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.

The association between bacterobilia and the risk of postoperative complications following pancreaticoduodenectomy.

BACKGROUND: Pre-operative biliary bacterial colonisation (bacterobilia) is considered a risk factor for infectious complications after pancreaticoduodenectomy (PD). This study aimed to investigate the role of the PD biliary microbiome grown in the development of post-PD complications. METHODS: In a retrospective study of 162 consecutive patients undergoing PD (2008-2018), intra-operative bile cultures were analyzed and sensitivities compared to pre-anesthetic antibiotics and thirty-day post-surgery complications. RESULTS: Bacterobilia was present in 136 patients (84%). Most bile cultures grew bacteria resistant to pre-operative antibiotics (n = 112, 82%). Patients with bacterobilia had significantly higher rates of major complication than patients without (P = 0.017), as well as higher rates of surgical-site infections (SSI) (P = 0.010). Patients with negative bile cultures (n = 26) had significantly lower rates of major complication and SSI than those growing sensitive (n = 24) or non-sensitive (n = 112) bacteria (major complication P = 0.029 and SSI P = 0.011). CONCLUSION: Positive bile cultures were associated with a higher incidence of major complications and SSI. Patients with sterile bile cultures had the lowest risk of post-operative complications and efforts to reduce rates of bacterobilia, such as limitation of biliary instrumentation, should be considered. Sensitivity to antibiotics had no effect upon the rate of post-operative complications, but this may reflect low cohort numbers.

Minimally invasive hepatectomy is associated with decreased morbidity and resource utilization in the elderly.

BACKGROUND: The aim of this study was to evaluate whether elderly patients undergoing elective hepatectomy experience increased morbidity/mortality and whether these outcomes could be mitigated by minimally invasive hepatectomy (MIH). METHODS: 15,612 patients from 2014 to 2017 were identified in the Hepatectomy Targeted Procedure Participant Use File of the American College of Surgeons National Surgical Quality Improvement Program. Multivariable logistic regression models were constructed to examine the effect of elderly status (age ≥ 75 years, N = 1769) on outcomes with a subgroup analysis of elderly only patients by open (OH) versus MIH (robotic, laparoscopic, and hybrid, N = 4044). Propensity score matching was conducted comparing the effect of MIH to OH in elderly patients to ensure that results are not the artifact of imbalance in baseline characteristics. RESULTS: Overall, elderly patients had increased risk for 30-day mortality, major morbidity, prolonged length of hospital stay, and discharge to destination other than home. In the elderly subgroup, MIH was associated with decreased major morbidity (OR 0.71, P = 0.031), invasive intervention (OR 0.61, P = 0.032), liver failure (OR 0.15, P = 0.011), bleeding (OR 0.46, P < 0.001), and prolonged length of stay (OR 0.46, P < 0.001). Propensity score-matched analyses successfully matched 4021 pairs of patients treated by MIH vs. OH, and logistic regression analyses on this matched sample found that MIH was associated with decreased major complications (OR 0.69, P = 0.023), liver failure (OR 0.14, P = 0.010), bile leak (OR 0.46, P = 0.009), bleeding requiring transfusion (OR 0.46, P < 0.001), prolonged length of stay (OR 0.46, P < 0.001), and discharge to destination other than home (OR 0.691, P = 0.035) compared to OH. CONCLUSION: MIH is associated with decreased risk of major morbidity, liver failure, bile leak, bleeding, prolonged length of stay, and discharge to destination other than home among elderly patients in this retrospective study. However, MIH in elderly patients does not protect against postoperative mortality.

Impact of surgical wait times on oncologic outcomes in resectable pancreas adenocarcinoma.

