Faculty Bibliography

Hilar cholangiocarcinoma (CCA) is a difficult malignancy to treat surgically because of its anatomical location and its frequent association with primary sclerosing cholangitis. Neoadjuvant chemoradiotherapy followed by liver transplantation in lymph node-negative patients has been advanced by select liver transplant centers for the treatment of patients with unresectable disease. This approach has most commonly used external-beam radiotherapy in combination with biliary brachytherapy and 5-fluorouracil-based chemotherapy. Our center recently embarked on a protocol using stereotactic body radiation therapy (SBRT) followed by capecitabine in lymph node-negative patients until liver transplantation. We, therefore, retrospectively determined the tolerability and pathological response in this pilot study. During a 3-year period, 17 patients with unresectable hilar CCA were evaluated for treatment under this protocol. In all, 12 patients qualified for neoadjuvant therapy and were treated with SBRT (50-60 Gy in 3-5 fractions over the course of 2 weeks). After 1 week of rest, capecitabine was initiated at 1330 mg/m(2) /day, and it was continued until liver transplantation. During neoadjuvant therapy, there were 35 adverse events in all, with cholangitis and palmar-plantar erythrodysesthesia being the most common. Capecitabine dose reductions were required on 5 occasions. Ultimately, 9 patients were listed for transplantation, and 6 patients received a liver transplant. The explant pathology of hilar tumors showed at least a partial treatment response in 5 patients, with extensive tumor necrosis and fibrosis noted. Additionally, high apoptotic indices and low proliferative indices were measured during histological examinations. Eleven transplant-related complications occurred, and the 1-year survival rate after transplantation was 83%. In this pilot study, neoadjuvant therapy with SBRT, capecitabine, and liver transplantation for unresectable CCA demonstrated acceptable tolerability. Further studies will determine the overall future efficacy of this therapy.

Optimal T cell response is dependent not only on T cell receptor activation, but also on additional signaling from coreceptors. The main coreceptors include B7 and tumor necrosis factor family members. They exert costimulatory or coinhibitory effects, and their balance determines the fate of T cell response. In normal conditions, costimulators facilitate the development of protective immune response, whereas coinhibitors dampen inflammation to avoid organ/tissue damage from excessive immune reaction. In the tumor microenvironment, the balance is garbled: inhibitory pathways predominate, and T cell response is impaired. The importance of cosignaling in the tumor immune response has been experimentally and clinically demonstrated. New therapeutic strategies targeting T cell cosignaling, especially coinhibitory molecules, are under active experimental and clinical investigation. This review summarizes the functions of main T cell cosignaling axes and discusses their clinical application.

Human tumors progress despite the presence of tumor associated antigen (TAA)-specific T cells. Many different molecular and cellular mechanisms contribute to the failure of T cells to eradicate the tumor. These include immune suppressive networks that impair ongoing T cell function and enable tumor escape. Recent studies have started to reveal the nature of effector T cells in the tumor microenvironment. In this article we discuss T cell anergy, exhaustion, senescence, and stemness, and review the phenotype of dysfunctional T cell subsets and the underlying molecular mechanisms in the tumor microenvironments. We suggest that targeting T cell dysfunctional mechanisms and introducing/promoting T cell stemness are important approaches to treat patients with cancer.

Tumor immune responses have prognostic importance to hepatocellular carcinoma (HCC). Serum cytokines may differentiate HCC patients from cirrhotic patients or have prognostic significance. Serum IL-8 was elevated in 90 HCC patients compared to 180 cirrhotic controls, whereas IL-1beta, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17, IL-21, and VEGF were similar. IL-8 predicted HCC presence with an area under the receiver-operator curve (ROC) of 0.68. HCC patients with highest IL-8 had worse survival. Multivariate analysis showed that high IL-8 (HR 2.15; 95%CI:1.21-3.74) and stage (HR 1.92; 95%CI:1.22-3.97) independently predicted mortality; while viral etiology was protective (HR 0.69; 95%CI:0.41-0.98). Therefore, HCC IL-8 mediated events may be worthy of future investigation.

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.

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.