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1.  Chemopreventive strategies in hepatocellular carcinoma 
Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer. The incidence and mortality of HCC are increasing in most Western countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Chemopreventive strategies aimed at decreasing the risk or delaying the onset of HCC are needed. Universal immunization against HBV and antiviral therapy against HBV and HCV in patients with established disease has consistently been associated with reduced HCC risk, especially in patients who achieve sustained virologic response. However, the cost-effectiveness of antiviral therapy for primary HCC prevention is not known. Several commonly prescribed medications seem promising as chemopreventive agents against HCC, including statins, antidiabetic medications and aspirin. Dietary agents such as coffee, vitamin E and fish oil as well as phytochemicals might also be associated with reduced risk of HCC. Though randomized controlled trials are ideally needed to firmly establish efficacy, such chemoprevention trials are logistically and ethically challenging. Well-designed, prospective, population-based cohort studies might provide the best evidence for chemopreventive efficacy of these agents.
PMCID: PMC4334449  PMID: 23938452
2.  Metformin does not improve survival in patients with hepatocellular carcinoma 
World Journal of Gastroenterology : WJG  2014;20(42):15750-15755.
AIM: To assess whether metformin, which has a chemopreventive effect in chronic liver disease, has any chemotherapeutic effect in hepatocellular carcinoma.
METHODS: This was a retrospective study of 701 patients with newly diagnosed hepatocellular carcinoma (HCC) seen between January 2005 and June 2011 at Mayo Clinic, Rochester, Minnesota. This patient cohort was a part of the global HCC BRIDGE study, which is a large longitudinal study of HCC determining the real-world experience of HCC characteristics, management and patient outcomes. We defined significant metformin exposure as continuation of this agent at least 90 d beyond diagnosis of HCC, and compared survival of diabetic patients on metformin to diabetic patients not on metformin and non-diabetics.
RESULTS: Our cohort was 72.9% male, with a mean ± SD age of 62.6 ± 12.3 years. The most common etiologies of liver disease were hepatitis C (34%), alcoholic liver disease (29%), fatty liver disease (15%) and hepatitis B (9%). By univariate analysis, using diabetics not on metformin as the reference group, diabetic patients with HCC on metformin had no survival advantage, with a HR (95%CI) of 1.0 (0.8-1.3). Non-diabetic HCC patients also did not appear to have a survival advantage as compared to diabetic HCC patients not on metformin, as demonstrated by a HR (95%CI) of 1.1 (0.7-1.7). Diabetics on metformin beyond 90 d after HCC diagnosis had a longer median survival at 34.2 mo, as compared to 25.5 mo among diabetic patients who were not on metformin or had discontinued metformin within 90 d after HCC diagnosis. This finding was likely due to potential survival bias among those who lived long enough to receive metformin.
CONCLUSION: Although the literature suggests a chemotherapeutic effect in other malignancies, our study demonstrates no survival benefit to the use of metformin in diabetic patients with HCC.
PMCID: PMC4229540  PMID: 25400459
Hepatocellular carcinoma; Metformin; Diabetes; Survival; Liver disease; Lactic acidosis
3.  Epigenetic signatures of alcohol abuse and hepatitis infection during human hepatocarcinogenesis 
Oncotarget  2014;5(19):9425-9443.
Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. Deregulated DNA methylation landscapes are ubiquitous in human cancers. Interpretation of epigenetic aberrations in HCC is confounded by multiple etiologic drivers and underlying cirrhosis. We globally profiled the DNA methylome of 34 normal and 122 liver disease tissues arising in settings of hepatitis B (HBV) or C (HCV) viral infection, alcoholism (EtOH), and other causes to examine how these environmental agents impact DNA methylation in a manner that contributes to liver disease. Our results demonstrate that each ‘exposure’ leaves unique and overlapping signatures on the methylome. CpGs aberrantly methylated in cirrhosis-HCV and conserved in HCC were enriched for cancer driver genes, suggesting a pathogenic role for HCV-induced methylation changes. Additionally, large genomic regions displaying stepwise hypermethylation or hypomethylation during disease progression were identified. HCC-HCV/EtOH methylomes overlap highly with cryptogenic HCC, suggesting shared epigenetically deregulated pathways for hepatocarcinogenesis. Finally, overlapping methylation abnormalities between primary and cultured tumors unveil conserved epigenetic signatures in HCC. Taken together, this study reveals profound epigenome deregulation in HCC beginning during cirrhosis and influenced by common environmental agents. These results lay the foundation for defining epigenetic drivers and clinically useful methylation markers for HCC.
