Faculty Bibliography

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.

B7-H1 is a recently identified B7 family member that, along with one of its receptors, programmed death-1 (PD-1), has been involved in multiple immunopathologic scenarios. However, the nature of B7-H1 and PD-1 in human hepatocellular carcinoma (HCC) remains poorly defined. We investigated the expression and functional relevance of this pathway in patients with HCC. We showed that B7-H1 expression on Kupffer cells (KC) was increased in tumor tissues compared with surrounding nontumor liver tissues in patients with HCC and this correlated with poorer survival. Coculture of HCC cells with monocytes showed that tumor-associated interleukin-10 contributed to the induction of B7-H1 in the HCC environment. We further observed that the levels of PD-1(+)CD8(+) T cells were higher in tumor tissues than in nontumor tissues. B7-H1(+) KCs and PD-1(+) T cells were colocalized in the HCC stroma. PD-1(+)CD8(+) T cells had decreased proliferative ability and effector function as shown by reduced granule and cytokine expression compared with PD-1(-) T cells. Importantly, blocking KC B7-H1 interaction with PD-1(+)CD8(+) cells using neutralizing antibodies recovered effector T-cell function. Our data indicate that the B7-H1/PD-1 axis contributes to immune suppression in human HCC, with blockade of this pathway carrying important therapeutic implications.

Th17 cells play an active role in autoimmune diseases. However, the nature of Th17 cells is poorly understood in cancer patients. We studied Th17 cells, the associated mechanisms, and clinical significance in 201 ovarian cancer patients. Tumor-infiltrating Th17 cells exhibit a polyfunctional effector T-cell phenotype, are positively associated with effector cells, and are negatively associated with tumor-infiltrating regulatory T cells. Tumor-associated macrophages promote Th17 cells through interleukin-1beta (IL-1beta), whereas tumor-infiltrating regulatory T cells inhibit Th17 cells through an adenosinergic pathway. Furthermore, through synergistic action between IL-17 and interferon-gamma, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome. Altogether, Th17 cells may contribute to protective human tumor immunity through inducing Th1-type chemokines and recruiting effector cells to the tumor microenvironment. Inhibition of Th17 cells represents a novel immune evasion mechanism. This study thus provides scientific and clinical rationale for developing novel immune-boosting strategies based on promoting the Th17 cell population in cancer patients.