Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The rise in metabolic syndrome has contributed to this trend. Adipokines, such as adiponectin, are associated with prognosis in several cancers, but have not been well studied in HCC. Methods: We prospectively enrolled 140 patients with newly diagnosed or recurrent HCC with Child-Pugh (CP) class A or B cirrhosis. We examined associations between serum adipokines, clinicopathological features of HCC, and time to death. We also examined a subset of tumors with available pathology for tissue adiponectin receptor (AR) expression by immunohistochemistry. Results: The median age of subjects was 62 years; 79% were men, 59% had underlying hepatitis C, and 36% were diabetic. Adiponectin remained a significant predictor of time to death (hazard ratio 1.90; 95% confidence interval 1.05-3.45; p = 0.03) in a multivariable adjusted model that included age, alcohol history, CP class, stage, and serum E-fetoprotein level. Cytoplasmic AR expression (AR1 and AR2) in tumors trended higher in those with higher serum adiponectin levels and in those with diabetes mellitus, but the association was not statistically significant. Conclusions: In this hypothesis-generating study, we found the serum adiponectin level to be an independent predictor of overall survival in a diverse cohort of HCC patients. Impact: Understanding how adipokines affect the HCC outcome may help develop novel treatment and prevention strategies. i 2014 S. Karger AG, Basel

Purpose To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Experimental Design Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Results Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Conclusion Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.

Objectives:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. CA19-9 is a glycoprotein that predicts poor prognosis in pancreatic and biliary malignancies. We evaluated it as a prognostic biomarker for patients with HCC.Methods:We prospectively enrolled 145 patients with HCC, diagnosed using American Association for Study of Liver Diseases criteria, between October 2008 and November 2012. We examined whether baseline serum CA19-9 levels predicted overall survival. We also examined immunostains of hepatic resections and explants of patients with elevated and normal serum CA19-9.Results:In a cohort of predominantly hepatitis C and B patients, CA19-9 ≥100 U/ml was associated with a 2.7-fold increased mortality (hazard ratio (HR): 2.72; 95% confidence interval (CI): 1.52–4.88, P<0.001). It remained a significant predictor (HR: 2.58; 95% CI: 1.41–4.72, P=0.002) in a multivariable model adjusted for Child–Pugh score, alpha-fetoprotein, Barcelona Clinic Liver Cancer stage, and Model for End-Stage Liver Disease. CA19-9 immunohistochemistry performed on a subset of liver resection and explant specimens showed increased CA19-9 immunostaining of non-tumor liver parenchyma in patients with elevated serum CA19-9. It also showed staining of native and reactive bile ducts, and of progenitor-like cells at the periphery of cirrhotic nodules.Conclusions:Elevated serum CA19-9 ≥100 U/ml is an independent predictor of poor overall survival in this hypothesis-generating study. The unfavorable prognosis seen with elevated serum levels may be related to progenitor-like cells in the non-tumor liver.

Background. More than 50% of US adults, and an even larger proportion of cancer patients, use dietary supplements. Since many supplements require hepatic metabolism, they may be particularly likely to cause toxicities in patients with hepatocellular carcinoma (HCC). However, little is known about supplement use in patients with HCC. Methods. From 2008 to 2012, we gave newly diagnosed HCC patients at our institution a standardized questionnaire about dietary supplement use, demographic factors, and clinical characteristics. We then followed patients for four years or until time to death to examine the relationship with supplement use. Results. Of 146 patients, 71% had used vitamins and 45% herbal supplements. Most commonly used supplements were antioxidants (51%), multivitamins (46%), vitamin D (25%), and milk thistle (23%). People in mid-higher income brackets were more likely to use herbal supplements (19% of those earning <$30 000, 50% of those earning $30 000-60 000, and 34% of those earning >$60 000 used supplements). Hepatitis C (HCV) patients were more likely to use milk thistle than those without HCV (30% vs 13%, P = .03), and patients with hepatitis B (HBV) were more likely than non-HBV patients to use vitamin C (32% vs 14%, P = .01). Supplement use was not associated with overall survival. Conclusions. Like cancer patients in other studies, the majority of our HCC patients used dietary supplements. Supplement use was not associated with overall survival but should be studied in larger patient samples.

e15037 Background: Vitamin and herbal supplement use has been steadily rising in the United States. Few data are available evaluating this use in patients with hepatocellular carcinoma (HCC). We analyzed our prospective database of patients with HCC to determine predictors of supplement use and associations with survival. Methods: We prospectively enrolled 146 patients with newly-diagnosed HCC between 10/2008 and 11/2012. Upon enrollment, patients completed an epidemiologic questionnaire and provided detailed demographic and lifestyle data including diet, exercise, smoking and use of vitamins and herbal supplements. Clinical characteristics and overall survival were collected from medical records. We assessed if socioeconomic, lifestyle, or clinical characteristics predicted vitamin and herbal supplement use in HCC patients. We also evaluated if use was predictive of overall survival. Results: The median age was 62, and 79% were men. 60% had underlying HCV and 38% had HBV; 64% were Child-Pugh A and 19% were metastatic. 71% of our cohort used vitamins and 45% used herbal supplements. Most commonly used were antioxidants (including vitamins C, E, A and selenium) (51%), multivitamins (46%), vitamin D (25%), and milk thistle (23%). Vitamin D use was higher in women and those without HCV. Use of vitamin C was associated with being HBV positive (OR = 3.01, P = 0.01) while HCV patients were more likely to use milk thistle (OR = 2.80, P = 0.03). In a univariable model, use of milk thistle at baseline was associated with a trend toward worse overall survival (HR = 1.78, P = 0.09), despite not being associated with other poor prognostic signs like higher stage or AFP, or worse Child-Pugh score. Use of other vitamin or herbal supplements did not predict survival. Conclusions: The majority of patients with newly-diagnosed HCC have used some form of vitamin or herbal supplement, with almost a quarter having used milk thistle in their lifetime. In our analyses, use of milk thistle may be associated with worse survival. Though our cohort is small, this emphasizes the prevalence of supplement use in patients with HCC and the need to further evaluate the safety and efficacy of these alternative treatments in various patient populations.