PMCID: PMC4253444  PMID: 25294808
hepatocellular carcinoma; cirrhosis; etiology; epigenetics; DNA methylation
4.  Methylated Bone Morphogenetic Protein 3 (BMP3) Gene: Evaluation of Tumor Suppressor Function and Biomarker Potential in Biliary Cancer 
Although cholangiocarcinoma (CC) is an uncommon and highly lethal malignancy, early detection enables the application of potentially curative therapies and improves survival. Consequently, tools to improve the early diagnosis of CC are urgently needed. During a screen for genes epigenetically suppressed by methylation in CC that might serve as methylation markers for CC, we found that the BMP3 gene is methylated in CC cell lines, but the potential diagnostic value and the function of BMP3 in CC are unknown.
We aimed to quantitatively assess BMP3 methylation in resected CC tumor specimens using methylation specific PCR and evaluate the tumor suppressor role of BMP3 in biliary cancer cell lines in comparison to an immortalized normal cholangiocyte cell line. Expression of BMP3 was quantified by mRNA levels before and after treatment with 5-Aza-2’-deoxycytidine and trichostatin A. After transfection with a BMP3-containing plasmid, cell viability was measured using the bromodeoxyuridine incorporation assay and apoptosis quantified by caspase assay.
In primary CC tumor tissue specimens significantly more methylated BMP3 copies were found when compared to matched benign bile duct epithelium from the same patient, with high specificity. BMP3 expression was absent in cell lines with BMP3 methylation; this suppression of BMP3 expression was reversed by treatment with a DNA demethylating agent and histone de-acetylase inhibitor. Transfection of a BMP3-expressing construct into a BMP3-negative biliary cancer cell line restored BMP3 mRNA expression and reduced cell proliferation and cell viability while increasing the rate of apoptosis.
These findings strongly support a tumor suppressor role for BMP3 in CC and suggest that BMP3 methylation may be a new biomarker for early detection of CCs. of the peptidome are also involved.
PMCID: PMC4112127  PMID: 25077038
Cholangiocarcinoma; Gallbladder neoplasms; Early detection of cancer; Biological markers
5.  Efficacy and Safety of Transarterial Radioembolization Versus Chemoembolization in Patients With Hepatocellular Carcinoma 
Intermediate-stage hepatocellular carcinoma (HCC) is usually treated with locoregional therapy using transarterial chemoembolization (TACE). Transarterial radioembolization (TARE) using β-emitting yttrium-90 integral to the glass matrix of the microspheres is an alternative to TACE. This retrospective case-control study compared the outcomes and safety of TARE versus TACE in patients with unresectable HCC.
Materials and Methods
Patients with unresectable HCC without portal vein thrombosis treated with TARE between 2005 and 2008 (n = 61) were retrospectively frequency-matched by age, sex, and liver dysfunction with TACE-treated patients (n = 55) in the Mayo Clinic Hepatobiliary Neoplasia Registry. Imaging studies were reviewed, and clinical and safety outcomes were abstracted from the medical records.
Complete tumor response was more common after TARE (12 %) than after TACE (4 %) (p = 0.17). When complete response was combined with partial response and stable disease, there was no difference between TARE and TACE. Median survival did not differ between the two groups (15.0 months for TARE and 14.4 months for TACE; p = 0.47). Two-year survival rates were 30 % for TARE and 24 % for TACE. TARE patients received fewer treatments (p <0.001). Fifty-nine (97 %) TARE patients received outpatient treatment. In contrast, 53 (98 %) TACE patients were hospitalized for ≥1 day (p <0.001). Compared with TACE, TARE was more likely to induce fatigue (p = 0.003) but less likely to cause fever (p = 0.02).
There was no significant difference in efficacy between TARE and TACE. TARE patients reported more fatigue but had less fever than TACE patients. Treatment with TARE required less hospitalization than treatment with TACE. These findings require confirmation in randomized trials.
PMCID: PMC3594060  PMID: 23093355
Chemoembolization; Efficacy; Hepatocellular carcinoma; Radioembolization; Safety; Yttrium-90
6.  Molecular bioluminescence imaging as a non-invasive tool for monitoring tumor growth and therapeutic response to MRI-guided laser ablation in a rat model of hepatocellular carcinoma 
Investigative radiology  2013;48(6):413-421.
To quantitatively compare tumor imaging by MRI and molecular bioluminescence imaging (BLI) and test the feasibility of monitoring the effect of MRI-guided laser ablation on tumor viability by 2D BLI and 3D DLIT in an orthotopic rat model of hepatocellular carcinoma (HCC).
Materials and Methods
This study was approved by the animal care committee. Rats underwent injection of N1S1 cells stably transfected with an empty vector (N=3) or a luciferase reporter (HSE-luc; N=4) into the liver. All rats underwent MR imaging to assess tumor establishment and volume and 2D BLI to assess tumor luminescence at day 7 with repeat MR imaging and 2D BLI and 3D diffuse luminescence tomography (3D DLIT) in select animals at day 14 and 21. MRI-guided laser ablation of the tumor was performed with pre and post-ablation 2D BLI and/or 3D DLIT (N=2). Tumors underwent histopathologic analysis to assess tumor viability.
MR imaging demonstrated hyperintense T2-weighted lesions at 3/3 and 4/4 sites in empty vector and HSE-luc rats, respectively. 2D BLI quantitation demonstrated 23.0 fold higher radiance in the HSE-luc group compared to the empty vector group at day 7 (p<0.01) and a significant correlation with tumor volume by MRI (r=0.86; p<0.03). Tumor dimensions by 3D DLIT and MRI demonstrated good agreement. 3D DLIT quantitation better agreed with the % of non-viable tumor by histopathology than 2D BLI quantitation following MRI-guided laser ablation.
Bioluminescence imaging is a feasible as non-invasive, quantitative tool for monitoring tumor growth and therapeutic response to thermal ablation in a rat model of HCC.
PMCID: PMC3904185  PMID: 23262791
Magnetic Resonance Imaging; Laser Ablation; Bioluminescence Imaging; Hepatocellular Carcinoma; Animal Model
7.  Myc, Max, and Mnt: Molecular Mechanisms of Enhancement of Cholangiocarcinogenesis by Cholestasis 
Gastroenterology  2011;141(1):32-34.
PMCID: PMC4040264  PMID: 21620848
8.  Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas 
Nature genetics  2013;45(12):1470-1473.
Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.
PMCID: PMC4013720  PMID: 24185509
9.  Self-Perceived Utilization of the Paretic Arm in Chronic Stroke Requires High Upper Limb Functional Ability 
To explore potential predictors of self-reported paretic arm use at baseline and after task-specific training (TST) in survivors of stroke.
Data were obtained from a randomized controlled trial of somatosensory stimulation and upper limb TST in chronic stroke.
University laboratory.
Chronic (≥3mo) survivors of stroke (N=33; mean age, 62y; mean stroke duration, 38mo).
Participants received 12 sessions of TST preceded by either active (n=16) or sham (n=17) somatosensory stimulation to all 3 peripheral nerves.
Main Outcome Measures
Demographic and clinical characteristics were entered stepwise into multiple linear regression analyses to determine the factors that best predict baseline Motor Activity Log (MAL) amount of use rating and change 3 months after TST.
The Action Research Arm Test (ARAT) score predicted the amount of use at baseline (R2=.47, P<.001); in using this model, an ARAT score of 54 (maximum of 57) is required to score 2.5 on the MAL (use described as between rarely and sometimes). After TST the change in the ARAT score predicted the change in the amount of use (R2=.31, P=.001). The predictive power of the model for change at 3 months increased if the Fugl-Meyer Assessment wrist component score was added (R2=.41, P=.001).
Utilization of the paretic upper limb in activities of daily living requires high functional ability. The increase in self-reported arm use after TST is dependent on the change in functional ability. These results provide further guidance for rehabilitation decisions.
PMCID: PMC4005465  PMID: 24480335
Rehabilitation; Stroke; Upper extremity; ARAT, Action Research Arm Test; CIMT, constraint-induced movement therapy; FMA, Fugl-Meyer Assessment; MAL, Motor Activity Log; MAS, Modified Ashworth Scale; RCT, randomized controlled trial; TST, task-specific training
10.  Brivanib Attenuates Hepatic Fibrosis In Vivo and Stellate Cell Activation In Vitro by Inhibition of FGF, VEGF and PDGF Signaling 
PLoS ONE  2014;9(4):e92273.
Background and Aims
Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both involved in mechanisms of liver fibrosis. We hypothesized that inhibition of VEGFR and FGFR by brivanib would inhibit liver fibrosis. We therefore examined the effect of brivanib on liver fibrosis in three mouse models of fibrosis.
