Abby B. Siegel

Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link.

Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer death in the United States. Although many risk factors for HCC are well defined, including hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol, most series have indicated that 5% to 30% of patients with HCC lack a readily identifiable risk factor for their cancer. The majority of “cryptogenic” HCC in the United States is attributed to nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome. The metabolic syndrome is a constellation of problems that includes insulin resistance, obesity, hypertension, and hyperlipidemia. Increasingly, components of the metabolic syndrome are being linked to various forms of cancer with respect to both increased risk of disease and worsened outcome. In this review, the authors focused on the relation between metabolic syndrome and HCC. They investigated the increased risks of HCC among individuals with features of metabolic syndrome, potentially worsened cancer outcomes in these patients, possible pathogenic mechanisms to explain these relations, and treatment options for those with NAFLD and its progressive counterpart, nonalcoholic steatohepatitis. It is predicted that metabolic syndrome will lead to large increases in the incidence of HCC over the next decades. A better understanding of the relation between these 2 diseases ultimately should lead to improved screening and treatment options for patients with HCC. Cancer 2009.

Exploring genome-wide DNA methylation profiles altered in hepatocellular carcinoma using Infinium HumanMethylation 450 BeadChips

Hepatocellular carcinoma (HCC) incidence has increased in the US and also has one of the fastest growing death rates of any cancer. The purpose of the current study was to discover novel genome-wide aberrant DNA methylation patterns in HCC tumors that are predominantly HCV-related. Infinium HumanMethylation 450K BeadChip arrays were used to examine genome-wide DNA methylation profiles in 66 pairs of HCC tumor and adjacent non-tumor tissues. After Bonferroni adjustment, a total of 130,512 CpG sites significantly differed in methylation level in tumor compared with non-tumor tissues, with 28,017 CpG sites hypermethylated and 102,495 hypomethylated in tumor tissues. Absolute tumor/non-tumor methylation differences ≥ 20% were found in 24.9% of the hypermethylated and 43.1% of the hypomethylated CpG sites; almost 10,000 CpG sites have ≥ 30% DNA methylation differences. Most (60.1%) significantly hypermethylated CpG sites are located in CpG islands, with 21.6% in CpG shores and 3.6% in shelves. In contrast, only a small proportion (8.2%) of significantly hypomethylated CpG sites are situated in islands, while most are found in open sea (60.2%), shore (17.3%) or shelf (14.3%) regions. A total of 2,568 significant CpG sites (2,441 hypermethylated and 127 hypomethylated) covering 589 genes are located within 684 differentially methylated regions defined as regions with at least two significant CpG sites displaying > 20% methylation differences in the same direction within 250-bp. The top 500 significant CpG sites can significantly distinguish HCC tumor from adjacent tissues with one misclassification. Within adjacent non-tumor tissues, we also identified 75 CpG sites significantly associated with gender, 228 with HCV infection, 17,207 with cirrhosis, and 56 with both HCV infection and cirrhosis after multiple comparisons adjustment. Aberrant DNA methylation profiles across the genome were identified in tumor tissues from US HCC cases that are predominantly related to HCV infection. These results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis.

Racial disparities in utilization of liver transplantation for hepatocellular carcinoma in the United States, 1998-2002.

