Outcomes of liver transplant recipients with high MELD scores: an experience from a Canadian centre.

BACKGROUND: The frequency with which patients with high Model for End-Stage Liver Disease (MELD) scores undergo liver transplantation has been increasing. Canadian literature regarding the outcomes of liver transplantation in recipients with high MELD scores is limited. The primary objective of this study was to assess patient and graft survival among recipients with high (> 35) and low (≤ 35) MELD scores. Secondary objectives were to potentially identify independent predictors of graft failure and patient mortality. METHODS: We conducted a retrospective chart review of patients undergoing liver transplantation at a single Canadian centre from 2012 to 2017. RESULTS: A total of 332 patients were included in the study: 280 patients had a MELD score of 35 or lower, and 52 had a MELD score above 35. Patients with high MELD scores had higher rates of pretransplant acute kidney injury and dialysis (p < 0.001), admission to the intensive care unit (ICU) or intubation (p < 0.001), intraoperative blood product transfusions (p < 0.001) and post-transplantation acute kidney injury and dialysis (p < 0.001), as well as longer ICU (p < 0.001) and hospital stays (p = 0.002). One- and 3-year patient survival in recipients with MELD scores of 35 or lower was 93.1% and 84.9% versus 85.0% and 80.0% in recipients with MELD scores above 35 (p = 0.37). One- and 3-year graft survival in recipients with MELD scores of 35 or lower was 91.7% and 90.9% versus 77.2% and 72.8% in recipients with MELD scores above 35 (p < 0.001). Prior liver transplant was an independent predictor of patient mortality, and no independent predictors of graft failure were identified. When MELD was replaced with D-MELD (donor age × recipient MELD), it predicted graft failure but not patient survival. CONCLUSION: No difference in patient mortality was found between MELD groups. Graft survival was significantly lower in recipients with MELD scores above 35. D-MELD may potentially be used as an adjunct in determining risk of graft failure in recipients with high MELD scores.

Comparison of inflammatory cytokines in peritoneal fluid at source control surgery for abdominal sepsis.

BACKGROUND: Open abdomen with vacuum assisted closure (VAC) is an alternate method to primary abdominal closure (PAC) in select situations for the management of severe surgical abdominal sepsis or septic shock. Peritoneal cytokines may potentially correlate with deranged physiology and help stratify severity of sepsis. The primary objective of the study was to identify if cytokines can differentiate between patients who underwent PAC or VAC at primary source control laparotomy (SCL). METHODS: Prospective case series including patients with severe abdominal sepsis/septic shock requiring urgent SCL. Peritoneal fluid (PF) was collected intra-operatively and blood samples were collected pre- and post SCL. Samples were analyzed with a Cytokine 30-plex Panel. APACHE-IV was used as a measure of disease severity between groups. RESULTS: 4 PAC and 8 VAC patients were included. PF concentrations of IL 6, IL-17, IL-5 and HGF were significantly elevated in VAC compared to PAC. Serum RANTES was increased in survivors compared to non-survivors. CONCLUSIONS: Patients who received VAC management had a more severe degree of local abdominal sepsis based on significantly elevated peritoneal cytokines.

Comparison of three caval reconstruction techniques in orthotopic liver transplantation: A retrospective review.

BACKGROUND: Classic caval reconstruction during liver transplantation involves complete cross-clamping and resection of the recipient inferior vena cava (IVC) followed by donor IVC interposition. Other techniques preserve the IVC, with piggyback (PB) to the hepatic veins or side-to-side (SS) caval anastomosis. Avoidance of cross-clamping may be beneficial for minimizing hemodynamic instability and transfusion requirements. METHODS: Retrospective review of a provincial transplant database (2007-2011). MELD score was used to measure disease severity. Intraoperative blood loss and volume resuscitation were compared between three caval reconstruction techniques using ANOVA. RESULTS: 200 deceased-donor transplants (Classic:58, PB:72, SS:70) were included. Baseline disease severity was equal. Mean case duration was shorter in the PB technique (Classic:366, PB:306, SS:385 min, p < 0.001). Despite similar blood loss, there was significantly less cell saver return, FFP, platelets, and overall resuscitation volume (Classic:12.8, PB:9.5, SS:13.2 L, p = 0.001) utilized in the piggyback technique. CONCLUSIONS: The PB technique was faster and used less cell saver return, FFP and platelets, despite similar blood loss. Availability of different caval reconstruction techniques allows for a breadth of options in difficult cases.

