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Background and study aims Endoscopic mucosal resection (EMR) is safe and cost-effective in management of patients with colon polyps. However, very little is known about the actions of the referring endoscopist following identification of these lesions at index colonoscopy, and the impact of those actions on the outcome of subsequent referral for EMR. The aim of this study was to identify practices at index colonoscopy that lead to failure of subsequent EMR. Patients and methods Two hundred and eighty-nine consecutive patients with biopsy-proven non-malignant colon polyps (> 20 mm) referred for EMR were analyzed to identify practices that could be improved from the time of identifying the lesion at index colonoscopy until completion of therapy. Results EMR was abandoned at colonoscopy at the EMR center in 71 of 289 patients (24.6 %). Reasons for abandoning EMR included diagnosis of invasive carcinoma (n = 9; 12.7 %), tethered lesions (n = 21; 29.6 %) from prior endoscopic interventions, and overly large (n = 22; 31 %) and inaccessible lesions (n = 17; 24 %) for complete and safe resection whose details were not recorded in the referring endoscopy report, or polyposis syndromes (n = 2; 2.8 %) that were not recognized. Conclusions In our practice, one in four EMR attempts were abandoned as a result of inadequate diagnosis or management by the referring endoscopist, which could be improved by education on optical diagnosis of polyps, comprehensive documentation of the procedure and avoidance of interventions that preclude resection.

Cholangiocarcinoma (CCA) is the second most common primary malignancy. Although it is more common in Asia, its incidence in Europe and North America has significantly increased in recent decades. The prognosis of CCA is dismal. Surgery is the only potentially curative treatment, but the majority of patients present with advanced stage disease, and recurrence after resection is common. Over the last two decades, our understanding of the molecular biology of this malignancy has increased tremendously, diagnostic techniques have evolved, and novel therapeutic approaches have been established. This review discusses the changing epidemiologic trends and provides an overview of newly identified etiologic risk factors for CCA. Furthermore, the molecular pathogenesis is discussed as well as the influence of etiology and biliary location on the mutational landscape of CCA. This review provides an overview of the diagnostic evaluation of CCA and its staging systems. Finally, new therapeutic options are critically reviewed, and future therapeutic strategies discussed.

Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury, and promotes the development of cancer. We report here a major role for the TGF-β/Smad3 adaptor β2-Spectrin (β2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. β2SP supports DNA repair through β2SP-dependent activation of Fancd2, a core component of the Fanconi anemia complex. Loss of β2SP leads to decreased Fancd2 levels and sensitizes β2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both Aldh2 and Fancd2, and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA cross-linking agents, and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/TGF-β stimulation is regulated by the β2SP/Smad3 complex. Thus, dysfunctional TGF-β/β2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. This article is protected by copyright. All rights reserved.

Background and Aims The adenoma detection rate (ADR) is a quality metric tied to interval colon cancer occurrence. However, manual extraction of data to calculate and track the ADR in clinical practice is labor-intensive. To overcome this difficulty, we developed a natural language processing (NLP) method to identify adenomas and sessile serrated adenomas (SSAs) in patients undergoing their first screening colonoscopy. We compared the NLP-generated results with that of manual data extraction to test the accuracy of NLP and report on colonoscopy quality metrics using NLP. Methods Identification of screening colonoscopies using NLP was compared with that using the manual method for 12,748 patients who underwent colonoscopies from July 2010 to February 2013. Also, identification of adenomas and SSAs using NLP was compared with that using the manual method with 2259 matched patient records. Colonoscopy ADRs using these methods were generated for each physician. Results NLP correctly identified 91.3% of the screening examinations, whereas the manual method identified 87.8% of them. Both the manual method and NLP correctly identified examinations of patients with adenomas and SSAs in the matched records almost perfectly. Both NLP and the manual method produced comparable values for ADRs for each endoscopist and for the group as a whole. Conclusions NLP can correctly identify screening colonoscopies, accurately identify adenomas and SSAs in a pathology database, and provide real-time quality metrics for colonoscopy.

Background Diarrhea and colitis are the second most common immune checkpoint inhibitor (ICPI)-induced adverse events. However, a comprehensive characterization of the endoscopic and histologic features of ICPI-induced diarrhea and colitis is lacking. Therefore, we aimed to describe endoscopic and histologic features of ICPI-induced gastrointestinal toxicities and to assess their association with patients' clinical characteristics and outcomes. Methods We retrospectively reviewed records of 53 patients with ICPI-related diarrhea/colitis between 2011 and 2017. We collected data on demographics, diarrhea/colitis grade, treatment, and endoscopic and histologic findings. Long-term follow-up included repeat endoscopy findings, diarrhea recurrence, and overall survival. We compared groups by treatment, endoscopic and histologic findings, and constructed Kaplan-Meier survival curves. Results Most patients had grade 2 or higher diarrhea (87%) and colitis (60%). Thirty-one patients were successfully treated with corticosteroids, and 22 additionally required infliximab. On endoscopy, 21 (40%) patients had ulcerations and 22 (42%) had nonulcerative inflammation. Patients with ulcerations had more steroid-refractory disease (P = 0.044) and high-grade diarrhea (P = 0.033). Histology showed mostly acute (23%) or chronic (60%) inflammation. During mean follow-up duration of 18.9 months, 19 (36%) developed recurrent diarrhea. Most patients had persistent endoscopic (8/13, 62%) and histologic (9/11, 82%) inflammation. Patients with higher-grade adverse events had improved survival. Higher-grade colitis was associated with endoscopic inflammation (P = 0.039), but grade of diarrhea was not associated with endoscopic inflammation or grade of colitis. Conclusion 10.1093/ibd/izy104_video1izy104.video15808053084001.