BACKGROUND: Timely surgical resection in patients with suspected or diagnosed pancreas adenocarcinoma is an essential part of care. We hypothesized that longer surgical wait time was associated with worse oncologic outcomes. METHODS: A retrospective cohort of patients (N = 144) with resectable pancreas adenocarcinoma was divided into four wait time groups (<4, 4-8, 8-12, and >12 weeks), defined from the time of diagnosis on cross-sectional imaging. Overall and recurrence-free survival were analyzed using the Kaplan-Meier method and Cox proportional hazards regression. A higher rate of conversion to palliative bypass in patients waiting over 4 weeks was observed and further analyzed using post-hoc multivariate regression. RESULTS: On multivariable analysis, longer wait time was associated with improved overall (HR 0.49, 95% CI: 0.28-0.85) and recurrence-free survival (HR 0.29, 95% CI: 0.15-0.56) in >12 weeks compared to <4 weeks group. On post-hoc analysis, longer wait time over 8 weeks was positively associated with palliative bypass (OR 5.33, 95% CI: 1.32-27.88). CONCLUSION: Wait time over 8 weeks was associated with a higher rate of palliative bypass. There was an improvement in overall and recurrence-free survival in patients who waited over 12 weeks, likely due to selection bias.

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.

Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma.

Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable disease-specific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables (P≤0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repair-deficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts (P=0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repair-deficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective evaluation of this finding is warranted.

HIV and liver transplantation: The British Columbia experience, 2004 to 2013.

BACKGROUND: The demand for definitive management of end-stage organ disease in HIV-infected Canadians is growing. Until recently, despite international evidence of good clinical outcomes, HIV-infected Canadians with end-stage liver disease were ineligible for transplantation, except in British Columbia (BC), where the liver transplant program of BC Transplant has accepted these patients for referral, assessment, listing and provision of liver allograft. There is a need to evaluate the experience in BC to determine the issues surrounding liver transplantation in HIV-infected patients. METHODS: The present study was a chart review of 28 HIV-infected patients who were referred to BC Transplant for liver transplantation between 2004 and 2013. Data regarding HIV and liver disease status, initial transplant assessment and clinical outcomes were collected. RESULTS: Most patients were BC residents and were assessed by the multidisciplinary team at the BC clinic. The majority had undetectable HIV viral loads, were receiving antiretroviral treatments and were infected with hepatitis C virus (n=16). The most common comorbidities were anxiety and mood disorders (n=4), and hemophilia (n=4). Of the patients eligible for transplantation, four were transplanted for autoimmune hepatitis (5.67 years post-transplant), nonalcoholic steatohepatitis (2.33 years), hepatitis C virus (2.25 years) and hepatitis B-delta virus coinfection (recent transplant). One patient died from acute renal failure while waiting for transplantation. Ten patients died during preassessment and 10 were unsuitable transplant candidates. The most common reason for unsuitability was stable disease not requiring transplantation (n=4). CONCLUSIONS: To date, interdisciplinary care and careful selection of patients have resulted in successful outcomes including the longest living HIV-infected post-liver transplant recipient in Canada.

HISTORIQUE: La demande d'une prise en charge définitive des maladies organiques terminales chez les Canadiens infectés par le VIH est en hausse. Jusqu'à tout récemment, malgré des données internationales faisant foi de résultats cliniques positifs, les Canadiens atteints d'une maladie hépatique terminale infectés par le VIH n'étaient pas admissibles à une transplantation, sauf en Colombie-Britannique (C.-B.), où le programme de transplantations de BC Transplant les accepte en vue d'un aiguillage, d'une évaluation, de l'inscription sur la liste d'attente et de l'exécution d'une allogreffe du foie. L'évaluation de l'expérience de la C.-B. s'impose pour déterminer les enjeux entourant la transplantation hépatique chez les patients infectés par le VIH. MÉTHODOLOGIE: Les chercheurs ont procédé à l'étude des dossiers des 28 patients infectés par le VIH qui ont été orientés vers BC Transplant pour subir une transplantation hépatique entre 2004 et 2013. Ils ont colligé les données sur l'état du VIH et de la maladie hépatique, l'évaluation initiale de la transplantation et les résultats cliniques. RÉSULTATS: La plupart des patients étaient des habitants de la C.-B. qui avaient été évalués par l'équipe multidisciplinaire de la clinique de C.-B. La majorité présentait des charges virales indétectables du VIH, prenaient des antirétroviraux et étaient infectés par le virus de l'hépatite C (n=16). Les comorbidités les plus courantes étaient l'anxiété et les troubles des humeurs (n=4), ainsi que l'hémophilie (n=4). Parmi les patients admissibles à la transplantation, quatre ont subi une transplantation consécutive à une hépatite auto-immune (5,67 ans après la transplantation), à une stéatose hépatique non alcoolique (2,33 ans), à un virus de l'hépatite C (2,25 ans) et à une co-infection par l'hépatite B et le virus delta (transplantation récente). Un patient est décédé d'une insuffisance rénale aiguë alors qu'il était en attente de transplantation. Dix sont décédés pendant la préévaluation et dix n'étaient pas des candidats adéquats pour la transplantation. La principale raison de ne pas être un candidat adéquat était une maladie stable ne nécessitant pas de transplantation (n=4). CONCLUSIONS: Jusqu'à présent, les soins interdisciplinaires et une sélection attentive des patients permettent d'obtenir des résultats positifs, y compris la présence au Canada du greffé hépatique infecté par le VIH ayant vécu le plus longtemps depuis sa transplantation.