Evaluation of APACHE-IV Predictive Scoring in Surgical Abdominal Sepsis: A Retrospective Cohort Study.

INTRODUCTION: Evaluation of the effectiveness of care and clinical outcomes in critically ill patients is dependent on predictive scoring models that calculate measures of disease severity and an associated likelihood of mortality. The APACHE scoring system is a logistic regression model incorporating physiologic and laboratory parameters. APACHE-IV is the most updated scoring system for ICU mortality prediction. However, APACHE scores may not accurately predict mortality in patients who require surgery for abdominal sepsis, whose trajectory is modulated by source control procedures. AIM: To evaluate the accuracy of APACHE-IV mortality prediction in a cohort of ICU patients with surgical abdominal sepsis (SABS) requiring emergent laparotomy for source control. MATERIALS AND METHODS: The study was conducted in a combined medical and surgical intensive care unit in a large urban Canadian tertiary care hospital. Retrospective review of 211 consecutive adult ICU admissions that fulfilled the 2012 ACCP/SCCM criteria for severe sepsis/septic shock due to abdominal source was performed. APACHE-IV score and predicted mortality rate (PMR) were calculated and evaluated using area under the ROC curve (AUROC). RESULTS: Overall in-hospital mortality was 28.4%. There was overestimation of PMR by the APACHE-IV model in the overall cohort with an absolute difference of 16.6% (relative difference 36.9%). APACHE-IV crudely distinguished between survivors and non-survivors, with a PMR of 40% vs. 59% (p<0.001). AUROC of the APACHE-IV score was 0.67, 95% CI (0.58, 0.76) while the AUROC for the PMR was 0.72, 95% CI (0.64, 0.80), indicating poor performance in this cohort. CONCLUSION: APACHE-IV has poor discrimination in SABS. Future research should explore disease-specific prediction models.

Open abdomen with negative pressure device vs primary abdominal closure for the management of surgical abdominal sepsis: a retrospective review.

BACKGROUND: Open abdomen with temporary abdominal closure remains a controversial management strategy for surgical abdominal sepsis compared with primary abdominal closure (PAC) and on-demand laparotomy. The primary objective was to compare mortality between PAC and open abdomen with vacuum assisted closure (VAC). METHODS: Retrospective review of a tertiary center intensive care unit database (2006 to 2010) including suspected/diagnosed severe abdominal sepsis/septic shock requiring source control laparotomy. Groups were categorized according to closure method at index source control laparotomy. APACHE-IV was used as a measure of disease severity. RESULTS: Of 211 patients, 75 PAC and 136 VAC cases were included. Controlling for disease severity, adjusted odds ratio of mortality for VAC was .41 95% confidence interval (.21, .81; P = .01) compared with PAC. PAC and VAC APACHE-1V predicted mortality rate were both 45%. VAC mortality was lower than PAC (22.8% vs 38.6%; P = .012). CONCLUSIONS: Open abdomen with VAC is associated with significantly improved survival compared with PAC in abdominal sepsis requiring laparotomy.

The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism, vascular function, cell proliferation, and tumor growth.

BACKGROUND: Metronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient-derived xenografts of pancreatic cancer. METHODS: Two primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly. Changes in tumor growth, vascular function, and metabolism over time were measured with magnetic resonance imaging, positron emission tomography, and immunofluorescence microscopy to determine the anti-tumor effects of the respective treatments. RESULTS: Tumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors' avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor's vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia. CONCLUSION: The aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy. Non-invasive imaging could be used to detect early changes in tumor physiology before reductions in tumor volume were evident.

Biliary and vascular anomalies in living liver donors: the role and accuracy of pre-operative radiological mapping.