AIM Immunocompromised patients can develop chronic hepatitis E virus (HEV) infection and progress to cirrhosis. Hepatitis C virus (HCV)-infected cancer patients who have received chemotherapeutic agents experience accelerated liver fibrosis progression. Our aim was to investigate the prevalence and impact of HEV seropositivity on liver-related outcomes in HCV-infected cancer patients. METHODS As part of a prospective study of HCV-infected cancer patients conducted at our center, we investigate the characteristics associated with progression of their liver disease. RESULTS Of the 115 patients tested, 13 (11%) were positive for HEV immunoglobulin G. HEV seropositivity was associated with advanced age (P = 0.004), race (P = 0.02), place of birth outside the USA (P = 0.021), cirrhosis (P = 0.027), history of reused needles/syringes during massive vaccination campaigns (P = 0.015) and coronary artery disease (P = 0.039). Overall, 47 (41%) of the patients had cirrhosis. Factors independently associated with cirrhosis were male sex (odds ratio [OR], 2.8; P = 0.028) and HEV seropositivity (OR, 4.1; P = 0.032). CONCLUSION HEV seropositivity is present in 11% of HCV-infected cancer patients and seems to be associated with cirrhosis. Our results suggest that HEV screening should be implemented in HCV-infected patients with cancer.

Background Adult hemophagocytic lymphohistiocytosis is a secondary immunopathologic phenomenon, mainly secondary to malignancy, infection, or autoimmune disorders. The performance of diagnostic criteria, studied in the pediatric population, is yet to be validated in the adult population. Some of the criteria include cytopenias and organomegaly that are inherent features to malignant processes, thus making the diagnosis of hemophagocytic lymphohistiocytosis a challenge in patients with cancer. Case presentation We describe the case of a 54-year-old white man with history of metastatic maxillary sinus adenoid cystic carcinoma who had severe liver injury and cytopenias with progressive clinical deterioration. We performed an evaluation, by flow cytometry, of the expression of surface markers in his natural killer cells that revealed remarkable abnormalities. His syndrome eventually fulfilled criteria for hemophagocytic lymphohistiocytosis and he received therapy with steroids with interval clinical improvement. Unfortunately, he refused further cytotoxic treatment and died 2 weeks later. Conclusions The conventional criteria for the diagnosis of hemophagocytic lymphohistiocytosis are suboptimal for adult patients with cancer resulting in delays in diagnosis and timely initiation of treatment. The diagnostic criteria have to be re-evaluated in patients with cancer; novel, easily available, and accurate diagnostic methods are needed.

Cholangiocarcinoma (CCA) is a malignancy arising in the biliary tree. Its incidence rates have increased, and it has surpassed gallbladder carcinoma as the most common biliary tract malignancy. Most patients are diagnosed with advanced stage disease and are not amenable to potentially curative surgical therapies. The prognosis is dismal with a median survival of

Severe hepatitis C reactivation as an early complication of hematopoietic cell transplantation

A 66-year-old male patient who is hepatitis C RNA positive, without cirrhosis, has been found to have a mass on ultrasound examination of the liver. Physical examination is unremarkable. The hemoglobin, white cell count and platelet counts are normal. The alkaline phosphatase is mildly elevated to 212 U/L(normal

Cholangiocarcinoma (CCA) is an epithelial cancer originating from the bile ducts with features of cholangiocyte differentiation.1 CCA is the second most common primary hepatic malignancy, and epidemiologic studies suggest its incidence is increasing in Western countries.2 Advanced CCA has a devastating prognosis, with a median survival of