Response to endoscopic therapy for biliary anastomotic strictures in deceased versus living donor liver transplantation.

BACKGROUND: Endoscopic therapy has been successful in the management of biliary complications after both deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT). LDLT is thought to be associated with higher rates of biliary complications, but there are few studies comparing the success of endoscopic management of anastomotic strictures between the two groups. This study aims to compare our experience in the endoscopic management of anastomotic strictures in DDLT versus LDLT. METHODS: This is a retrospective database review of all liver transplant patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) after liver transplantation. The frequency of anastomotic stricture and the time to develop and to resolve anastomotic stricture were compared between DDLT and LDLT. The response of anastomotic stricture to endoscopic therapy was also analyzed. RESULTS: A total of 362 patients underwent liver transplantation between 2003 and 2011, with 125 requiring ERCP to manage biliary complications. Thirty-three (9.9%) cases of DDLT and 8 (27.6%) of LDLT (P=0.01) were found to have anastomotic stricture. When comparing DDLT and LDLT, there was no difference in the mean time to the development of anastomotic strictures (98+/-17 vs 172+/-65 days, P=0.11), likelihood of response to ERCP [22 (66.7%) vs 6 (75.0%), P=0.69], mean time to the resolution of anastomotic strictures (268+/-77 vs 125+/-37 days, P=0.34), and the number of ERCPs required to achieve resolution (3.9+/-0.4 vs 4.7+/-0.9, P=0.38). CONCLUSIONS: Endoscopic therapy is effective in the majority of biliary complications relating to liver transplantation. Anastomotic strictures occur more frequently in LDLT compared with DDLT, with equivalent endoscopic treatment response and outcomes for both groups.

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.

Primary hepatic neuroendocrine tumour requiring live donor liver transplantation: case report and concise review.

Primary hepatic neuroendocrine tumours are rare tumours effecting relatively young patients. As metastatic neuroendocrine tumours to the liver are much more common, extensive investigations are crucial to exclude a primary tumour elsewhere. We report a case of a 27 year old woman who presented with fatigue, increased abdominal girth and feeling of early satiety and bloating. Extensive work up failed to show tumour at another primary site. Hepatic artery embolization showed no effect, so the patient underwent total hepatectomy and live-donor liver transplant. Grossly the tumour measured 27 cm. Microscopic examination showed bland, monomorphic cells growing in tubuloglandular and trabecular growth patterns. Cells were positive for neuroendocrine (synaptophysin, chromogranin, CD56) and epithelial markers (MOC31, CK7, CK19). Cytoplasmic dense neurosecretory vesicles were seen on ultrastructural examination. Based on the Ki-67 rate, mitotic count, lack of marked nuclear atypia and absence of necrosis, a diagnosis of primary neuroendocrine grade 2 was conferred.

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.

The role of intraperitoneal chemotherapy in the surgical management of pancreatic ductal adenocarcinoma: a systematic review.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis, particularly for patients with metastatic disease. Treatment for oligometastatic presentation has been reported in recent literature, but the role of intraperitoneal chemotherapy for patients with peritoneal metastases (PM) remains unclear. We performed a systematic literature search of the PubMed, Cochrane and Embase databases in order to identify clinical trials and case-series reporting on the safety and efficacy of intraperitoneal chemotherapy in patients with PDAC-derived PM. Eight publications reporting on 85 patients were identified, using three different therapeutic strategies. First, 37 patients received cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for PDAC with PM. Grade 3 and 4 complications occurred in 37.8% of patients, without perioperative mortality. Median disease-free survival and overall survival (OS) rates varied from 4 to 36 months and 4 to 62 months, respectively. Secondly, 40 patients with resectable PDAC without PM received prophylactic HIPEC following pancreatic resection, with postoperative morbidity and mortality rates of 30% and 5%, and 5-year OS rates of 23-24%. Finally, eight patients with PDAC-derived peritoneal disease were converted to resectable disease after receiving neoadjuvant intraperitoneal chemotherapy and operated on with curative intent, achieving a median OS of 27.8 months. In conclusion, CRS with HIPEC for PDAC-derived PM appears to be safe, conferring the same postoperative morbidity and mortality as reported on non-pancreatic malignancies. In highly selected patients, it could be considered for short-term disease control. However, long-term survival remains poor. The addition of prophylactic HIPEC for resectable PDAC cannot be recommended.

End stage liver disease etiology & transplantation referral outcomes of major ethnic groups in British Columbia, Canada: A cohort study.

ABSTRACT: Liver disease etiology and transplantation outcomes may vary by ethnicity. We aimed to determine if disparities exist in our province.We reviewed the provincial database for liver transplant referrals. We stratified cohorts by ethnicity and analyzed disease etiology and outcomes.Four thousand nine hundred sixteen referrals included 220 South Asians, 413 Asians, 235 First Nations (Indigenous), and 2725 Caucasians. Predominant etiologies by ethnicity included alcohol (27.4%) and primary sclerosing cholangitis (PSC) (8.8%) in South Asians, hepatitis B (45.5%) and malignancy (13.9%) in Asians, primary biliary cholangitis (PBC) (33.2%) and autoimmune hepatitis (AIH) (10.8%) in First Nations, and hepatitis C (35.9%) in Caucasians. First Nations had lowest rate of transplantation (30.6%, P = .01) and highest rate of waitlist death (10.6%, P = .03). Median time from referral to transplantation (268 days) did not differ between ethnicities (P = .47). Likelihood of transplantation increased with lower body mass index (BMI) (hazard ratio [HR] 0.99, P = .03), higher model for end stage liver disease (MELD) (HR 1.02, P < .01), or fulminant liver failure (HR 9.47, P < .01). Median time from referral to ineligibility status was 170 days, and shorter time was associated with increased MELD (HR 1.01, P < .01), increased age (HR 1.01, P < .01), fulminant liver failure (HR 2.56, P < .01) or South Asian ethnicity (HR 2.54, P < .01). Competing risks analysis revealed no differences in time to transplant (P = .66) or time to ineligibility (P = .91) but confirmed increased waitlist death for First Nations (P = .04).We have noted emerging trends such as alcohol related liver disease and PSC in South Asians. First Nations have increased autoimmune liver disease, lower transplantation rates and higher waitlist deaths. These data have significance for designing ethnicity specific interventions.

Human hephaestin expression is not limited to enterocytes of the gastrointestinal tract but is also found in the antrum, the enteric nervous system, and pancreatic {beta}-cells.

Hephaestin (Hp) is a membrane protein with ferroxidase activity that converts Fe(II) to Fe(III) during the absorption of nutritional iron in the gut. Using anti-peptide antibodies to predicted immunogenic regions of rodent Hp, previous immunocytochemical studies in rat, mouse, and human gut tissues localized Hp to the basolateral membranes of the duodenal enterocytes where the Hp was predicted to aid in the transfer of Fe(III) to transferrin in the blood. We used a recombinant soluble form of human Hp to obtain a high-titer polyclonal antibody to Hp. This antibody was used to identify the intracellular location of Hp in human gut tissue. Our immunocytochemical studies confirmed the previous localization of Hp in human enterocytes. However, we also localized Hp to the entire length of the gastrointestinal tract, the antral portion of the stomach, and to the enteric nervous system (both the myenteric and submucous plexi). Hp was also localized to human pancreatic beta-cells. In addition to its expression in the same cells as Hp, ferroportin was also localized to the ductal cells of the exocrine pancreas. The localization of the ferroxidase Hp to the neuronal plexi and the pancreatic beta cells suggests a role for the enzymatic function of Hp in the protection of these specialized cell types from oxidative damage.