BACKGROUND: The aim of the present study was to determine the utility of computed tomography (CT) and magnetic resonance imaging (MRI) anatomic mapping in the detection of biliary and vascular anomalies prior to a living liver donor (LLD) operation. METHODS: A retrospective study of all LLD patient charts, operative and radiology reports from 1 January 2002 to 1 January 2012 was conducted. Primary post-operative outcomes assessed included mortality, re-operation, readmission and need for endoscopic or percutaneous intervention. Sensitivity and specificity of MR and CT pre-operative screening was calculated against the gold standard of intra-operative findings. RESULTS: A total of 34 donors had an average age of 38 years (range: 22-58) with a body mass index (BMI) of 25.6 kg/m(2) (range: 19.8-32.5) and a length of stay (LOS) of 10.1 days (range: 5-41). There were no donor mortalities. Sensitivity and specificity of CT was 70.0% and 91.3%, and of MRI screening 23.1% and 100.0%, respectively. Patients with inaccurate pre-operative CT or MRI did not have an increased risk of complications. CONCLUSIONS: Even although it was specific, pre-operative MR screening missed up to 77.0% of biliary anomalies. An impeccable surgical technique remains the key in preventing biliary complications of a living donor hepatectomy where pre-operative MRI screening is false.

Hepatic artery transection reconstructed with splenic artery transposition graft.

INTRODUCTION: Hepatic artery transection presents a technical challenge in vascular reconstruction. Formal arterial repair is indicated in patients with underlying liver disease and those undergoing bile duct reconstructions because of a higher risk of complication following hepatic artery injury. This report highlights a novel approach to hepatic artery transection with splenic artery transposition. METHODS: A case of hepatic artery transection repaired with splenic artery transposition is presented with an accompanying literature review. RESULTS: During elective pancreaticoduodenectomy, the common hepatic artery was injured at its origin. The splenic artery was divided and transposed to the hepatic artery, thus restoring arterial flow to the liver and bile duct. CONCLUSION: Various strategies to manage a hepatic artery injury have been described, ranging from ligation to complex vascular reconstruction. In hemodynamically stable patients, arterial transposition using the splenic artery is a feasible method to ensure adequate arterial supply to the liver and biliary tract.

Determination of factors predictive of outcome for patients undergoing a pancreaticoduodenectomy of pancreatic head ductal adenocarcinomas.

INTRODUCTION: A pancreaticoduodenectomy is the reference treatment for a resectable pancreatic head ductal adenocarcinoma. The probability of 5-year survival in patients undergoing such treatment is 5-25% and is associated with relatively high peri-operative morbidity and mortality. The objective of the present study was to evaluate risk factors predictive of outcome for patients undergoing a pancreaticoduodenectomy for a pancreatic adenocarcinoma. METHODS: This retrospective analysis incorporated data from the Vancouver General Hospital and the British Columbia Cancer Agency (BCCA) from 1999-2007. RESULTS: The 5-year survival of 100 patients was 12% with a median survival of 16.5 months. Ninety-day mortality was 7%. Predictors of 90-day mortality included age ≥ 80 years (P < 0.001) and an American Society of Anesthesiologists (ASA) score = 3 (P= 0.012) by univariate analysis and age ≥80 years (P < 0.001) by multivariate analysis. The identifiable predictive factor for poor 5-year survival was an ASA score = 3 (P= 0.043) whereas a Dindo-Clavien surgical complication grade ≥ 3 was associated with a worse outcome (P= 0.013). Referral to the BCCA was associated with a favourable 5-year survival (P= 0.001). CONCLUSIONS: The present study identifies risk factors for patient selection to enhance survival benefit in this patient population.

Optimization of doxorubicin loading for superabsorbent polymer microspheres: in vitro analysis.

PURPOSE: This study was designed to establish the ability of super-absorbent polymer microspheres (SAP) to actively uptake doxorubicin and to establish the proof of principle of SAP's ability to phase transfer doxorubicin onto the polymer matrix and to elute into buffer with a loading method that optimizes physical handling and elution characteristics. METHODS: Phase I: 50-100 µm SAP subject to various prehydration methods (normal saline 10 cc, hypertonic saline 4 cc, iodinated contrast 10 cc) or left in their dry state, and combined with 50 mg of clinical grade lyophilized doxorubicin reconstituted with various methods (normal saline 10 cc and 25 cc, sterile water 4 cc, iodinated contrast 5 cc) were placed in buffer and assessed based on loading, handling, and elution utilizing high-performance liquid chromatography (HPLC). Phase II: top two performing methods were subject to loading of doxorubicin (50, 75, 100 mg) in a single bolus (group A) or as a serial loading method (group B) followed by measurement of loading vs. time and elution vs. time. RESULTS: Phase I revealed the most effective loading mechanisms and easiest handling to be dry (group A) vs. normal saline prehydrated (group B) SAP with normal saline reconstituted doxorubicin (10 mg/mL) with loading efficiencies of 83.1% and 88.4%. Phase II results revealed unstable behavior of SAP with 100 mg of doxorubicin and similar loading/elution profiles of dry and prehydrated SAP, with superior handling characteristics of group B SAP at 50 and 75 mg. CONCLUSIONS: SAP demonstrates the ability to load and bulk phase transfer doxorubicin at 50 and 75 mg with ease of handling and optimal efficiency through dry loading of SAP.