Attenuated measles viruses (MVs) propagate selectively in human tumor cells, and phase I clinical trials are currently underway to test their oncolytic activity. A major theoretical impediment to systemic MV application is the presence of pre-existing antiviral immunity. We hypothesized that autologous MV-infected cells might be a more reliable vehicle than cell-free virions to deliver the infection to tumor cells in subjects with neutralizing titers of anti-measles antibodies. Our in vitro studies, using a dual-color fluorescent model, demonstrated efficient cell-to-cell transfer of infection via heterofusion. In contrast to infection by naked virions, heterofusion between infected cell carriers and tumor cells was more resistant to antibody neutralization. Infected monocytic, endothelial, or stimulated peripheral blood cells could deliver oncolytic MV to tumor lesions in vivo, after intravenous (i.v.) or intraperitoneal (i.p.) administration. Single or repeated i.p. injections of monocytic carriers significantly improved survival of animals bearing human ovarian cancer xenografts. Systemic or i.p. injection of MV-infected cells successfully transferred infection by heterofusion to Raji lymphomas or hepatocellular carcinoma tumors in the presence of neutralizing antibodies. These results suggest a novel strategy for systemic delivery of oncolytic virotherapy in cancer patients that can "bypass" the pre-existing humoral immunity against MV.

Nonalcoholic steatohepatitis describes a hepatic disorder with the typical characteristics of an alcoholic pathogenesis without alcohol consumption. It was first described in 1962 and named NASH by Ludwig et al. 1980. Many researchers worked on this disease since this time. It represents the hepatic manifestation of the syndrome X. The pathogenesis is a two-hit phenomenon. The first hit leads to steatosis hepatis and makes the liver vulnerable to the second hit. Central factors of the second hit are oxygen-radicals, oxidative stress, lipid-peroxidation and cytokines. The exact pathogenic mechanisms are still unknown. NASH is a hepatic disease which can end up in liver cirrhosis and liver failure. Up to now a curative drug therapy does not exist. The poor prognosis in some cases, the increasing incidence in western populations and the lack of therapeutic options renders NASH to a serious problem. The aim of this article is to show the actual knowledge of this disease, especially focussed on the pathogenesis, by review of the literature from 1979 up to the present time.

67 Background: Immune-based cancer treatment (IBCT) is increasingly used to treat a variety of cancers. Despite the promising results, adverse events such as dermatitis, colitis, and hepatitis remain a concern. Hepatitis is usually mild but may be severe, requiring modification or cessation of treatment. Here, we describe several cases of immune-mediated hepatitis. Methods: We identified patients enrolled in clinical trials using IBCT through the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, between January 2010 and July 2015. Charts were reviewed for mention of “autoimmune hepatitis”, “hepatitis” or abnormal transaminases, all of which were attributed to IBCT by the treating physician. Hepatotoxicity was graded based on CTCAE v4.0. Results: We identified 12 cases of immune-related hepatotoxicity out of 290 patients. Three patients (1.03%) had grade 3 elevation of transaminases, designated as “autoimmune hepatitis.” Each required systemic steroids and transaminases returned to baseline within a month. IBCT was temporarily held in 2 cases and was permanently discontinued in the third due to grade 4 myositis rather than hepatitis. One patient (0.3%) had grade 2, and eight patients (2.8%) had grade 1 transaminases elevations that were possibly attributable to immunotherapy, but which resolved spontaneously without alteration in treatment. Other significant reported immune-related toxicities ≥ grade 3 were: dermatitis (n = 4), enterocolitis (n = 3), myasthenia gravis (n = 2), myositis (n = 2), pneumonitis, pleuritis, and pancreatitis (n = 1 each). Conclusions: 1.03% of patients experienced grade 3 elevation of transaminases that were attributable to immune therapy. Hepatic adverse events related to immunotherapy in our study were manageable. Further studies are needed to develop biomarkers to identify patients at risk to develop such toxicities. [Table: see text]

Unsere Wohlstandsgesellschaft fuhrt in Folge von ubermasigem Alkoholkonsum, Ubergewicht und Bewegungsmangel zu einer steigenden Pravalenz der Fettleber (Steatosis hepatis). Die vorliegende Ubersicht beschreibt Definition und pathogenetische Vorstellungen von Fettleber und Fettleberhepatitis. Die diagnostischen Moglichkeiten zur Differenzierung dieser Entitaten werden aufgezeigt. Darauf aufbauend werden Konzepte zur Therapie der alkoholischen und nichtalkoholischen Fettleber vorgestellt. Diese ist zunachst auf die Ausschaltung der pathogenetischen Faktoren ausgerichtet und umfasst erst in zweiter Linie eine symptomatische medikamentose Therapie.

Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy. It is classified into intrahepatic and extrahepatic forms, the latter including perihilar (involvement of right and/or left hepatic ducts and their union to form the common hepatic duct) and distal bile duct CCA. Growth patterns are differentiated into periductal-infiltrating, mass-forming and papillary or intraductal growth. The different forms of CCA are distinct and differ clinically, etiologically, pathophysiologically and in management [1]. Global incidence rates of intrahepatic cholangiocarcinoma (ICC) have significantly increased while annual incidence rates of the more common extrahepatic form has remained relatively stable throughout the last four decades [2]. The prognosis of CCA is devastating with survival of

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy. Its incidence and prevalence is globally heterogeneous with the highest rates in Southeast Asia and Sub-Saharan Africa. In Western Industry nations, its incidence has significantly increased throughout the previous three decades. Its global heterogeneity is in part a reflection of the global distribution of its risk factors. Its prognosis is dismal with a 5-year survival of 11 %. The only potentially curative treatment is surgical with either resection or orthotopic liver transplantation. However, the majority of HCC patients are diagnosed at an advanced stage at which surgical therapies are not feasible. HCC is considered chemotherapy-resistant—a characteristic thought to be mediated in part through stem-like tumor initiating cells (STICs). Recent studies have provided significant insights in the hepatocarcinogenesis and the molecular signaling pathways of this malignancy resulting in the development of novel, molecular targeted therapies with modest therapeutic benefit. Our growing understanding of the biology of this malignancy will help in the development of novel, molecular-targeted therapies.

Paracrine signaling between hepatic stellate cells (HSCs) and liver endothelial cells (LECs) modulates fibrogenesis, angiogenesis, and portal hypertension. However, mechanisms regulating these processes are not fully defined. Sorafenib is a receptor tyrosine kinase inhibitor that blocks growth factor signaling in tumor cells but also displays important and not yet fully characterized effects on liver nonparenchymal cells including HSCs and LECs. The aim of this study was to test the hypothesis that sorafenib influences paracrine signaling between HSCs and LECs and thereby regulates matrix and vascular changes associated with chronic liver injury. Complementary magnetic resonance elastography, micro–computed tomography, and histochemical analyses indicate that sorafenib attenuates the changes in both matrix and vascular compartments that occur in response to bile duct ligation–induced liver injury in rats. Cell biology studies demonstrate that sorafenib markedly reduces cell–cell apposition and junctional complexes, thus reducing the proximity typically observed between these sinusoidal barrier cells. At the molecular level, sorafenib down-regulates angiopoietin-1 and fibronectin, both released by HSCs in a manner dependent on the transcription factor Kruppel-like factor 6 , suggesting that this pathway underlies both matrix and vascular changes associated with chronic liver disease. Conclusion: Collectively, the results of this study demonstrate that sorafenib inhibits both matrix restructuring and vascular remodeling that accompany chronic liver diseases and characterize cell and molecular mechanisms underlying this effect. These data may help to refine future therapies for advanced gastrointestinal and liver diseases characterized by abundant fibrosis and neovascularization. (HEPATOLOGY 2011;)

