Faculty Bibliography

We sought to estimate the effect of smoking on the biliary complication rate following orthotopic liver transplantation. We retrospectively evaluated the records of liver transplant recipients at our center from July 1, 1999 to October 26, 2007. Using Cox proportional hazards models, we estimated the time to the earliest biliary complication (leak or stricture) based on smoking exposure, as active, former, or lifetime nonsmoker, adjusting for other clinical factors. Overall, 409 liver transplant recipients were evaluated. The overall biliary complication rate was 37.7% (n = 154). Biliary complications included 66 anastomotic leaks, 60 anastomotic strictures, and 28 nonanastomotic lesions. ERCP was the primary diagnostic modality (n = 112). 18.1% of liver transplant recipients were active smokers (n = 74) and 42.8% were former smokers (n = 175). Active smokers were at greatest risk for biliary complications on unadjusted analysis (P = 0.022). After multivariable adjustment, active smokers had a 92% higher rate of biliary complication rates compared with lifetime nonsmokers (HR 1.92, 95% CI 1.07-3.43), but no difference was noted in the rate of complication resolution. Smoking clearly portends a significant risk of biliary complications following liver transplantation. Smoking status should be clearly defined when evaluating transplant candidacy and in counseling patients with cirrhosis.

BACKGROUND & AIMS: Growth of many different tumor types requires a population of self-renewing cancer stem cells (CSCs). c-Met is a marker of normal mouse pancreatic stem and progenitor cells; we investigated whether it is also a marker of human pancreatic CSCs that might be developed as a therapeutic target. METHODS: We studied growth of primary human pancreatic adenocarcinoma in NOD SCID mice. The self-renewal capability of pancreatic cancer cells that expressed high levels of c-Met (c-Met(high)) was assessed using in vitro sphere assays and compared with those that were c-Met negative or expressed low levels of c-Met. The tumorigenicity of c-Met(high) pancreatic cancer cells was evaluated in NOD SCID mice. RESULTS: c-Met(high) cells readily formed spheres, whereas c-Met-negative cells did not. Use of the c-Met inhibitor XL184 or c-Met knockdown with small hairpin RNAs significantly inhibited tumor sphere formation. c-Met(high) cells had increased tumorigenic potential in mice; those that expressed c-Met and CD44 (0.5%-5% of the pancreatic cancer cells) had the capability for self-renewal and the highest tumorigenic potential of all cell populations studied. In pancreatic tumors established in NOD SCID mice, c-Met inhibitors slowed tumor growth and reduced the population of CSCs when given alone or in combination with gemcitabine. Administration of XL184 for 2 weeks after cardiac injection of cancer cells prevented the development of metastases. CONCLUSIONS: c-Met is a new marker for pancreatic CSCs. It is required for growth and metastasis of pancreatic tumors in mice and is a therapeutic target for pancreatic cancer.

BACKGROUND: The effect of obesity on perioperative outcomes following hepatic resection is not clearly defined. We sought to understand the implications of obesity on post-hepatectomy outcomes in a nationally represented cohort of patients. METHODS: Using a retrospective cohort design, we studied the effect of obesity on complications and 30-day mortality using multivariable logistic regression using comprehensive clinical data from the American College of Surgeons National Surgical Quality Improvement Program (2005-2008). RESULTS: During our study period, 3,960 patients underwent hepatic resection; 32.4% had a normal body mass index (BMI; 18.5-24.9 kg/m(2)), 2.5% were underweight (<18.5 kg/m(2)), 33.4% were overweight (25.0-29.9 kg/m(2)), and 31.7% were obese (>30.0 kg/m(2)). 23.3% had at least one post-operative complication and the overall mortality rate was 2.5%. Compared to normal patients, obese patients had significantly higher unadjusted odds of having a complication (26.5% vs. 21.3%, OR 1.34, 95% CI 1.12-1.61) and dying (3.0% vs. 1.7%, OR 1.79, 95% CI 1.05-3.05). The obese were also more likely to have multiple complications compared to normal BMI patients (6.1% vs. 3.7%, OR 1.70, 95% CI 1.17-2.46). After risk adjustment, obesity was associated with attenuated but significantly higher odds of having any perioperative complication (OR 1.24, 95% CI 1.01-1.55), but was not a significant predictor of mortality. CONCLUSIONS: After adjusting for other clinical factors, the degree of obesity is independently associated with an increasing complication rate but not mortality. Risk adjustment may not capture the total clinical risk of patients at the extremes of BMI.

