Alcohol, Stem Cells and Cancer.

Dosage, gender, and genetic susceptibility to the effects of alcohol remained only partially elucidated. In this review, we summarize the current knowledge of the mechanisms underlying the role of alcohol in liver and gastrointestinal cancers. In addition, two recent pathways- DNA repair and TGF-β signaling which provide new insights into alcohol in the regulation of cancers and stem cells are also discussed here

Emricasan (IDN-6556) Lowers Portal Pressure in Patients with Compensated Cirrhosis and Severe Portal Hypertension

Caspases play a central role in apoptosis, inflammation and fibrosis. They produce hemodynamically-active, pro-inflammatory microparticles that cause intrahepatic inflammation, vasoconstriction and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (HVPG >5 mmHg). Emricasan 25 mg BID was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings.Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were NASH and HCV. Subjects were Child class A (87%) with median MELD score of 8 (range 6-15). Twelve had severe PH (HVPG?12mmHg). Overall, there was no significant change in HVPG after emricasan (mean [SD] -1.1[4.57] mmHg). HVPG decreased significantly (mean [SD] -3.7[4.05] mmHg; p=0.003) in those with severe PH. 4/12 had a ?20% decrease; 8/12 had a ?10% decrease; and 2/12 HVPG decreased below 12mmHg. There were no significant changes in blood pressure or heart rate. AST/ALT decreased significantly in the entire group and in severe PH. Serum cCK18 and caspase-3/7 decreased significantly. Emricasan was well-tolerated. One subject discontinued for non-serious adverse events.Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH. An effect upon portal venous inflow is likely and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect

Genetic susceptibility to hepatocellular carcinoma in chromosome 22q13.31, findings of a genome-wide association study.

Background and Aim: Chronic hepatitis C virus (HCV) infection, long-term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene-environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome-wide association study (GWAS). Methods: Two case-control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. Results: In this GWAS, we found that two SNPs were associated with HCC at Conclusions: SNPs i

Use of Adjuvant Sorafenib in Liver Transplant Recipients with High-Risk Hepatocellular Carcinoma

The efficacy of liver transplantation (LT) for hepatocellular (HCC) is limited by tumor recurrence rates of 10–15%. We undertook this pilot study to examine the use of sorafenib as adjuvant therapy in high-risk LT recipients. Methods. We prospectively enrolled patients transplanted for HCC into a treatment protocol utilizing sorafenib if their explant examination showed evidence of viable tumor exceeding Milan criteria. We utilized as historical controls patients transplanted previously, whose explant tumor characteristics exceeded Milan criteria, but who were not “preemptively” treated with sorafenib. Wilcoxon two-sample test and Fisher’s exact test were used to compare survival and recurrence rates between the two groups. Results. Seven patients were treated with sorafenib and compared to 12 historical “controls.” Two of 7 treated patients suffered from HCC recurrence. Of the comparison group, 9 experienced HCC recurrence and all succumbed to disease. Dose reduction improved tolerance of drug. The overall rate of HCC recurrence was decreased in the adjuvant therapy group compared to historical controls (29% versus 75%, P=0.07). Disease free 1-year survival for the treated versus untreated group was 100% versus 66%, respectively. Conclusion. Adjuvant use of sorafenib is safe and decreases risk of HCC recurrence in high-risk LT recipients

Liver transplantation should be offered to patients with small solitary hepatocellular carcinoma and a positive serum alpha fetoprotein rather than resection

Background: As debate continues as to what surgical modality should be offered to patients with hepatocellular carcinoma, the authors submit that serum α-fetoprotein (AFP) is an important variable to consider. Methods: Using the Surveillance, Epidemiology and End Results database, patients with solitary tumors within the Milan criteria were further stratified into 2 groups, those who underwent orthotopic liver transplantation (OLT) and those who underwent segmentectomy, lobectomy, or extended lobectomy (resection). Patients were further grouped according to serum AFP status (negative or positive). Relative survival was retrospectively evaluated for 3 years using the log-rank test. Results: In the AFP-negative group, resection (n = 165) offered equivalent survival compared with OLT (n = 116); 3-year survival was 73.8% and 81.6%, respectively (P =.245). In the AFP-positive group, 3-year survival for resection (n = 200) was 59%, while survival was 75.3% for OLT (n = 181), which showed a clear survival advantage (P =.001). Conclusions: The results of this study demonstrate that patients with solitary hepatocellular carcinoma lesions within the Milan criteria and AFP-positive status should not undergo resection but rather be offered OLT. © 2013 Elsevier Inc. All rights reserved

Liver transplantation should be offered to patients with small solitary hepatocellular carcinoma and a positive serum alpha fetoprotein rather than resection

Background: As debate continues as to what surgical modality should be offered to patients with hepatocellular carcinoma, the authors submit that serum α-fetoprotein (AFP) is an important variable to consider. Methods: Using the Surveillance, Epidemiology and End Results database, patients with solitary tumors within the Milan criteria were further stratified into 2 groups, those who underwent orthotopic liver transplantation (OLT) and those who underwent segmentectomy, lobectomy, or extended lobectomy (resection). Patients were further grouped according to serum AFP status (negative or positive). Relative survival was retrospectively evaluated for 3 years using the log-rank test. Results: In the AFP-negative group, resection (n = 165) offered equivalent survival compared with OLT (n = 116); 3-year survival was 73.8% and 81.6%, respectively (P =.245). In the AFP-positive group, 3-year survival for resection (n = 200) was 59%, while survival was 75.3% for OLT (n = 181), which showed a clear survival advantage (P =.001). Conclusions: The results of this study demonstrate that patients with solitary hepatocellular carcinoma lesions within the Milan criteria and AFP-positive status should not undergo resection but rather be offered OLT. © 2013 Elsevier Inc. All rights reserved