Faculty Bibliography

The liver is the most common site of adenocarcinoma metastases, even in patients who initially present with early disease. We postulated that immune-suppressive cells in the liver of tumor-bearing hosts inhibit anti-tumor T cells, thereby accelerating the growth of liver metastases. Using models of early preinvasive pancreatic neoplasia and advanced colorectal cancer, aims of this study were to determine immune phenotype, stimulus for recruitment, inhibitory effects, and tumor-enabling function of immune-suppressive cells in the liver of tumor-bearing hosts. We found that in mice with intra-abdominal malignancies, two distinct CD11b(+)Gr1(+) populations with divergent phenotypic and functional properties accumulate in the liver, becoming the dominant hepatic leukocytes. Their expansion is contingent on tumor expression of KC. These cells are distinct from CD11b(+)Gr1(+) populations in other tissues of tumor-bearing hosts in terms of cellular phenotype and cytokine and chemokine profile. Liver CD11b(+)Gr1(+) cells are highly suppressive of T cell activation, proliferation, and cytotoxicity and induce the development of Tregs. Moreover, liver myeloid-derived suppressor cells accelerate the development of hepatic metastases by inactivation of cytotoxic T cells. These findings may explain the propensity of patients with intra-abdominal cancers to develop liver metastases and suggest a promising target for experimental therapeutics

Hepatic fibrosis occurs during most chronic liver diseases and is driven by inflammatory responses to injured tissue. Because DCs are central to modulating liver immunity, we postulated that altered DC function contributes to immunologic changes in hepatic fibrosis and affects the pathologic inflammatory milieu within the fibrotic liver. Using mouse models, we determined the contribution of DCs to altered hepatic immunity in fibrosis and investigated the role of DCs in modulating the inflammatory environment within the fibrotic liver. We found that DC depletion completely abrogated the elevated levels of many inflammatory mediators that are produced in the fibrotic liver. DCs represented approximately 25% of the fibrotic hepatic leukocytes and showed an elevated CD11b+CD8- fraction, a lower B220+ plasmacytoid fraction, and increased expression of MHC II and CD40. Moreover, after liver injury, DCs gained a marked capacity to induce hepatic stellate cells, NK cells, and T cells to mediate inflammation, proliferation, and production of potent immune responses. The proinflammatory and immunogenic effects of fibrotic DCs were contingent on their production of TNF-alpha. Therefore, modulating DC function may be an attractive approach to experimental therapeutics in fibro-inflammatory liver disease

BACKGROUND: The pathogenesis of biliary cancers is ill-defined. This study investigates changes in gene expression and copy number in biliary cancers and correlates these changes with anatomical site of origin, histopathology and outcome. METHODS: We performed gene expression and CGH analysis on 34 biliary tract cancer specimens. Results were confirmed by RT-PCR. Clinical-pathologic correlation was made using functional over-representation analysis of the top 100 mutations associated with each variable. RESULTS: There were 545 genes with altered expression in extrahepatic cholangiocarcinoma, 2,354 in intrahepatic cholangiocarcinoma, and 1,281 in gallbladder cancer. Unsupervised hierarchical clustering analysis indicated there was no difference in the global gene expression patterns between each biliary cancer subgroup. CGH analysis revealed that short segments of chromosomes 1p, 3p, 6q, 8p, 9p, and 14q were commonly deleted across all cancer subtypes. Commonly amplified regions included segments of 1q, 3q, 5p, 7p, 7q, 8q, and 20q. Over-representation analysis revealed an association between altered expression of functional gene groupings and pathologic features. CONCLUSION: This study defined regions of the genome associated with changes in DNA copy number and gene expression in specific subtypes of biliary cancers. The findings have implications for identification of therapeutic targets, screening, and prognostication