BACKGROUND AND AIMS:The extent of use of liver transplantation on a population scale to treat hepatocellular carcinoma (HCC) in the United States is unknown. We assessed recent predictors of use of liver transplantation and its effect on survival for those with nonmetastatic HCC.METHODS:The Surveillance, Epidemiology, and End Results (SEER) program is a collection of population-based cancer registries. We identified adults registered in SEER with HCC between 1998 and 2002. We examined determinants for receipt of a liver transplant in univariate and multivariable analyses. Kaplan–Meier survival curves were constructed for those who received and did not receive a transplant for HCC.RESULTS:We identified 1,156 adults with small (5 cm or less) nonmetastatic HCC. Approximately 45% were white, 29% Asian, 17% Hispanic, and 9% African American. Only 21% received a transplant. More recent year of diagnosis, younger age, being married, white race, and smaller tumor size each predicted receipt of transplant. African Americans and Asians were about half as likely to receive a transplant as compared with white patients (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.21–0.90 for African Americans, and 0.57, 95% CI 0.36–0.89 for Asians). Hispanics trended in the same direction, but this was not statistically significant (OR 0.66, 95% CI 0.39–1.12). Those who underwent liver transplantation for localized HCC had 3- and 5-yr survivals of 81% and 75%, respectively.CONCLUSIONS:Only one-fifth of those with small, nonmetastatic HCC received liver transplantation. Transplanted patients have long-term survival similar to that of the best single-institution studies. However, marked racial variations were seen, with African Americans and Asians significantly less likely to receive a transplant after controlling for other variables.

Sorafenib: Where Do We Go from Here?

The approval of sorafenib as the first effective drug for the treatment of hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. A better understanding of HCC pathogenesis has led to the development of several novel targeted treatments. HCC is treated in a uniquely multidisciplinary way requiring surgeons, hepatologists, interventional radiologists, and oncologists. This review describes the molecular pathogenesis of HCC, explores current and future treatments based on these pathways, and describes how these new therapies may augment existing approaches to HCC treatment.(HHEPATOLOGY 2010;)

SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma

PURPOSE The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen. PATIENTS AND METHODS Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine (1,000 mg/m(2) intravenously on days 1 and 8) and capecitabine (1,500 mg/m(2) per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m(2) per day) and radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively. RESULTS A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage. CONCLUSION This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials.

Exploration of Genome-Wide Circulating MicroRNA in Hepatocellular Carcinoma: MiR-483-5p as a Potential Biomarker

Background: MicroRNAs (miRNA) are abundant in the circulation and play a central role in diverse biologic processes; they may be useful for early diagnosis of hepatocellular carcinoma. Methods: We conducted a two-phase, case–control study (20 pairs for the discovery set and 49 pairs for the validation set) to test the hypothesis that genome-wide dysregulation of circulating miRNAs differentiates hepatocellular carcinoma cases from controls. Taqman low-density arrays were used to examine genome-wide miRNA expression for the discovery set, and quantitative real-time PCR was used to validate candidate miRNAs for both discovery and validation sets. Results: Sixty-six miRNAs were found to be significantly overexpressed in plasma of hepatocellular carcinoma cases compared with controls after adjusting for false discovery rate (P < 0.05). A volcano plot indicated that seven miRNAs had greater than 2-fold case–control differences with P < 0.01. Four significant miRNAs (miR-150, miR-30c, miR-483-5p, and miR-520b) detectable in all samples with varied expression levels were further validated in a validation set. MiR-483-5p was statistically significantly overexpressed in hepatocellular carcinoma cases compared with controls (3.20 vs. 0.82, P < 0.0001). Hepatocellular carcinoma risk factors and clinic-pathological characteristics did not influence miR-483-5p expression. The combination of plasma miR-483-5p level and hepatitis C virus status can significantly differentiate hepatocellular carcinoma cases from controls with an area under the curve of 0.908 (P < 0.0001). The sensitivity and specificity were, respectively, 75.5% and 89.8%. Conclusions: These preliminary results suggest the importance of dysregulated circulating miR-483-5p as a potential hepatocellular carcinoma biomarker. Impact: Confirmation of aberrant expression of miR-483-5p in a large prospective hepatocellular carcinoma study will provide support for its application to hepatocellular carcinoma detection. Cancer Epidemiol Biomarkers Prev; 22(12); 2364–73. ©2013 AACR.