In vivo, we induced liver fibrosis by bile duct ligation (BDL), chronic carbon tetrachloride (CCl4), and chronic thioacetamide (TAA) administration. Liver fibrosis was examined by immunohistochemistry and Western immunoblotting. In vitro, we used LX-2 human hepatic stellate cells (HSCs) to assess the effect of brivanib on stellate cell proliferation and activation.
After in vivo induction with BDL, CCl4, and TAA, mice treated with brivanib showed reduced liver fibrosis and decreased expression of collagen Iα1 and α-smooth muscle actin in the liver. In vitro, brivanib decreased proliferation of HSCs induced by platelet-derived growth factor (PDGF), VEGF, and FGF. Brivanib also decreased stellate cell viability and inhibited PDGFBB-induced phosphorylation of its cognate receptor.
Brivanib reduces liver fibrosis in three different animal models and decreases human hepatic stellate cell activation. Brivanib may represent a novel therapeutic approach to treatment of liver fibrosis and prevention of liver cancer.
PMCID: PMC3977817  PMID: 24710173
11.  Epidemiology and Management of Hepatocellular Carcinoma 
PMCID: PMC3949429  PMID: 20937457
Hepatitis B; Hepatitis C; Pathogenesis; Liver transplantation; Transarterial chemoembolization; Radiofrequency ablation
12.  Cirrhosis is Present in Most Patients with Hepatitis B and Hepatocellular Carcinoma 
Background& Aims
There is not much data available about the prevalence or effects of cirrhosis in patients with hepatocellular carcinoma (HCC) from viral hepatitis. We compared patients with HCC and hepatitis B virus (HBV) or hepatitis C virus (HCV) infections to determine the proportions of cirrhosis in each group, virologic and tumor characteristics, and overall survival.
This analysis includes patients with HBV (n=64) or HCV (n=118) infection who were diagnosed with HCC at the Mayo Clinic in Rochester MN from 1994 to 2008; groups were matched for age and sex. The diagnosis of cirrhosis was based on histology and, if histologic information was insufficient or unavailable, clinical indicators that included ascites or varices, thrombocytopenia or splenomegaly, and radiographic configuration of cirrhosis. Virologic characteristics, tumor stage, and patient survival were also assessed.
The prevalence of histologic cirrhosis was 88% among patients with HBV infection and 93% among those with HCV infection (P=0.46). When the most inclusive criteria for cirrhosis were applied, cirrhosis was present in 94% of patients with HBV and 97% with HCV (P=0.24). Among HCV patients, 5.2% were negative for HCV RNA following antiviral treatment; 63.4% of HBV patients had HBV DNA < 2000 u/ml with or without treatment. Patients with HBV tended to have less surveillance and more advanced stages of HCC, without differences in survival from those with HCV infection (P=0.75).
Most patients with HCC and chronic viral hepatitis had evidence of cirrhosis, including those with HBV infection and those without active viral replication.
PMCID: PMC3951426  PMID: 20831903
Liver cancer; liver disease; virology; survival
13.  Hepatocellular carcinoma: a global view 
Hepatocellular carcinoma (HCC) is a global health problem, although developing countries are disproportionally affected: over 80% of HCCs occur in such regions. About three-quarters of HCCs are attributed to chronic HBV and HCV infections. In areas endemic for HCV and HBV, viral transmission occurs at an early age, and infected individuals develop HCC in mid-adulthood. As these are their most productive years of life, HCC accounts for a substantial burden on the health-care system and drain of productive capacity in the low-income and middle-income countries most affected by HCV and HBV infections. Environments with disparate resource levels require different strategies for the optimal management of HCC. In high-resource environments, guidelines from the American Association for the Study of Liver Diseases or European Association for the Study of the Liver should be applied. In intermediate-resource or low-resource environments, the fundamental focus should be on primary prevention of HCC, through universal HBV vaccination, taking appropriate precautions and antiviral treatments. In intermediate-resource and low-resource environments, the infrastructure and capacity for abdominal ultrasonography, percutaneous ethanol injection, radiofrequency ablation and surgical resection should be established. Programs to provide targeted therapy at low cost, similar to the approach used for HIV therapy in the developing world, should be pursued.
PMCID: PMC3926946  PMID: 20628345
14.  Differential Roles of Thought Suppression and Dispositional Mindfulness in Posttraumatic Stress Symptoms and Craving 
Addictive behaviors  2012;38(2):1555-1562.
Exposure to traumatic events often results in severe distress which may elicit self-medication behaviors. Yet, some individuals exposed to trauma do not develop post-traumatic stress symptoms and comorbid addictive impulses. In the wake of traumatic events, psychological processes like thought suppression and mindfulness may modulate post-traumatic stress and craving for substances. We examined the differential roles of mindfulness and suppression in comorbid post-traumatic stress and craving in a sample of 125 persons with extensive trauma histories and psychiatric symptoms in residential treatment for substance dependence. Results indicated that thought suppression, rather than extent of trauma history, significantly predicted post-traumatic stress symptom severity while dispositional mindfulness significantly predicted both post-traumatic stress symptoms and craving. In multiple regression models, mindfulness and thought suppression combined explained nearly half of the variance in post-traumatic stress symptoms and one-quarter of the variance in substance craving. Moreover, multivariate path analysis indicated that prior traumatic experience was associated with greater thought suppression, which in turn was correlated with increased post-traumatic stress symptoms and drug craving, whereas dispositional mindfulness was associated with decreased suppression, post-traumatic stress, and craving. The maladaptive strategy of thought suppression appears to be linked with adverse psychological consequences of traumatic life events. In contrast, dispositional mindfulness appears to be a protective factor that buffers individuals from experiencing more severe post-traumatic stress symptoms and craving.
PMCID: PMC3376182  PMID: 22385734
craving; comorbidity; mindfulness; post-traumatic stress; thought suppression
15.  Risk Factors for Intrahepatic Cholangiocarcinoma: Association between Metformin use and Reduced Cancer Risk 
Hepatology (Baltimore, Md.)  2012;57(2):648-655.
The associations between diabetes, smoking, obesity and intrahepatic cholangiocarcinoma (ICC) risk remain inconclusive. Metformin is purportedly associated with a reduced risk for various cancers. This case-control study evaluated risk factors for ICC and explored the effects of metformin on ICC risk in a clinic/hospital-based cohort. ICC patients seen at Mayo Clinic, Rochester, MN between January 2000 and May 2010 were identified. Age, sex, ethnicity, and residential area-matched controls were selected from among Mayo Clinic Biobank participants. The associations between potential factors and ICC risk were determined. Six hundred and twelve cases and 594 controls were identified. Factors associated with increased ICC risk included biliary tract diseases (Adjusted Odds Ratio [AOR] 81.8, 95% confidence interval [CI]: 11.2–598.8, P<0.001), cirrhosis (AOR 8.0, 95%CI: 1.8–36.5, P=0.007), diabetes (AOR 3.6, 95%CI: 2.3–5.5, P<0.001), and smoking (AOR 1.6, 95%CI: 1.3–2.1, P<0.001). Compared to diabetic patients not treated with metformin, odds ratio (OR) for ICC for diabetic patients treated with metformin was significantly decreased (OR 0.4, 95%CI: 0.2–0.9, P=0.04). Obesity and metabolic syndrome were not associated with ICC.
This study confirmed diabetes and smoking as independent risk factors for ICC. A novel finding was that treatment with metformin was significantly associated with a 60% reduction in ICC risk in diabetic patients.
PMCID: PMC3565026  PMID: 23055147
bile duct cancer; epidemiology; oral hypoglycemic agent; diabetes
16.  AS30D Model of Hepatocellular Carcinoma: Tumorigenicity and Preliminary Characterization by Imaging, Histopathology, and Immunohistochemistry 
This study was designed to determine the tumorigenicity of the AS30D HCC cell line following orthotopic injection into rat liver and preliminarily characterize the tumor model by both magnetic resonance imaging (MRI) and ultrasound (US) as well as histopathology and immunohistochemistry.
AS30D cell line in vitro proliferation was assessed by using MTT assay. Female rats (N = 5) underwent injection of the AS30D cell line into one site in the liver. Rats subsequently underwent MR imaging at days 7 and 14 to assess tumor establishment and volume. One rat underwent US of the liver at day 7. Rats were euthanized at day 7 or 14 and livers were subjected to gross, histopathologic (H&E), and immunohistochemical (CD31) analysis to assess for tumor growth and neovascularization.
AS30D cell line demonstrated an in vitro doubling time of 33.2 ± 5.3 h. MR imaging demonstrated hyperintense T2-weighted and hypointense T1-weighted lesions with tumor induction in five of five and three of three sites at days 7 and 14, respectively. The mean (SD) tumor volume was 126.1 ± 36.2 mm3 at day 7 (N = 5). US of the liver demonstrated a well-circumscribed, hypoechoic mass and comparison of tumor dimensions agreed well with MRI. Analysis of H&E- and CD31-stained sections demonstrated moderate-high grade epithelial tumors with minimal tumor necrosis and evidence of diffuse intratumoral and peritumoral neovascularization by day 7.