Cholangiocarcinoma (CCA) is a devastating disease with features of bile duct epithelial differentiation. Considerable progress has been made regarding the imaging characteristics of this disease, diagnostic criteria, surgical approaches and palliative management. Conversely, progress regarding medical therapy for advanced CCA has been limited. The design and implementation of Phase II trials has been hampered by the lack of staging systems to stratify patient populations. Until refined stratification schemes are available, results from Phase II trials, even randomized Phase II trials, will be difficult if not impossible to interpret due to marked patient heterogeneity. In this commentary, we will propose schemes to help stratify patients with CCA based on our current understanding of the disease. Biliary tract malignancies include intrahepatic cholangiocarcinoma, ductal cholangiocarcinoma, gallbladder cancers and cancers of the ampulla of Vater. Often, all of these biliary tract cancer subsets are included in medical trials on biliary tract cancers. However, gallbladder cancers, CCA and cancers of the ampulla of Vater are distinct entities with unique molecular signatures, mechanisms of disease dissemination and natural history. Furthermore, CCA exists as two types of cancer, intrahepatic mass forming cancers and cancers involving the large bile ducts. We propose that these two subsets be defined as intrahepatic CCA and ductal CCA (Table 1). Intrahepatic CCA would be classified as intrahepatic mass lesions without causing bile duct obstruction or jaundice. Ductal CCA would involve cancers of the common bile duct, common hepatic duct, right and/or left hepatic ducts including their secondary bifurcation. Terms such as Klatskin tumor, or perihilar CCA, which is a form of ductal CCA should be discouraged. Likewise, the erroneous classification by the Surveillance, Epidemiology, End Result (SEER) database of perihilar CCA as intrahepatic CCA must be corrected [1]. Biliary tract cancers should not be ‘lumped’ together in clinical trials, but rather examined and treated as individual, distinct subsets of biliary tract cancers. Clinical trials should be limited to each specific subset of these cancers including unique trials for intrahepatic and ductal CCA. Staging systems of gallbladder cancer have been well defined [2,3] and therefore, this cancer population can be appropriately stratified and emerging therapies assessed. Table 1 Proposed classification of cholangiocarcinoma Recently, a staging system for intrahepatic CCA has been proposed [4]. This classification is based on number of intrahepatic lesions, presence or absence of vascular invasion and lymph node metastases. In contrast, there is no proposed staging system for ductal CCA. Prior staging systems such as the Bismuth-Collette and the Memorial Sloan Kettering staging system pertain to selection of patients for surgery but were never meant to correlate with survival and do not pertain to patients with advanced disease [5,6]. The optimal staging system for ductal CCA should take into account the following parameters: the stage of the tumor; magnitude of ductal and vascular obstruction and their functional consequences for hepatic function and selection for surgery; the performance status of the patient; and the availability and effectiveness of therapy. Such a staging system has been developed for hepatocellular carcinoma and has been externally validated [7–10]. The tumor stage should take into account the size of the primary lesion, vascular encasement, the presence or absence of lobar atrophy and extrahepatic spread of the disease. Most primary ductal CCA are difficult to visualize as mass lesions and lack a measurable radial diameter. These neoplasms have a tropism for bile and as such, often encircle and stricture the bile duct causing jaundice. Given this tropism, the cancers also grow longitudinally along the bile duct before growing radially away from the biliary apparatus. Therefore, the identification of mass should be considered as a more advanced cancer than nonvisualized lesions, despite the lack of metastases or a similar clinical presentation (e.g. painless jaundice). We also propose that mass lesions be stratified as 3 cm or less or more than 3 cm based upon our experience. Vascular encasement (a frequent occurrence in this disease) and lobar atrophy (due to longstanding lobar bile duct and/or vascular obstruction) have been identified as adverse prognostic features in surgical studies [5,11]. Such features often suggest a prolonged disease interval between disease development and presentation; a feature favoring sufficient time to develop regional micrometastases. Also, lobar bile duct involvement (e.g. right hepatic duct) with contralateral vascular encasement (e.g. left portal vein encasement) precludes surgical resection, the only established, potentially curative therapy for ductal CCA. Thus, each of these tumor/liver anatomic relationships needs to be incorporated into the staging system. Extrahepatic spread signifies metastases and is always an adverse prognostic finding in any human cancer. CCA has three types of regional metastases: lymphatic spread into regional and more distant lymph nodes; venous invasion with intrahepatic metastases; and peritoneal metastases. Which one of these features portends the more adverse prognosis is not readily apparent and will require further study. Lymph node metastases can be regional with involvement of hilar lymph nodes, periduodenal lymph nodes and/or periaortic lymph nodes. Likely, the more distant the lymph node metastases are from the primary tumor, the worse the prognosis; but again, this is a concept that requires careful validation. Although the presence or absence of lymph node metastases can be difficult to confirm by imaging criteria, the use of endoscopic ultrasound with fine needle aspirates for lymph node cytology has made this distinction more reliable. The ability to relieve cholestasis with placement of biliary stents must also be taken into effect. A recent study suggests that if the bilirubin is less than or equal to 10 mg/dl, jaundice (defined as a serum bilirubin >3 mg/dl) should resolve within 3 weeks [12]. For bilirubin values more than 10mg/dl, it may take 6 weeks to obtain resolution of jaundice. Given these data, the parameters for jaundice resolution would be bilirubin and time-dependent. The inability to relieve jaundice results in impaired liver function secondary to persistent cholestasis and impacts on the overall heath and performance status of the patient. This cholestatic liver dysfunction adversely effects survival and, therefore, is a critical component of the staging system. Also, whether surgical exploration is or is not feasible (the only current therapy) will also affect patient outcomes. Based on this analysis and the rationale developed for HCC, we have assimilated these factors into a proposed staging system (Table 2). Any positive parameter within a column would relegate the patient to this stage. Table 2 Proposed staging system for ductal cholangiocarcinoma This proposed staging system is virtual at this point in time; however, we are in the process of validating this stratification scheme. Perhaps other objective parameters will also help add precision to this staging system (e.g. serum CA19-9 values >1000 U/ml, CCA complicating primary sclerosing cholangitis, etc.). We encourage others to also validate and refine this proposed schema. We also hope this commentary will galvanize a multidisciplinary effort to develop staging systems for this disease, perhaps lead by a major society (e.g. the American Association for the Study of Liver Diseases, American Society of Clinical Oncology, etc.). Only once such a staging system has been validated can randomized Phase II trials be reliably conducted with more homogenous patient populations for ductal CCA. This is a pressing need as promising targeted therapies are being developed and need to be applied to this subset of biliary tract cancers.

