigris® can ameliorate experimental acute pancreatitis without causing pancreatic haemorrhage. METHODS: Sprague Dawley rats were allocated as follows: Group 1: control (n=7); Group 2: acute pancreatitis (n=6); Group 3: administration of Xigris® 500 µg/kg body weight before induction of acute pancreatitis (n=6); and Group 4: Administration of Xigris® 500 µg/kg body weight 30 minutes after induction of acute pancreatitis (n=6). Acute pancreatitis was induced by intraperitoneal administration of L-arginine 300 mg/100 g body weight. Animals were sacrificed at 48 hours and biochemical, haematological, and histological markers of pancreatic haemorrhage and inflammation assessed. RESULTS: Median lipase in animals with acute pancreatitis was 10 U/mL (range: 7-16 U/mL) compared to 5.5 (range: 3-8 U/mL) in controls (P=0.028). Lipase was also elevated in animals given Xigris® both before (12 U/mL, range: 8-22 U/mL; P=0.031 vs. control group) and after (46 U/mL, range: 9-71 U/mL; P=0.015 vs. control group) induction of acute pancreatitis). Haemoglobin levels were similar among all groups (P=0.323). There was no histological evidence of pancreatic haemorrhage in animals treated with Xigris®. Pre-treatment with Xigris® was associated with a significant reduction in pancreatic injury. This effect was absent when Xigris® was administered after induction of acute pancreatitis. CONCLUSION: Xigris® did not lead to pancreatic haemorrhage in experimental acute pancreatitis. Administration of Xigris® prior to induction of acute pancreatitis was associated with amelioration of injury. This effect was not seen with administration of Xigris® after induction of acute pancreatitis.

Current status in the multidisciplinary management of duodenal fistula.

INTRODUCTION: Paradigms in the management of duodenal fistula have evolved over the last half a century. Despite advances, morbidity and mortality still remain high. This paper provides a comprehensive, up to date, systematic review in the management of duodenal fistula, classifying the various strategies in the management of duodenal fistula MATERIALS AND METHODS: A review was performed on Medline, Embase and Cochrane library databases using the Cochrane systematic reviews methodology. A final population of 42 studies reported on 349 patients, with a median (range) number of patients per study of two (1-68). The manuscripts were broadly divided in to "non-interventional" and "interventional". The interventional group was subdivided in to "minimally invasive" and the "open surgical approach". RESULTS: A total of 147 patients were treated conservatively (non-interventional group), with a median duration of 28 days (range 13-42 days) with 13 (9%) deaths recorded in this group. No deaths were reported in the 8 reports on minimally invasive approach.166 patients had open surgical approach with a mortality rate of 30% (50 patients). DISCUSSION AND CONCLUSION: In the absence of randomised controlled trials, no one interventional modality can be considered superior. Initial multidisciplinary conservative approach with sepsis control and nutritional augmentation should be for 6 weeks. It would seem reasonable, in those fistulae that fail to close spontaneously, to attempt a low risk "minimally invasive" intervention where necessary expertise is available. More risky open surgical approaches should clearly be reserved for those that fail and are best performed in specialist centres.

Recombinant human activated protein C as a disease modifier in severe acute pancreatitis: systematic review of current evidence.

BACKGROUND: The severity of organ failure caused by acute pancreatitis (AP) is the most important determinant of mortality in the disease. Recombinant human activated protein C (Drotrecogin Alfa; Xigris, APC, rhAPC) is the first drug to show a decrease in all-cause mortality due to multiple organ failure caused by sepsis. As the systemic inflammatory response syndrome (SIRS) that causes organ failure in early AP is similar to that caused by severe sepsis, the use of rhAPC in the management of AP has been investigated in experimental and clinical studies which are collated in this review. METHODS: A literature review of published material identified from MEDLINE and EMBASE databases, for the period from January 1985 to January 2011, reporting rhAPC usage in AP. RESULTS: 3 of 4 experimental studies reported an improvement in outcome in animals with AP given rhAPC. The clinical randomized trial showed no improvement in outcome in the treatment arm. CONCLUSION: The experimental evidence of disease amelioration in AP following intervention with rhAPC has not translated to the small clinical RCT. Given that there were only 16 patients in the treatment arm, further clinical evaluation is justified.

Recombinant human activated protein C (Xigris) attenuates murine cerulein-induced acute pancreatitis via regulation of nuclear factor κB and apoptotic pathways.

OBJECTIVES: Microvascular thrombosis occurs in severe acute pancreatitis (AP). Exploiting this knowledge, we used human recombinant activated protein C (Xigris; Eli Lilly, Indianapolis, Ind) known to preserve microvascular patency, in evaluating the role of Xigris in experimental AP. METHODS: In accordance with European union experimentation regulations, AP was induced by hourly injection of cerulein 50 µg/kg body weight over 6 hours. Male rats of median weight of 231 g (range, 176-312 g) were allocated at random into groups: group 1, control; group 2, vehicle; group 3, AP; group 4, cerulein + Xigris at induction of AP and killing at 24 h; and group 5, cerulein + Xigris 24 hours after induction and killing at 48 hours. In addition to enzymatic and histological markers of pancreatic injury, apoptosis, nuclear factor κB (NF-κB) p65/IκB, cytokine response, and endothelial injury were assessed. Western blot quantified by densitometry was used to assess marker of apoptosis and endothelial injury. RESULTS: Cerulein injection resulted in acute necrotizing pancreatitis. Intervention with recombinant human activated protein C did not modify coagulation parameters or lead to hemorrhage but ameliorated pancreatic injury with preservation of IκB and reduction of NF-κB p65 and modulation of apoptosis. CONCLUSIONS: Our study indicates that recombinant human activated protein C ameliorates experimental cerulein-induced pancreatitis through apoptotic and NF-κB pathways without causing pancreatic hemorrhage.