AS30D HCC cell line is tumorigenic following orthotopic injection into rat liver and can be used to generate an early vascularizing, slower-growing rat HCC tumor model.
PMCID: PMC3904804  PMID: 22923329
Hepatocellular carcinoma; Rat model; Magnetic resonance imaging
17.  Development and Preliminary Testing of a Translational Model of Hepatocellular Carcinoma for Magnetic Resonance Imaging and Interventional Oncologic Investigations 
To develop a translational rat hepatocellular carcinoma (HCC) disease model for magnetic resonance imaging and image-guided interventional oncologic investigations.
Methods and Materials
Male rats underwent sham control surgery (N=6), selective bile duct ligation (SBDL; N=4) or common bile duct ligation (CBDL; N=6) with procedure optimization in 4 rats and N1S1 cell injection into 2–3 sites in the liver of 12 rats. All rats subsequently underwent MRI to assess tumor establishment and volume. Mesenteric angiography and percutaneous MR-guided laser ablation of the liver were performed in a subgroup of animals (N=4). Animal weight and liver tests were monitored. After harvesting, the livers were subjected to gross and microscopic analysis. Tumor volume and laboratory parameters were assessed between ligation groups.
MRI demonstrated hyperintense T2 and hypointense T1 lesions with tumor induction in 5/10 (50.0%), 7/8 (87.5%) and 12/12 (100%) sites in the control, SBDL and CBDL groups, respectively. Tumor volumes differed significantly by group (p<0.02). Mesenteric angiography demonstrated an enhancing tumor stain. Clinical and laboratory assessment revealed a significant decrease in weight (p = 0.01) and albumin (p<0.01) and increase in total bilirubin (p = 0.02) in CBDL rats but not SBDL rats (p=1.0). Histologic examination showed high-grade HCCs with local and vascular invasion within the context of early fibrosis in CBDL and SBDL rats. MR-guided laser ablation generated a 1–2 cm ablation zone with histology consistent with reversible and irreversible injury.
A biologically relevant rat hepatocellular carcinoma disease model was developed for MR imaging and preliminary interventional oncologic applications.
PMCID: PMC3904802  PMID: 22265247
18.  Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma 
Cancer research  2012;73(2):897-907.
Cancer associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAF are `activated' and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma (CCA) as a desmoplastic tumor model, we investigated the sensitivity of liver CAF to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells, but lacked similar effects in quiescent fibroblasts or CCA cells. Unlike CCA cells, niether CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAF or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAF appeared to be due in part to upregulation of the pro-apoptotic protein Bax. shRNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors and apoptotic cell death. In a syngeneic rat model of CCA, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAF in the tumor microenvironment as a general strategy to attack solid tumors.
PMCID: PMC3549008  PMID: 23221385
Bcl-2 proteins; BH3 mimetic; carcinoma associated fibroblasts; hepatic stellate cells; tumor stroma
19.  The Human Sulfatase 2 Inhibitor 2,4-Disulfonylphenyl-tert-Butylnitrone (OKN-007) has an Antitumor Effect in Hepatocellular Carcinoma Mediated via Suppression of TGFB1/SMAD2 and Hedgehog/GLI1 Signaling 
Genes, chromosomes & cancer  2012;52(3):225-236.
Human sulfatase 2 (SULF2) functions as an oncoprotein in hepatocellular carcinoma (HCC) development by promoting tumor growth and metastasis via enhancement of fibroblast growth factor-2/extracellular signal-regulated kinase and WNT/ β-catenin signaling. Recent results implicate that SULF2 activates the transforming growth factor beta (TGFB) and Hedgehog/GLI1 pathways in HCC. OKN-007 is a novel phenyl–sulfonyl compound that inhibits the enzymatic activity of SULF2. To investigate the antitumor effect of OKN-007 in HCC, we treated Huh7 cells, which express high levels of SULF2, with OKN-007 and found that it significantly promoted tumor cell apoptosis and inhibited cell proliferation, viability, and migration. To understand the action of OKN-007 on SULF2, we used Huh7 cells which normally express SULF2 and Hep3B cells that do not normally express SULF2. Utilizing Huh7 cells transfected with short hairpin RNA targeting SULF2 and transfection of Hep3B cells with a SULF2 plasmid to enhance SULF2 expression, we showed that the antitumor activity of OKN-007 was more pronounced in cells expressing SULF2. Furthermore, in vivo experiments verified that OKN-007 repressed tumor growth significantly. These results identify SULF2 as an important target of the antitumor effect of OKN-007. To determine the molecular mechanism of the antitumor effect of OKN-007, both TGFB1/SMAD and Hedgehog/GLI1 signaling pathway activity were measured by Western blot and SMAD- or GLI-reporter luciferase assays. We found that both signaling pathways were inhibited by OKN-007. Together, these results show that OKN-007 can suppress TGFB1/SMAD and Hedgehog/GLI1 signaling via its inhibition of SULF2 enzymatic activity. We conclude that OKN-007 or more potent derivatives may be promising agents for the treatment of HCC.