Background: The Tumor Growth Factor-β (TGF-β) pathway is a potent tumor suppressor pathway. Its inactivation has been implicated in hepatocarcinogenesis. However, in patients with advanced stage Hepatocellular Carcinoma (HCC), TGF-β1 serum concentrations are elevated and correlated to tumor size, recurrence and shortened survival. The mechanisms mediating TGF-β1 ligand overexpression in HCC are unknown. Material and Methods: Immunohistochemical analysis of human HCC samples was performed using Tissue Micro Array. Established human HCC cell lines were used for in vitro studies. Gene expression was assessed by qRT-PCR, ELISA and immunoblot analysis. shRNA was used for gene silencing. Transcription factor DNA binding was evaluated by chromatin immunoprecipitation. For promoter analysis, transcription factor binding site containing DNA fragments were cloned into the enhancer or promoter position of luciferase expression vectors and subsequent transfected. Results: In up to 68% of advanced stage HCC tumors Stem Cell Factor (SCF) is overexpressed, and SMAD2 and STAT3 are constitutively activated. SCF expression in human HCC tumors is intratumorally and intracellularly correlated to expression of pSer465/467SMAD2 and pTyr705STAT3. In HCC cell lines, SCF stimulation induces TGF-β1 transcription, expression and secretion, all of which are abrogated by genetic silencing of STAT3. TGF-β1 stimulation of human HCC cells induces TGF-β1 transcription, and genetic silencing of SCF prevents TGF-β1 autoregulation. We identified two STAT3 recognition sites within the TGF-β1 gene. In human HCC cells, TGF-β1 stimulation results in STAT3 binding to one of the identified recognition sites. TGF-β1 activates luciferase expression vectors under control of the corresponding STAT3 binding site but not in its absence. TGF-β1-induced STAT3 binding and expression vector activation is abrogated in HCC cells with genetically silenced SCF. TGF-β1 induces SCF expression but SMAD2 knockdown inhibits TGF-β1-induced SCF transcription and expression. We identified 7 putative SMAD2-binding elements (SBE) within the SCF promoter. TGF-β1 stimulation results in SMAD2 binding to the SCF promoter and activation of luciferase expression vectors regulated by the SCF promoter; conversely, genetic silencing of SMAD2 abrogates TGF-β1-induced SCF promoter activation. Importantly, knockdown of SCF restored the antiproliferative functions of TGF-β, and prevented TGF-β-induced tumor cell migration and invasion. Conclusion: In advanced stage HCC, SCF drives TGF-β1 autoregulation through STAT3-mediated regulation of the TGF-β1 promoter. Thereby, SCF and TGF-β1 form a positive feedback loop that functionally switches the TGF-β pathway from a tumor suppressor to a tumor promoter in advanced stage HCC. Citation Format: Pingyu Zhang, Andres Rojas, Ying Wang, Nina M. Munoz, Lianchun Xiao, Jing Wang, Gregory J. Gores, Mien-Chie Hung, Boris R. A. Blechacz. A positive feedback loop between TGF-β and SCF mediates TGF-β1 ligand overexpression in advanced hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3911. doi:10.1158/1538-7445.AM2015-3911

With the increasing incidence and mortality of cancer worldwide, there is an urgent need for new therapeutic approaches. Gene therapy is one such approach and preliminary data are promising. Viral and nonviral vector systems for gene delivery are available, but most of the current systems suffer from disadvantages such as low transfection efficiencies, in vivo instability, targeting problems, mutagenic potential and immunogenicity. Viruses of the Parvoviridae family, which are characterised by their oncotropism, oncosuppression, long-term gene expression and human apathogenicity, potentially offer advantages as viral vectors. This article evaluates their usefulness in gene therapy strategies for cancer.

Cholangiocarcinoma (CCA) is the most common biliary tract malignancy. CCA is classified as intrahepatic, perihilar or distal extrahepatic; the individual subtypes differ in their biologic behavior, clinical presentation, and management. Throughout the last decades, CCA incidence rates had significantly increased. In addition to known established risk factors, novel possible risk factors (i.e. obesity, hepatitis C virus) have been identified that are of high importance in developed countries where CCA prevalence rates have been low. CCA tends to develop on the background of inflammation and cholestasis. In recent years, our understanding of the molecular mechanisms of cholangiocarcinogenesis has increased, thereby, providing the basis for molecularly targeted therapies. In its diagnostic evaluation, imaging techniques have improved, and the role of complementary techniques has been defined. There is a need for improved CCA biomarkers as currently used ones are suboptimal. Multiple staging systems have been developed, but none of these is optimal. The prognosis of CCA is considered dismal. However, treatment options have improved throughout the last two decades for carefully selected subgroups of CCA patients. Perihilar CCA can now be treated with orthotopic liver transplantation with neoadjuvant chemoradiation achieving 5-year survival rates of 68%. Classically considered chemotherapy-resistant, the ABC-02 trial has shown the therapeutic benefit of combination therapy with gemcitabine and cisplatin. The benefits of adjuvant treatments for resectable CCA, local ablative therapies and molecularly targeted therapies still need to be defined. In this article, we will provide the reader with an overview over CCA, and discuss the latest developments and controversies.

e15092 Background: Hepatitis C virus (HCV)-infected patients (pts) are at increased risk of developing hepatocellular carcinoma (HCC). Approximately 7% of HCV-infected pts with non-liver primary ma...