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) overexpression in pancreatic ductal adenocarcinoma correlates with poor survival.

BACKGROUND: Pancreatic ductal adenocarcinoma is a lethal disease with a 5-year survival rate of 4% and typically presents in an advanced stage. In this setting, prognostic markers identifying the more aggressive tumors could aid in management decisions. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3, also known as IMP3 or KOC) is an oncofetal RNA-binding protein that regulates targets such as insulin-like growth factor-2 (IGF-2) and ACTB (beta-actin). METHODS: We evaluated the expression of IGF2BP3 by immunohistochemistry using a tissue microarray of 127 pancreatic ductal adenocarcinomas with tumor grade 1, 2 and 3 according to WHO criteria, and the prognostic value of IGF2BP3 expression. RESULTS: IGF2BP3 was found to be selectively overexpressed in pancreatic ductal adenocarcinoma tissues but not in benign pancreatic tissues. Nine (38%) patient samples of tumor grade 1 (n = 24) and 27 (44%) of tumor grade 2 (n = 61) showed expression of IGF2BP3. The highest rate of expression was seen in poorly differentiated specimen (grade 3, n = 42) with 26 (62%) positive samples. Overall survival was found to be significantly shorter in patients with IGF2BP3 expressing tumors (P = 0.024; RR 2.3, 95% CI 1.2-4.8). CONCLUSIONS: Our data suggest that IGF2BP3 overexpression identifies a subset of pancreatic ductal adenocarcinomas with an extremely poor outcome and supports the rationale for developing therapies to target the IGF pathway in this cancer.

Predictors of relapse to significant alcohol drinking after liver transplantation.

BACKGROUND: End-stage alcoholic liver disease is common, with many of these patients referred for liver transplantation (LT). Alcohol relapse after LT can have detrimental outcomes such as graft loss and can contribute to a negative public perception of LT. OBJECTIVE: To identify factors that predict the recurrence of harmful alcohol consumption after LT. METHODS: A total of 80 patients who underwent LT for alcoholic cirrhosis or had significant alcohol consumption in association with another primary liver disease, from July 1992 to June 2006 in British Columbia, were retrospectively evaluated by chart review. Several demographic-, psychosocial- and addiction-related variables were studied. Univariate and multivariate logistic regression analyses were used to test possible associations among the variables studied and a return to harmful drinking after LT. RESULTS: The relapse rate of harmful alcohol consumption post-liver transplant was 10%, with two patient deaths occurring directly as a result of alcohol relapse. Univariate analysis revealed relapse was significantly associated with pretransplant abstinence of less than six months (P=0.003), presence of psychiatric comorbidities (P=0.016), female sex (P=0.019) and increased personal stressors (P=0.044), while age at transplant of younger than 50 years approached significance (P=0.054). Multivariate logistic regression analysis revealed the following independent factors for relapse: pretransplant abstinence of less than six months (OR 77.07; standard error 1.743; P=0.013) and female sex (OR 18.80; standard error 1.451; P=0.043). CONCLUSION: The findings of the present study strongly support a required minimum of six months of abstinence before LT because duration of abstinence was found to be the strongest predictor of recidivism. Female sex, younger age at transplant and psychiatric comorbidities were also associated with relapse to harmful drinking.

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.

Choledochal cysts. Part 3 of 3: management.

Much about the etiology, pathophysiology, natural course and optimal treatment of cystic disease of the biliary tree remains under debate. Gastroenterologists, surgeons and radiologists alike still strive to optimize their roles in the management of choledochal cysts. To that end, much has been written about this disease entity, and the purpose of this 3-part review is to organize the available literature and present the various theories currently argued by the experts. In part 3, we discuss the management of choledochal cysts, thus completing our comprehensive review.

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.