The effect of alcohol on Sirt1 expression and function in animal and human models of hepatocellular carcinoma (HCC).

INTRODUCTION: Chronic heavy alcohol use is an independent risk factor for developing hepatocellular carcinoma (HCC). Sirtuin-1 (Sirt1) is a NAD+-dependent deacetylase implicated in alcohol-induced liver injury and overexpressed in human HCC. The aims of this study were to investigate Sirt1 expression in mouse models of HCC and chronic EtOH-feeding, and in human HCC cells expressing alcohol metabolizing enzymes. METHODS: C57BL/6 and B6C3 mice were injected with DEN and randomized to receive drinking water (DW) or EtOH-DW for 8 weeks at 36 weeks. Livers were analyzed for HCC incidence, size, and Sirt1 expression. In parallel, human HepG2 cells or HepG2 cells transfected to express ADH and CYP2E1 (VL-17a cells) were treated with alcohol (0-50 mM) and/or CAY10591 (Sirt1 activator) or EX-527 (Sirt1 inhibitor). RESULTS: B6C3 mice exhibited significantly elevated Sirt-1 expression vs. C57BL/6 mice and Sirt-1 expression was elevated in HCC vs. non-tumor liver. However, EtOH-feeding did not further affect Sirt1 expression in mice of either background despite EtOH increasing HCC size and incidence in B6C3 mice. In vitro, EtOH treatment significantly decreased Sirt1 expression in VL-17a-cells and stimulated cell growth, an effect not observed in HepG2 cells. The effects of ethanol on VL-17a cells were abrogated by pretreatment with CAY10591. CONCLUSIONS: Sirt1 expression correlates with susceptibility to form HCC, but is not further affected by alcohol feeding. Conversely Sirt1 expression and function is impacted by alcohol metabolism capacity in human HCC cells in vitro. These discrepancies in Sirt1-expression-function may reflect differences in enzyme expression compared to activity, or more complex changes in genes targeted for deacetylation during tumor progression in the setting of chronic alcohol ingestion.

Laparoscopic microwave ablation of human liver tumours using a novel three-dimensional magnetic guidance system.

BACKGROUND: Accurate antenna placement is essential for effective microwave ablation (MWA) of lesions. Laparoscopic targeting is made particularly challenging in liver tumours by the needle's trajectory as it passes through the abdominal wall into the liver. Previous optical three-dimensional guidance systems employing infrared technology have been limited by interference with the line of sight during procedures. OBJECTIVE: The aim of this study was to evaluate a newly developed magnetic guidance system for laparoscopic MWA of liver tumours in a pilot study. METHODS: Thirteen patients undergoing laparoscopic MWA of liver tumours gave consent to their participation in the study and were enrolled. Lesion targeting was performed using the InnerOptic AIM™ 3-D guidance system to track the real-time position and orientation of the antenna and ultrasound probe. RESULTS: A total of 45 ablations were performed on 34 lesions. The median number of lesions per patient was two. The mean ± standard deviation lesion diameter was 18.0 ± 9.2 mm and the mean time to target acquisition was 3.5 min. The first-attempt success rate was 93%. There were no intraoperative or immediate postoperative complications. Over an average follow-up of 7.8 months, one patient was noted to have had an incomplete ablation, seven suffered regional recurrences, and five patients remained disease-free. CONCLUSIONS: The AIM™ guidance system is an effective adjunct for laparoscopic ablation. It facilitates a high degree of accuracy and a good first-attempt success rate, and avoids the line of site interference associated with infrared systems.

Optimal ablation volumes are achieved at submaximal power settings in a 2.45-GHz microwave ablation system.

INTRODUCTION: Local ablative therapies, including microwave ablation (MWA), are common treatment modalities for in situ tumor destruction. Currently, 2.45-GHz ablation systems are gaining prominence because of the shorter application times required. The aims of this study were to determine optimal power and time to ablation volume (AbV) ratios for a new 1.8-mm-2.45-GHz antenna using ex vivo tissue models. METHODS: The 1.8-mm-2.45-GHz Accu2i MWA system was employed to perform ablations in bovine liver, porcine muscle, and porcine kidney ex vivo. Whole tissues were prewarmed (35°C) and multiple ablations performed at power settings of 60 to 180 W for 2- to 6-minute time intervals. Postablation, tissues were dissected, AbVs calculated, and correlations to power and time settings made. RESULTS: Significant increases in AbV were measured between each of the time points for a constant power setting in all 3 tissues. Increasing power settings led to significant increases in AbV at power settings ≤140 W. However, no significant increase in AbV was obtained at power settings >140 W. CONCLUSIONS: Optimal efficiency for MWA using a new 1.8-mm-2.45-GHz system is achieved at settings of ≤140 W for 6 minutes in a range of ex vivo tissue and no additional benefit occurs by increasing the power setting to 180 W in these tissues.