Although it is the most common cancer of the biliary tree, gallbladder carcinoma remains an uncommon disease. As a result, many clinicians rarely encounter it and there is uncertainty regarding proper management. Resection is the most effective and only potentially curative treatment. Early stage tumors are often curable with a proper resection; however, many patients present late in the course of the disease when surgical intervention is no longer effective. While other treatment modalities are used in patients with advanced disease, there is limited data on efficacy. In many cases, the diagnosis is made after a cholecystectomy has been performed and an incidental tumor is identified in the specimen. In such cases, reoperation and definitive resection is appropriate and effective for patients with invasive lesions

CONTEXT: The main pancreatic duct can form a fistulous communication with another epithelium in the setting of prolonged inflammation, operative manipulation, or direct trauma. We present a rare complication of a pancreaticoureteral fistula following a trauma nephrectomy. CASE REPORT: A 17-year-old male who sustained a gunshot wound to the back arrived to our Emergency Room hyopotensive, tachycardic, and with free intraperitoneal fluid on focused assessment sonography for trauma (FAST) exam. He was taken to the operating room for an exploratory laporatomy where a left nephrectomy was performed to control active bleeding from the left renal hilum. Significant bleeding was also encountered at the portal venous confluence. After packing and damage control laparotomy, the periportal/pancreatic bleeding was controlled during a second procedure 6 hours later. After one month in the Intensive Care Unit with an open abdomen, a computed tomography (CT) scan revealed a fluid collection in the splenic fossa which was drained by catheter. Persistent drainage revealed a high amylase concentration (greater than 50,000 U/L). A fistulogram revealed interruption of the main pancreatic duct, and a fluid collection by the tail of the pancreas that was in communication with the left ureter. The patient's urine amylase was also elevated. The patient was treated non-operatively given the healing open abdomen and controlled fistula. He had an otherwise uncomplicated recovery. CONCLUSIONS: This is the second report of a pancreaticoureteral fistula in the literature. Treatment of this communication should be similar to that of other pancreatic fistulae

BACKGROUND: Surgical resection of isolated hepatic or pulmonary colorectal metastases prolongs survival in selected patients. But the benefits of resection and appropriate selection criteria in patients who develop both hepatic and pulmonary metastases are ill defined. STUDY DESIGN: Data were prospectively collected from 131 patients with colorectal cancer who underwent resection of both hepatic and pulmonary metastases over a 20-year period. Median followup was 6.6 years from the time of resection of the primary tumor. Patient, treatment, and outcomes variables were analyzed using log-rank, Cox regression, and Kaplan-Meier methods. RESULTS: The site of first metastasis was the liver in 65% of patients, the lung in 11%, and both simultaneously in 24%. Multiple hepatic metastases were present in 51% of patients, and multiple pulmonary metastases were found in 48%. Hepatic lobectomy or trisegmentectomy was required in 61% of patients; most lung metastases (80%) were treated with wedge excisions. Median survival rates from resection of the primary disease, first site of metastasis, and second site of metastasis were 6.9, 5.0, and 3.3 years, respectively. After resection of disease at the second site of metastasis, the 1-, 3-, 5-, and 10-year disease-specific survival rates were 91%, 55%, 31%, and 19%, respectively. An analysis of prognostic factors revealed that survival was significantly longer when the disease-free interval between the development of the first and second sites of metastases exceeded 1 year, in patients with a single liver metastasis, and in patients younger than 55 years old. CONCLUSIONS: Surgical resection of both hepatic and pulmonary colorectal metastases is associated with prolonged survival in selected patients. Patients with a longer disease-free interval between metastases and those with single liver lesions had the best outcomes

This review addresses the optimal use of imaging in the diagnosis, staging, and treatment planning of patients with hepatobiliary neoplasms. We focus on primary liver cancers, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma as well as extrahepatic biliary tract malignancies, including hilar cholangiocarcinoma and gallbladder cancer. In each section, we provide an overview of the staging requirements for each disease followed by a discussion of various imaging modalities that can be used to optimally stage the disease and plan therapy