Sa1412 Adenoma Detection Rate & Sessile Serrated Adenoma Detection Rate Trends With Increasing Age: a Study Using a Natural Language Processing Computer Program Selvi Thirumurthi*, William A. Ross, Phillip Lum, Ethan Miller, Brian R. Weston, Mala Pande, Patrick M. Lynch, Mehnaz A. Shafi, Manoop S. Bhutani, Alexander A. Dekovich, Boris Blechacz, Jeffrey H. Lee, Marta L. Davila, Robert S. Bresalier, Rebecca S. Slack, Sushovan Guha, Asif Rashid, Mark Routbort, Gladis Shuttlesworth, Lopa Mishra, John R. Stroehlein, Gottumukkala S. Raju Gastroenterology, Hepatology & Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX; Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX; Department of Internal Medicine, Division of Gastroenterology, University of Texas Houston Health Science Center, Houston, TX Background/Aims: Adenoma detection rate (ADR) is a quality metric used by gastroenterologists to evaluate their performance in colonoscopy and polyp detection. There is a trend toward higher ADR and advanced adenoma detection in both men and women with increasing age over 50. Another emerging quality indicator is sessile serrated adenoma detection rate (SDR). However, little is known about the differences in SDR between genders and trends with increasing patient age. We aim to describe trends in ADR, SDR, advanced adenomas and multiple adenomas for average risk patients over age 50 undergoing their first screening colonoscopy using a natural language processing (NLP) computer program. Methods: Three computer programs were developed for data extraction, processing and presentation using NLP (figure 1). Data was extracted from chart notes, endoscopy and pathology databases. NLP was used to link a colonoscopy with its corresponding pathology record, search for prior exams and pathology reports and review chart notes to confirm an indication of screening. This process has been validated at our institution and is submitted for review in a separate abstract. ADR, SDR and rates of advanced adenomas (O 1 cm, villous features) and of multiple adenomas (O3) were obtained for all study patients from 2009 to 2013. We calculated these metrics by patient age group (60-70 andO70) using the age group!60 as a reference point. We also report adenoma burden (# of adenomas/patient with a positive exam) and SSA burden. Results: A total of 3212 colonoscopies were performed during the study period (Table 1). While both ADR and SDR increased with age, only ADR trends were statistically significant among both men and women. ADR for those O age 70 was 3 times higher among women and 2 times higher among men compared to those! age 60. Among women, the rate of advanced adenomas and multiple adenomas increased with increasing age. WomenO age 70 were at nearly 5 times greater risk for advanced polyps and at nearly 6 times greater risk for having O 3 polyps compared to women! age 60. Conclusions: Our study reports a higher rate of ADR and SDR among male and female patients than has been previously reported. We find that ADR increases over each decade of life for men and women O age 60 and female ADR approaches male ADR with age. SDRs did not differ significantly among different age groups suggesting a different biology. Advanced adenoma detection rates were significantly higher in older female patients. All patientsO age 60 had a higher likelihood of having multiple adenomas than patients! age 60. Although further study is required, these findings suggest the importance of performing screening colonoscopy in older patients and female patients. ADR, SDR and Advanced Adenoma Detection Rate and Multiple Adenoma Detection Rates by Age and Gender

Top of pageAbstract Attenuated measles virus (MV) propagates selectively in human tumor cells and phase I clinical trials are currently underway to test their oncolytic activity. However, rapid antibody-mediated neutralization of the therapeutic viruses in blood or peritoneal fluid poses a major threat to the success of the approach. Classical and alternative complement pathway activation also contributes to complete virus neutralization in the plasma. Viremia during natural measles infection is exclusively cell-associated such that live MV can be isolated only from infected PBMC and not as cell-free virions from serum samples. We therefore hypothesized that autologous measles infected cells might be a more reliable vehicle than cell free virions to deliver the infection to tumor cells in subjects with neutralizing titers of anti-measles antibodies. Our in vitro studies, using a dual color fluorescent model, demonstrated the efficiency of cell-to-cell transfer of infection. In contrast to naked virions, heterofusion between infected monocytic line and tumor cells was 16-32 times more resistant to antibody neutralization. Systemically and intraperitoneally (i.p.) administered infected monocytes or stimulated peripheral blood cells successfully delivered oncolytic MV to the tumor lesions. Repeated i.p. injections of cell carriers significantly improved survival in an ovarian cancer xenograft model. MV survived antibody and complement neutralization within infected cells. In contrast to the naked virus, cell delivered MV and heterofusion escaped from the neutralizing antibodies after systemic or i.p. injection in a lymphoma metastatic model, and an i.p. hepatocellular cancer model. In addition, we demonstrated antibody-enhanced infectivity in monocytes/macrophages and subsequent transfer of MV infection to the target cells. These results suggest a novel strategy for systemic delivery of oncolytic virotherapy in cancer patients that can |[ldquo]|by-pass|[rdquo]| the pre-existing humoral immunity against MV.

Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer mortality worldwide, causing nearly 1 million deaths annually. Its therapy is mainly based on surgery, local-regional therapy and chemotherapy. Despite a variety of different new therapeutic approaches, its prognosis remains poor with a median survival of

Background: More than 80% of Hepatocellular carcinoma (HCC) patients present at advanced stages not amenable to curative therapies. Currently existing palliative therapies achieve a minimal survival benefit of 3 months. Hence, there is an urgent need for novel therapeutic strategies. Tumor Growth Factor-β (TGF-β) is a potent tumor suppressor via its Smad2/3 signaling axis. Inactivation of this axis has been implicated in hepatocarcinogenesis. In patients with advanced HCC, TGF- β serum concentrations are elevated and correlated to disease stage, metastases and worse prognosis. Our aims were to evaluate the status and function of the TGF-β/Smad2 signaling axis in advanced HCC. Material and Methods: Immunohistochemical analysis for pSer465/467-Smad2 in human HCC samples was performed using Tissue Micro Arrays. In vitro studies were performed using established human HCC cell lines (HepG2, Hep3B, PLC/PRF/5, HUH-7, SNU-398, SNU-449). Pathway activation following TGF-β stimulation was evaluated by immunoblot analysis and immunofluorescence microscopy. Cell proliferation was assessed by cell quantification and MTS-assay. Apoptosis was quantified morphologically by DAPI stain and fluorescence microscopy, and biochemically by caspase-3/7 assay. Migration was assessed by gap closure assay, and invasion by Matrigel invasion assay. Results: Intranuclear pSer465/467-Smad2 was identified in up to 51% of advanced HCC (n=73) and in 89% of HCC metastases (n=9). In 50% of human HCC cell lines, TGF-β treatment (10 ng/mL) resulted in Ser465/467-phosphorylation and nuclear translocation of the transcription factor Smad2. Exclusively in HCC cells with an intact TGF-β/Smad2-signaling cascade, TGF-β stimulation induced Tyr705-phosporylation of the transcription factor STAT3. TGF-β induced STAT3 Tyr705-phosporylation is inhibited by Smad2-directed gene silencing. Further, pyridine 6 mediated Janus Kinase-1/2 (JAK1/2) inhibition prevented TGF-β induced Tyr705-phosporylation of STAT3. Cell proliferation of HCC cells was inhibited by TGF-β. However, TGF-β treatment significantly induced invasion and migration in HCC cell lines with intact TGF-β/Smad2 signaling. Further, TGF-β induced resistance to TRAIL-induced apoptosis in these cells. However, co-treatment with the STAT3-inhibitor Stattic (10 nM) completely abrogates TGF-β mediated HCC cell migration and invasion, and sensitizes these HCC cell lines to TRAIL-mediated apoptosis. Conclusion: In advanced HCC, the TGF-β/Smad signaling axis is constitutively activated in the majority of primary HCC tumors and HCC metastases. The function of TGF-β/Smad2 in human HCC cell lines has switched from tumor inhibitor to a driver of tumor progression via JAK/STAT3 signaling. STAT3-inhibition reverses the TGF-β tumor-promoting effects. Hence, JAK/STAT3 targeting might be a promising new strategy to restore TGF-β tumor suppressor function in advanced HCC. Citation Format: Andres Rojas, Jessica Cromheecke, Mong-Hong Lee, Mien-Chie Hung, Boris Blechacz. TGF-β drives tumor-progression via JAK/STAT3-signaling in advanced HCC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2046. doi:10.1158/1538-7445.AM2013-2046

Objective To investigate the association between treatment induced change in high density lipoprotein cholesterol and total death, coronary heart disease death, and coronary heart disease events (coronary heart disease death and non-fatal myocardial infarction) adjusted for changes in low density lipoprotein cholesterol and drug class in randomised trials of lipid modifying interventions. Design Systematic review and meta-regression analysis of randomised controlled trials. Data sources Medline, Embase, Central, CINAHL, and AMED to October 2006 supplemented by contact with experts in the field. Study selection In teams of two, reviewers independently determined eligibility of randomised trials that tested lipid modifying interventions to reduce cardiovascular risk, reported high density lipoprotein cholesterol and mortality or myocardial infarctions separately for treatment groups, and treated and followed participants for at least six months. Data extraction and synthesis Using standardised, pre-piloted forms, reviewers independently extracted relevant information from each article. The change in lipid concentrations for each trial and the weighted risk ratios for clinical outcomes were calculated. Results The meta-regression analysis included 108 randomised trials involving 299 310 participants at risk of cardiovascular events. All analyses that adjusted for changes in low density lipoprotein cholesterol showed no association between treatment induced change in high density lipoprotein cholesterol and risk ratios for coronary heart disease deaths, coronary heart disease events, or total deaths. With all trials included, change in high density lipoprotein cholesterol explained almost no variability (