The performance of organ dysfunction scores for the early prediction and management of severity in acute pancreatitis: an exploratory phase diagnostic study.

OBJECTIVE: To evaluate contemporary organ dysfunction scoring systems for early prediction of severity in acute pancreatitis (AP). METHODS: In a consecutive cohort of 181 patients with AP, organ dysfunction scores (logistic organ dysfunction system [LODS] score, Marshall organ dysfunction score, and sequential organ failure assessment score) were collected at 24 and 48 hours. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated on admission and 24 and 48 hours and C-reactive protein level measured at 48 hours. Patients who died or used critical care facilities (level 2/3) during admission were classed as severe. RESULTS: Area under curve for APACHE II score at admission was 0.78 (95% confidence interval, 0.69-0.86). At 24 hours, area under curve for LODS, Marshall organ dysfunction system, sequential organ failure assessment, and APACHE II scores were 0.82, 0.80, 0.80, and 0.82, respectively. The LODS score at cutoff of 1 achieved 90% sensitivity and 69% specificity, corresponding to a positive predictive value of 38%. Acute Physiology and Chronic Health Evaluation II score as a rule-out for selection of mild cases at a test threshold of 9 (scores ≤ 8 being selected) gives homogeneity of 91% and efficiency of 79%. CONCLUSIONS: Contemporary organ dysfunction scoring systems provides an objective guide to stratification of management, but there is no perfect score. All scores evaluated here perform equivalently at 24 hours. Acute Physiology and Chronic Health Evaluation II may have practical clinical value as a rule-out test.

Open pancreatic necrosectomy in the multidisciplinary management of postinflammatory necrosis.

OBJECTIVE: To examine clinical outcome in a consecutive cohort of patients undergoing open necrosectomy for postinflammatory necrosis. BACKGROUND INFORMATION: The last decade has witnessed major developments in the surgical management of pancreatic necrosis. Minimally invasive approaches have become established. However, there are limited data from contemporary open necrosectomy, in particular where multidisciplinary care and aggressive interventional radiology are used. This report provides data on outcome from open necrosectomy in a tertiary referral Hepatobiliary unit over the last decade. METHODS: During the period January 1, 2000 to July 31, 2008, 1535 patients were admitted with a final discharge code of acute pancreatitis. Twenty-eight (1.8%) of all admissions underwent open surgical necrosectomy. Twenty-four (86%) were tertiary referral patients. RESULTS: The median APACHE II score on admission was 10.5 (5-26). Median logistic organ dysfunction score on admission was 3 (0-10). Median LODS score after surgery was 2 (0-8). Twenty patients (71%) underwent radiologically guided drainage of collections before surgery. Thirty-day mortality occurred in 2 (7%), 4 further deaths occurred in patients after discharge from intensive care resulting in a total of 6 (22%) episode-related deaths. CONCLUSIONS: Modern open necrosectomy can be performed without the procedure-related deterioration in organ dysfunction associated with major debridement. Multidisciplinary care with an emphasis on aggressive radiologic intervention before and after surgery results in acceptable outcomes in this cohort of critically ill patients. Newer laparoscopic techniques must demonstrate similar outcomes in the setting of stage-matched severity before wider acceptance.

Green tea polyphenols ameliorate pancreatic injury in cerulein-induced murine acute pancreatitis.

OBJECTIVE: Green tea polyphenols (GTPs) are naturally occurring antioxidants acting through pathways that include reactive oxygen species and nuclear factor kappa B (NF-kappaB). This study investigates the effect of GTPs in a cerulein-induced murine model of acute pancreatitis (AP). METHODS: Male CD mice (median weight, 37.7 g) were divided into 4 groups: mice administered with cerulein alone, cerulein and GTP, saline alone (sham), and GTP alone. Acute pancreatitis was induced by serial intraperitoneal administration of cerulein (50 microg/kg, x6). Green tea polyphenol was administered intraperitoneally at 25 mg/kg on the first, third, and sixth hours after pancreatitis induction.We analyzed histologic and biochemical features of AP, NF-kappaB pathway activity, leukocyte-mediated damage, cytokine levels, oxidative stress injury, lipid peroxidation, expression of poly-(adenosine diphosphate-ribose) synthetase, and presence of apoptosis. RESULTS: Treatment with GTP reduced the histologic and biochemical features of AP. Western blot revealed significant NF-kappaB inactivation. Immunostaining for P selectin and intercellular adhesion molecule 1, tumor necrosis factor alpha, transforming growth factor beta, vascular endothelial growth factor, nitrotirosine, poly-(adenosine diphosphate ribose) synthetase, and malondialdheide levels were significantly reduced. There was a significant down-regulation of apoptotic markers. CONCLUSIONS: Our results demonstrated that GTP significantly ameliorated the effects of cerulein-induced AP in mice. These effects of GTP are mediated by actions at the NF-kappaB/IkB (inhibitor kB) proteins and oxidative stress pathways.