Hepatocellular carcinoma: review of current treatment with a focus on targeted molecular therapies

The treatment of hepatocellular carcinoma (HCC) remains a challenge, with 1- and 3-year survival rates of 20% and 5%, respectively, and a median survival of 8 months. However, a better understanding of the pathogenesis of HCC, and advances in targeted molecular therapies provide physicians treating this disease with new hope. The treatment of HCC is multidisciplinary, requiring surgeons, hepatologists, interventional radiologists and oncologists. Thus, there is enormous potential to combine various treatment modalities to improve survival for patients. This review will describe what is currently known about the molecular pathogenesis of HCC, explore current and future treatments based on these pathways, and describe how these new therapies fit into existing approaches to HCC treatment.

Diabetes, body mass index and outcomes in hepatocellular carcinoma patients undergoing liver transplantation

&NA; For many cancers, features of the metabolic syndrome, such as diabetes and obesity, have been associated with both increased risk of cancer development and poor outcomes. Methods We examined a large retrospective cohort of 342 consecutive patients who underwent liver transplantation for hepatocellular carcinoma between January 1999 and July 2010 at our institution. We evaluated the relationship between diabetes, obesity, hepatocellular carcinoma (HCC) recurrence, and overall survival. Results We found that a body mass index (BMI) higher than 30 was an independent predictor of poor overall survival in a multivariable Cox model, approximately doubling the risk of death after transplantation. A BMI higher than 30 was also a predictor of recurrent HCC, although this was of borderline statistical significance (hazard ratio for recurrence, 1.9; 95% confidence interval, 0.9–4.1). We also found increased BMI to be an independent predictor of microvascular invasion within HCC tumors, lending a possible explanation to these results. Those with diabetes showed worsened overall survival compared with those without diabetes in univariate but not multivariable analysis, possibly related to longer wait times. Conclusions Our findings suggest a relationship between higher BMI, tumor vascular invasion, increased recurrence, and worsened overall survival. These findings may help explain why those with high BMI have worse outcomes from their cancers. A better understanding of the role of obesity and diabetes in patients with cancer should help develop better predictors of outcome and improved treatment options for patients with HCC.

Clinical Practice Guidelines for Hepatocellular Carcinoma Differ between Japan, United States, and Europe

Hepatocellular carcinoma (HCC) is a malignant tumor that is the fifth most common type of cancer and the third leading cause of cancer-related death globally. Although HCC was once thought to be a special type of cancer prevalent only in Southeast Asia and Africa, it has rapidly become more common in other regions, particularly Europe and the United States, which has led to greater interest in the diagnosis and treatment of HCC worldwide. Consequently, the American Association for the Study of Liver Diseases (AASLD) [1] and the European Association for the Study of the Liver and the European Organisation for Research and Treatment of Cancer (EASL-EORTC) [2] have published clinical practice guidelines for liver cancer. In Japan, the first edition of evidence-based clinical practice guidelines was published in 2005 [3, 4], followed by a revised edition in 2009 and a third revision in 2013 [5, 6]. In addition, 1 or 2 years after the publication of each revised edition of the evidence-based treatment guidelines, The Japan Society of Hepatology (JSH) has also published consensusbased clinical practice manuals for HCC. The first edition was published in 2007 and the second edition in 2010 [7, 8]. A third edition will be published in 2015. In this article, differences between the aforementioned European and American clinical practice guidelines and Japanese clinical practice guidelines will be discussed. Specifically, as these guidelines primarily consist of both a surveillance and diagnostic algorithm and a treatment algorithm, each component of the algorithms will be explained in detail.

S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma.

Background:Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages. On the basis of evidence of dysregulation of the epidermal growth factor receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers.Methods:Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function. Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily, respectively.Results:Thirty-four eligible patients were recruited. The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months. There were two unconfirmed partial responses (6%, 95% CI: 1–20%), with a median progression-free survival of 2 months (95% CI: 2–3), and median overall survival of 6 months (95% CI: 3–8 months). Grade 3 and 4 adverse events included hypertension, AST/ALT increase, bilirubin increase, diarrhoea, hypokalaemia, hypophosphatemia and rash.Conclusions:Despite compelling preclinical rationale, the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers. Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease.