AA

SL

DA

bst

ract

s

639

Female Gender Associated With Less Aggressive Tumor Phenotype and BetterSurvival in HCCRenumathy Dhanasekaran, George Saffouri, Ju Dong Yang, Nasra H. Giama, Seth W.Slettedahl, William S. Harmsen, Terry M. Therneau, Lewis R. Roberts

Background: The incidence of hepatocellular carcinoma (HCC) has been consistently shownto be higher in men than in women in several studies. However, gender differences in tumorphenotype and clinical outcome have not been clearly understood. Methods: All patientsdiagnosed with HCC at the Mayo Clinic, Rochester between 2005 and 2011 were identifiedusing data tracking systems. Clinical, laboratory and survival data were abstracted. Patientswere stratified based on their gender. Chi square and Student t tests were used to comparecategorical and continuous variables respectively. Kaplan Meier analysis was used for survivalanalysis. Results: A total of 885 patients were diagnosed with HCC in 2005-2011; 74%were males and 26% females (ratio 3:1). The mean age at diagnosis was not different betweenmen (63.1 yr) and women (62.2 yr) (p=0.098). Hepatitis C was the most common underlyingetiology for HCC in both genders but women had a higher rate of NAFLD (19.65 vs. 9.8%;p<0.001) and a lower rate of alcoholic liver disease (17.3% vs. 7.4%; p<0.001) than men.Women had a higher BMI than men at the time of HCC diagnosis (23.9 vs. 22.9; p=0.04).Rates of alcohol abuse (p<0.001) and tobacco abuse (p<0.001) were lower among women.Women had lower mean bilirubin (p=0.008), ALT (p=0.040) and creatinine (p=0.003) atthe time of diagnosis than men. As a result, the mean MELD score was lower in womenthan men (12.2 vs. 10.2; p=0.015). Men had a trend towards a higher prevalence of ascitesthan women (85.5% vs. 81.3%; p=0.08). Comparing the tumor burden between the twogroups, women had lower rates of multifocal disease than men (45.5% vs 55.0%; p<0.021).Women also had lower rates of macrovascular invasion (12.6% vs. 24.4%; p<0.001) andportal vein invasion (10.5% vs. 17.7%; p=0.019) than men. A larger percentage of women(33.5%) underwent curative surgeries such as resection and transplantation than men (25.2%)(p=0.016). Overall median survival from diagnosis was better in women (1.21 years) thanin men (0.94) (p=0.038). Conclusions: Female gender appears to confer a survival advantagein patients with HCC. Women have better liver synthetic function at diagnosis, a smallernumber of tumors at diagnosis and lower rates of vascular invasion. All of the above factorsalong with increased rates of curative surgeries among women probably contribute to theirbetter overall survival.

640

Therapeutic Phlebotomy to Maintain Iron Depletion Reduces Alpha-Fetoprotein and Reduces Incidence of Hepatocellular Carcinoma in ChronicHepatitis CEstela E. Mogrovejo, Otavio Pereira-Rodrigues, Mohamad R. Alsibae, Tusar K. Desai

BACKGROUND: Increased hepatic iron stores in advanced chronic hepatitis C (CHC)patients contribute to liver injury and correlate with progression-poor clinical outcome, andhepatocellular carcinoma (HCC). The aim of this study is to present our experience withtherapeutic phlebotomy in advanced CHC patients with an initially elevated alpha-fetoprotein

S-918AASLD Abstracts

(AFP) and compare their clinical outcome with a population that did not undergo phlebot-omy. METHODS: CHC patients with an AFP> 10ng/mL and negative imaging studies forHCC were identified. Exclusion criteria: HCC identified within the first year of follow-up,follow-up< 36 months in patients with negative imaging for HCC or decompensation,concomitant HIV or hepatitis B infection. Compared demographic and clinical data of thephlebotomy and non-phlebotomy groups. Sub-divided patients into progressors and non-progressors, according to their clinical outcome. RESULTS: A total of 752 charts werereviewed. Obtained 24 phlebotomy and 52 non-phlebotomy patients. 21 patients haveremained on maintenance phlebotomy to this time. The mean baseline charactaristics of the2 groups are presented in table below (Table 1). At the time of starting phlebotomy 11patients had biopsy proven cirrhosis, 7 had bridging fibrosis, 4 had clinical evidence ofcirrhosis with decompensation and 2 had no biopsy or clinical evidence of cirrhosis buthad an AFP> 10ng/mL; nineteen of them had failed anti-viral therapy and 5 were disqualifiedfrom treatment. The non-phlebotomy and phlebotomy group showed a 76.9% and 12.5%of disease progression respectively. HCC was diagnosed in 22 (42%) patients from the non-phlebotomy group and in 1 (4.7%) patient from the phlebotomy group. The mean time fordeveloping HCC in the non-phlebotomy group was 71.3 months, ranging from 14 to 201months. The mean follow up time was 82.5 and 69.3 months for the non-phlebotomy andphlebotomy groups respectively. 3 patients voluntarily dropped out of the phlebotomy groupafter achieving a dramatic reduction in their AFP. 1 of these patients developed hepatoma4 years after stopping the phlebotomy regimen, and the 2 other patients who stopped thephlebotomy regimen required a liver transplant 2 and 4 years later. CONCLUSIONS:Therapeutic phlebotomy to lower iron levels reduces AFP levels and appears to reduce theincidence of hepatoma in this retrospective single-center review. A large prospective trial toevaluate therapeutic phlebotomy in patients with CHC, iron overload and high AFP shouldbe conducted.Table 1. Baseline Characteristics

641

TGF-β Regulated E3 Ligase Are Novel Therapeutic Targets for Primary LiverCancerJian Chen, Jiun-Sheng Chen, YoungJin Gi, Lior H. Katz, Ji-Hyun Shin, Liem M. Phan,Wilma Jogunoori, Vivek Shukla, Bibhuti Mishra, Shulin Li, Milind Javle, Mien-ChieHung, Lopa Mishra

Background: Hepatocellular Cancer (HCC) is lethal and difficult to treat due to late diagnosis,few viable targeted therapeutics and unclear molecular profiling of each stage of tumordevelopment, from cirrhosis to nodule formation to carcinoma. A large number of studieshave demonstrated that the TGF-β pathway plays a fundamental role in the biology of theGI tract, and as such, several components of the pathway are commonly targeted in variousGI cancers. TGF-β signaling is regulated by the ubiquitin-proteasome pathway, in whichE3 ubiquitin ligases recognize and target proteins for degradation by the proteasome. Numer-ous E3 ubiquitin ligases have been identified as negative regulators of different componentsof the TGF-β pathway. More recently, Praja and Keap1 have been identified as E3 ligasesthat ubiquitinates β2-spectrin (β2SP) in a TGF-β-dependent manner. Accordingly, Praja E3ligase activity regulates TGF-β signaling by controlling β2SP abundance through ubiquitin-mediated degradation. Therefore, we hypothesis is that Specific E3 ligases, which disruptTGF-β/β2SP/Smad3 tumor suppressor pathway lead to uncontrolled activation of chromatinand tumor formation. Therefore, small molecule inhibitors that specifically target these E3ligases could present a novel therapeutic approach for liver cancer. Materials & Methods:Broad genome datasets including 110 cases of HCC patients were retrieved from The CancerGenome Atlas (TCGA) and analyzed. 23 HCC and normal liver tissue specimens wereimmunostained with anti-Praja1 antibody. A small chemical compound library was screenedfor E3 ligase inhibitors targeting Praja1. Results: (1) Broad genome analysis reveals that E3ubiquitin ligases regulating the TGF-β pathway are altered in GI cancers mainly by increasein mRNA and that they negatively correlate with patient survival. (2) Praja1 expression isdramatically raised in human HCCs with loss of TGF- β signaling. (3) Praja1 inhibits TGF-β/Smad3 tumor suppressor function and increases c-Myc activities. (4) Inhibition of Praja1leads to apoptosis and suppresses its oncogenic activities. (5) Small chemical inhibitorssuppress Praja1 activities and restores TGF- β tumor suppressor function in HCC cells. (6)Small chemical inhibitors induce apoptosis and inhibit HCC cell growth and tumorigenesis.Conclusions: E3 ubiquitin ligases that modulate the TGF- βpathway are frequently increasedin HCC. Praja1 presents a therapeutic target- it disrupts the TGF- β tumor suppressorpathway, and its overexpression promotes cancer cell survival and proliferation. Smallmolecule inhibitors such as triterpenoids that specifically target Praja1 could be very usefulin HCC therapy, through targeting c-Myc, restoring TGF- β tumor suppressor function. Thisstudy may lead to new therapeutics targeting this lethal cancer and potentially a Phase Iclinical trial in HCC.