PMCID: PMC3889201  PMID: 23109092
20.  Caloric Intake, Aging, and Mild Cognitive Impairment: A Population-Based Study 
In a population-based case-control study, we examined whether moderate and high caloric intakes are differentially associated with the odds of having mild cognitive impairment (MCI). The sample was derived from the Mayo Clinic Study of Aging in Olmsted County, Minnesota. Non-demented study participants aged 70–92 years (1,072 cognitively normal persons and 161 subjects with MCI) reported their caloric consumption within 1 year of the date of interview by completing a Food Frequency Questionnaire. An expert consensus panel classified each subject as either cognitively normal or having MCI based on published criteria. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age, sex, education, depression, medical comorbidity, and body mass index. We also conducted stratified analyses by apolipoprotein E ε4 genotype status. Analyses were conducted in tertiles of caloric intake: 600 to <1,526 kcals per day (reference group); 1,526 to 2,143 kcals per day (moderate caloric intake group); and >2,143 kcals per day (high caloric intake group). In the primary analysis, there was no significant difference between the moderate caloric intake group and the reference group (OR 0.87, 95% CI 0.53–1.42, p = 0.57). However, high caloric intake was associated with a nearly two-fold increased odds of having MCI (OR 1.96, 95% CI 1.26–3.06, p = 0.003) as compared to the reference group. Therefore, high caloric intake was associated with MCI but not moderate caloric intake. This association is not necessarily a cause-effect relationship.
PMCID: PMC3578975  PMID: 23234878
aging; APOE ε4 genotype; caloric intake; mild cognitive impairment; population-based
21.  Mutations in Isocitrate Dehydrogenase 1 and 2 Occur Frequently in Intrahepatic Cholangiocarcinomas and Share Hypermethylation Targets with Glioblastomas 
Oncogene  2012;32(25):3091-3100.
Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas, and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine (5hmC) and higher 5-methylcytosine (5mC) levels, as well as increased dimethylation of histone H3K79. Mutations in IDH1 or IDH2 were associated with longer overall survival (p = 0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (p = 0.021). IDH1 and IDH2 mutations are significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2,309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.
PMCID: PMC3500578  PMID: 22824796
DNA methylation; Epigenetics; Tumor metabolism
22.  Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment 
Cancer research  2012;72(16):4047-4059.
The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here we report that neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin (FN) that promote α5β1 integrin-dependent FN fibril assembly, matrix stiffness, and tumor growth. Tumor growth and FN fibril assembly was reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in FN fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl, that augmented α5β1 FN fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of FN fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment.
PMCID: PMC3421041  PMID: 22738912
Fibronectin; Integrin; Neuropilin; Matrix; Myofibroblast
23.  A Model to Estimate Survival in Ambulatory Patients with Hepatocellular Carcinoma 
Hepatology (Baltimore, Md.)  2012;56(2):614-621.
Background and Aims
Survival of patients with hepatocellular carcinoma (HCC) is determined by the extent of the tumor and the underlying liver function. We aimed to develop a survival model for HCC based on objective parameters including the Model for End stage Liver Disease (MELD) as a gauge of liver dysfunction.
This analysis is based on 477 patients with HCC seen at Mayo Clinic Rochester between 1994 and 2008 (derivation cohort) and 904 patients at the Korean National Cancer Center between 2000 and 2003 (validation cohort). Multivariable proportional hazards models and corresponding risk score were created based on baseline demographic, clinical, and tumor characteristics. Internal and external validation of the model was performed. Discrimination and calibration of this new model were compared against existing models including Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), and Japan Integrated Staging (JIS) scores.