Multimodal therapy for hepatocellular carcinoma: a complementary approach to liver transplantation.

OBJECTIVE: To evaluate the survival benefit of multimodal therapy for the treatment of HCC. BACKGROUND: Orthotopic liver transplantation (OLT) is considered the treatment of choice for selected patients with hepatocellular carcinoma (HCC). However, donor organ shortages and patients whose HCCs exceed OLT criteria require consideration of alternate therapeutic options such as hepatic resection, radiofrequency ablation (RFA), ethanol injection (EI), transarterial chemoembolization (TACE), and chemotherapy (CTX). This study was performed to evaluate the survival benefit of multimodal therapy for treatment of HCC as complementary therapy to OLT. METHODS: A retrospective review was conducted of HCC patients undergoing therapy following multidisciplinary review at our institution from 1996 . 2006 with a minimum of a 2 year patient follow-up. Data were available on 247/252 patients evaluated. Relevant factors at time of diagnosis included symptoms, hepatitis B (HBV) and C (HCV) status, antiviral therapy, Child-Pugh classification, portal vein patency, and TNM staging. Patients underwent primary treatment by hepatic resection, RFA, EI, TACE, CTX, or were observed (best medical management). Patients with persistent or recurrent disease following initial therapy were assessed for salvage therapy. Survival curves and pairwise multiple comparisons were calculated using standard statistical methods. RESULTS: Mean overall survival was 76.8 months. Pairwise comparisons revealed significant mean survival benefits with hepatic resection (93.2 months), RFA (66.2 months), and EI (81.1 months), compared with TACE (47.4 months), CTX (24.9 months), or observation (31.4 months). Shorter survival was associated with symptoms, portal vein thrombus, or Child-Pugh class B or C. HCV infection was associated with significantly shorter survival compared with HBV infection. Antiviral therapy was associated with significantly improved survival in chronic HBV and HCV patients only with earlier stage disease. CONCLUSION: Multimodal therapy is effective therapy for HCC and may be used as complementary treatment to OLT.

Effects of implementation of an urgent surgical care service on subspecialty general surgery training.

BACKGROUND: In July 2007, a large Canadian teaching hospital realigned its general surgery services into elective general surgery subspecialty-based services (SUBS) and a new urgent surgical care (USC) service (also know in the literature as an acute care surgery service). The residents on SUBS had their number of on-call days reduced to enable them to focus on activities related to SUBS. Our aim was to examine the effect of the creation of the USC service on the educational experiences of SUBS residents. METHODS: We enrolled residents who were on SUBS for the 6 months before and after the introduction of the USC service. We collected data by use of a survey, WEBeVAL and recorded attendance at academic half days. Our 2 primary outcomes were residents' attendance at ambulatory clinics and compliance with the reduction in the number of on-call days. Our secondary outcomes included residents' time for independent study, attendance at academic half days, operative experience, attendance at multidisciplinary rounds and overall satisfaction with SUBS. RESULTS: Residents on SUBS had a decrease in the mean number of on-call days per resident per month from 6.28 to 1.84 (p = 0.006), an increase in mean attendance at academic half days from 65% to 87% (p = 0.028), at multidisciplinary rounds (p = 0.002) and at ambulatory clinics and an increase in independent reading time (p = 0.015), and they reported an improvement in their work environment. There was no change in the amount of time residents spent in the operating room or in their overall satisfaction with SUBS. CONCLUSION: Residents' education in the SUBS structure was positively affected by the creation of a USC service. Compliance with the readjustment of on-call duties was high and was identified as the single most significant factor in enabling residents to take full advantage of the unique educational opportunities available only while on SUBS.