BACKGROUND: Following hepatectomy for malignancy, the effect of body mass index (BMI) on hepatic and oncologic outcomes is unknown. METHODS: Two hundred seventy-nine post-hepatectomy patients with malignancy from our center were included in the cohort (1996-2006). BMI was categorized using World Health Organization criteria. The effect of BMI was evaluated using risk-adjusted Cox models for time to recurrence and overall survival. RESULTS: Seventy-nine patients (28.3%) had primary hepatobiliary cancers, 134 (48.0%) had colorectal metastases, and 66 (25.3%) had other metastases. Thirty-five percent of patients were obese (BMI > 30). Obese patients had more hepatic-specific perioperative complications (27.8% vs. 15.9%, p = 0.018), bile leaks (18.6% vs. 9.9%, p = 0.030), post-operative pneumonia (9.3% vs. 2.2%, p = 0.0074), intra-abdominal abscesses (7.2% vs. 1.7%, p = 0.017), acute renal failure (7.2% vs. 1.7%, p = 0.017), urinary tract infections (16.4% vs. 7.7%, p = 0.024), and longer lengths of stay (10.5 vs.8.6 days, p = 0.029). Obese and non-obese patients had similar perioperative mortality, time to recurrence, and overall survival on univariate analysis. However, after adjusting for demographic, tumor, and operative characteristics, and complications, increasing BMI displayed improved recurrence-free (HR 0.90, 95% CI 0.86-0.95) and overall survival (HR 0.96, 95% CI 0.92-0.99). CONCLUSIONS: High BMI patients may have better oncologic outcomes despite higher perioperative morbidity and hepatic complications following hepatectomy. These findings have important clinical and biological implications.

BACKGROUND: The incidence of cholangiocarcinoma is rising. Accurate predictors of survival at diagnosis are not well defined. AIM: To clarify the clinical presentation and prognostic factors of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma in a contemporary cohort of patients. METHODS: Records for consecutive patients at the University of Michigan hospital diagnosed with cholangiocarcinoma between January 2003 and April 2008 were reviewed. RESULTS: In all, 136 patients had cholangiocarcinoma (79 intra- and 57 extrahepatic cholangiocarcinoma). Median survival was 27.3 months-25.8 months for intrahepatic cholangiocarcinoma and 30.3 months for extrahepatic cholangiocarcinoma. Independent predictors of mortality at presentation on multivariate analysis were elevated bilirubin level (HR 1.04, 95%CI 1.01-1.07), CA 19-9 levels >100 U/mL (HR 1.90, 95%CI 1.17-3.08) and stage of disease (HR 1.51, 95%CI 1.16-1.96). After adjusting for baseline prognostic factors, surgical therapy was associated with improved survival (HR 0.48; 95% CI 0.26-0.88). There were no significant differences regarding clinical presentation, disease stage (P = 0.98), and survival (P = 0.51) between intra- and extrahepatic cholangiocarcinoma. CONCLUSIONS: Survival for cholangiocarcinoma remains poor with no significant difference in outcomes between intra- and extrahepatic cholangiocarcinoma. Stage of disease, bilirubin level and CA 19-9 level are important prognostic factors at presentation. Surgical therapy provides similar efficacy for both tumours when adjusted for other prognostic variables.

The effects of occlusive portal vein thrombosis (PVT) on the survival of patients with cirrhosis are unknown. This was a retrospective cohort study at a single center. The main exposure variable was the presence of occlusive PVT. The primary outcome measure was time-dependent mortality. A total of 3295 patients were analyzed, and 148 (4.5%) had PVT. Variables independently predictive of mortality from the time of liver transplant evaluation included age [hazard ratio (HR), 1.02; 95% confidence interval (CI), 1.01-1.03], Model for End-Stage Liver Disease (MELD) score (HR, 1.10; 95% CI, 1.08-1.11), hepatitis C (HR, 1.44; 95% CI, 1.24-1.68), and PVT (HR, 2.61; 95% CI, 1.97-3.51). Variables independently associated with the risk of mortality from the time of liver transplant listing included age (HR, 1.02; 95% CI, 1.01-1.03), transplantation (HR, 0.65; 95% CI, 0.50-0.81), MELD (HR, 1.08; 95% CI, 1.06-1.10), hepatitis C (HR, 1.50; 95% CI, 1.18-1.90), and PVT (1.99; 95% CI, 1.25-3.16). The presence of occlusive PVT at the time of liver transplantation was associated with an increased risk of death at 30 days (odds ratio, 7.39; 95% CI, 2.39-22.83). In conclusion, patients with cirrhosis complicated by PVT have an increased risk of death.