The majority of the patients had viral hepatitis as the underlying liver disease (100% in the derivation cohort and 85% in the validation cohort). The survival model incorporated MELD, age, number of tumor nodules, size of the largest nodule, vascular invasion, metastasis, serum albumin, and alpha-fetoprotein. In cross validation, the coefficients remained largely unchanged between iterations. Observed survival in the validation cohort matched closely with what was predicted by the model. The c-statistic for this model (0.77) was superior to that for BCLC (0.71), CLIP (0.70), or JIS (0.70). The score was able to further classify patient survival within each stage of the BCLC classification.
A new model to predict survival of HCC patients based on objective parameters provides refined prognostication and supplements the BCLC classification.
PMCID: PMC3564594  PMID: 22370914
liver cancer; BCLC; staging
24.  Biliary Tract Cancers in Olmsted County, Minnesota, 1976-2008 
The epidemiology of biliary tract cancers has changed in the United States in the past several decades. The aim of this study is to evaluate biliary tract cancers with regard to the incidence rates, etiology, treatment, and survival in Olmsted County between 1976 and 2008.
Community residents over 20 years of age with a newly diagnosed biliary tract cancers were identified using the Rochester Epidemiology Project. Clinical information, including tumor stage, treatment, and survival status was abstracted from the medical records. The incidence rate was calculated considering the entire population of Olmsted County to be at risk and adjusted by age and sex according to US Census 2000 population. Temporal trends of patient survival with biliary tract cancers were assessed.
A total of 116 subjects met the study criteria. The age-sex-adjusted incidence rate of intrahepatic cholangiocarcinoma(ICC) increased from 0.3 to 2.1 (p=0.02) but one of gall bladder (GB) cancer decreased from 4.0 to 2.2 (p=0.04)per 100,000 person-years between 1976 and 2008 (p<0.01). Overall incidence rates of remaining biliary tract cancers have not changed. Overall 59% of patients presented with stage 3 or 4 cancers and a median survival was 6.3 months. Survival in patients with biliary tract cancer has minimally improved from median survival of 4.2 to 7.7 months between 1976 and 2008 (p=0.05).
In Olmsted County, the incidence of ICC and GB cancer has increased and decreased, respectively. The prognosis remains poor in community residents diagnosed with biliary tract cancers.
PMCID: PMC3654834  PMID: 22751468
Etiology; incidence rates; treatment; survival; cause of death
25.  Hepatic Artery Embolization for Neuroendocrine Tumors: Postprocedural Management and Complications 
The Oncologist  2012;17(5):725-731.
The duration of hospitalization, biochemical patterns, medication usage, morbidity, and procedure-related mortality of patients who underwent hepatic artery embolization for metastatic neuroendocrine tumors are examined.
Learning Objectives:
After completing this course, the reader will be able to: Identify the components of the “postembolization syndrome”: elevated liver function tests, right upper quadrant pain, nausea and vomiting, and fever.Distinguish the postembolization syndrome from rare complications of embolization that would merit an extended hospitalization.
This article is available for continuing medical education credit at
There is scant evidence to guide the management of patients after hepatic artery embolization (HAE). We examined length of stay (LOS), laboratory patterns, medication usage, morbidity, and mortality of patients hospitalized after HAE for metastatic neuroendocrine tumors.
Data were abstracted retrospectively from electronic medical records on LOS, liver function tests (LFTs), i.v. antibiotics, analgesia, peak temperature, bacteremia, hepatic abscess formation, carcinoid crisis, and metastatic burden on cross-sectional imaging.
In 2005–2009, 72 patients underwent 174 HAEs for carcinoid and islet cell tumors. The median LOS was 4 days (range, 1–8 days). There was no correlation between peak LFTs and tumor burden. Declines in LFTs were not uniform before hospital discharge; 25%, 37%, 30%, 53%, and 67% of patients were discharged before their respective aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total and direct bilirubin levels began to decline, with no readmissions for acute hepatic failure. The median i.v. analgesia dose was 60 mg oral morphine equivalents (range, 3–1,961 mg). Pre-HAE i.v. antibiotics were administered in 99% of cases; post-HAE fever occurred in 37% of patients, with no documented bacteremia. One patient developed a hepatic abscess after HAE. There were two carcinoid crises. The single in-hospital death was associated with air in the portal veins.
The duration and intensity of in-hospital care following HAE should be managed on an individual basis. A downward trend in LFTs is not required before discharge. Modest use of i.v. analgesia suggests that many patients could exclusively receive oral analgesics. Given the rarity of serious complications, hospital stays could be shortened, thereby reducing costs and nosocomial risks.
PMCID: PMC3360912  PMID: 22511263
Liver metastasis; Neuroendocrine; Embolization; Practice improvement

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