Tumor expression of integrin-linked kinase (ILK) correlates with the expression of the E-cadherin repressor snail: an immunohistochemical study in ductal pancreatic adenocarcinoma.

Integrin-linked kinase (ILK) is a key molecule involved in mediating several biological functions including cell-matrix interactions, angiogenesis, and invasion, as well as playing a role in epithelial to mesenchymal transition (EMT) in cancer cells. In ductal pancreatic adenocarcinoma, increased expression of ILK has been linked to tumor prognosis and correlated with increased chemoresistance to drugs, such as gemcitabine. However, the precise relationship between ILK, Snail, E-cadherin, and N-cadherin expression on the stepwise development of pancreatic cancer is unknown. Hence, the purpose of this work was to investigate levels of expression of ILK, Snail, and the cadherins in pancreatic intraepithelial neoplasia (PanIN), and cancer. Resection specimens of 25 randomly selected patients, who underwent a pyloric preserving pancreatoduodenectomy for ductal pancreatic adenocarcinoma, were utilized for this study. Formalin-fixed paraffin embedded pancreatic tissue was immunostained for ILK, E-cadherin, N-cadherin, and Snail by standard techniques. The extent of staining positivity was scored and the results correlated with clinicopathological parameters. In 23 of 25 cases, ILK expression showed extensive positivity (>50%), while two cases did not demonstrate any ILK staining. PanIN grades 1 (n = 16), 2 (n = 11), and 3 (n = 19) lesions demonstrated only focal positivity (<10%) for ILK. E-cadherin showed a reciprocal staining pattern to ILK in 21 of 25 cases, with only focal expression of the marker in pancreatic adenocarcinoma. Interestingly, 15 of 19 PanIN-3 lesions expressed extensive E-cadherin staining. N-cadherin, however, was moderately expressed in the majority of cases (n = 18). Snail expression (n = 22) correlated with ILK expression in ductal pancreatic adenocarcinoma (rho = 0.8168, p = 0.02), but only minimal Snail staining activity was detected in PanIN lesions. The increase in expression of the E-cadherin repressor Snail, as well as the related increase in the ILK expression, may point towards an ILK-mediated induction, opening possible avenues for targeted drug therapy.

Parvovirus B19 induced hepatic failure in an adult requiring liver transplantation.

Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation. We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation. This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation. This case suggests that Parvovirus B19 induced liver disease can affect adults, can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation.

Perioperative analysis of laparoscopic versus open liver resection.

BACKGROUND: Over the past decade there has been an increasing trend toward minimally invasive liver surgery. Initially limited by technical challenges, advances in laparoscopic techniques have rendered this approach safe and feasible. However, as health care costs approach 50% of some provincial budgets, surgical innovation must be justifiable in costs and patient outcomes. With introduction of standardized postoperative liver resection guidelines to optimize patient hospital length of stay, the advantages of laparoscopic liver resection (LLR) compared with open liver resection (OLR) measured by perioperative outcomes and resource utilization are not well defined. It remains to be established whether LLR is superior to OLR by these measurements. METHODS: Eighteen LLRs performed at the Vancouver General Hospital from 2005 to 2007 were prospectively analyzed. These data were compared with an equivalent group of 12 consecutive OLRs undertaken immediately prior to the introduction of LLR. Outcomes were evaluated for differences in perioperative morbidity, hospital length of stay, and operative costs. RESULTS: There were no differences between LLRs and OLRs in demographics, pathology, cirrhosis, tumour location or extent of resection. There were no deaths. LLRs had significantly decreased intraoperative blood loss (287 ml versus 473 ml, p = 0.03), postoperative complications (6% versus 42%, p = 0.03), and length of stay (4.3 versus 5.8 days, p = 0.01) compared with OLRs. There were no differences in operating time for LLRs compared to OLRs (135 min versus 138 min, respectively), total time in the operating theatre (214 min versus 224 min), or costs related to stapler/trocar devices (CA $1267 versus CA $1007). CONCLUSIONS: LLR is associated with decreased morbidity and decreased resource utilization compared with OLR. Perioperative patient outcomes and cost-effectiveness justify LLR despite introduction of standardized postoperative liver resection guidelines and decreased length of stay for OLR.