Survival analysis of patients with stage I and II hepatocellular carcinoma after a liver transplantation or liver resection.

INTRODUCTION: Liver transplantation (LT) is a treatment option in select patients with hepatocellular carcinoma (HCC). The aim of the present study was to compare survival in Stage I or II HCC patients undergoing either liver transplant (LT) or a liver resection (LR). METHOD: The study is a retrospective analysis of the National Cancer Data Base (1998-2011). In total, 148,882 patients with liver cancer were identified, of which 5-year survival data (1998-2006) were available for 64,227 patients. Patients were stratified by the American Joint Committee on Cancer (AJCC) clinical stage I and II. Kaplan-Meier curves and log-rank tests were used for statistical analysis. RESULTS: 3340 HCC patients met analysis criteria. Among stage I HCC, 860 had LT and 871 had LR. Among stage II HCC, 833 had LT and 776 LR. In stage I patients the median survival for LT and LR were 127.9 and 56.7 months, respectively, (P < 0.0001) and in stage II patients the median survival was 110.8 and 42.8 months (P < 0.0001). Unlike LT patients, LR patients with Stage I HCC had a longer median survival compared with Stage II patients (P = 0.0002). CONCLUSION: Liver transplantation offers a survival advantage compared with a liver resection among patients with Stage I and II HCC. LT is the best surgical treatment for early stage (I/II) HCC in patients with advanced fibrosis or cirrhosis, whereas LR provides equivalent outcomes to LT in patients without advanced fibrosis and should be considered as the first surgical option.

The impact of regionalization of pancreaticoduodenectomy for pancreatic Cancer in North Carolina since 2004.

Pancreaticoduodenectomy (PD) carries a significant risk. High-volume centers (HVCs) provide improved outcomes and regionalization is advocated. Rapid regionalization could, however, have detrimental effects. North Carolina has multiple HVCs, including an additional HVC added in late 2006. We investigated regionalization of PD and its effects before, and after, the establishment of this fourth HVC. The North Carolina Hospital Discharge Database was queried for all PDs performed during 2004 to 2006 and 2007 to 2009. Hospitals were categorized by PD volume as: low (one to nine/year), medium (10 to 19/year), and high (20/year or more). Mortality and major morbidity was assessed by comparing volume groups across time periods. Number of PDs for cancer increased 91 per cent (129 to 246 cases) at HVCs, whereas decreasing at low-volume (62 to 58 cases) and medium-volume (80 to 46 cases) centers. Percentage of PD for cancer performed at HVCs increased significantly (47.6 to 70.3%) while decreasing for low- and medium-volume centers (P < 0.001). Mortality was significantly less at HVCs (2.8%) compared with low-volume centers (10.3%) for 2007 to 2009. Odds ratio for mortality was significantly lower at HVCs during 2004 to 2006 (0.31) and 2007 to 2009 (0.34). Mortality for PD performed for cancer decreased from 6.6 to 4.6 per cent (P = 0.31). Major morbidity was not significantly different between groups within either time period; however, there was a significant increase in major morbidity at low-volume centers (P = 0.018). Regionalization of PD for cancer is occurring in North Carolina. Mortality was significantly lower at HVCs, and rapid regionalization has not detracted from the superior outcomes at HVCs.

Altered lysophosphatidic acid (LPA) receptor expression during hepatic regeneration in a mouse model of partial hepatectomy.

BACKGROUND: Hepatic regeneration requires coordinated signal transduction for efficient restoration of functional liver mass. This study sought to determine changes in lysophosphatidic acid (LPA) and LPA receptor (LPAR) 1-6 expression in regenerating liver following two-thirds partial hepatectomy (PHx). METHODS: Liver tissue and blood were collected from male C57BL/6 mice following PHx. Circulating LPA was measured by enzyme-linked immunosorbent assay (ELISA) and hepatic LPAR mRNA and protein expression were determined. RESULTS: Circulating LPA increased 72 h after PHx and remained significantly elevated for up to 7 days post-PHx. Analysis of LPAR expression after PHx demonstrated significant increases in LPAR1, LPAR3 and LPAR6 mRNA and protein in a time-dependent manner for up to 7 days post-PHx. Conversely, LPAR2, LPAR4 and LPAR5 mRNA were barely detected in normal liver and did not significantly change after PHx. Changes in LPAR1 expression were confined to non-parenchymal cells following PHx. CONCLUSIONS: Liver regeneration following PHx is associated with significant changes in circulating LPA and hepatic LPAR1, LPAR3 and LPAR6 expression in a time- and cell-dependent manner. Furthermore, changes in LPA-LPAR post-PHx occur after the first round of hepatocyte division is complete.

Laparoscopic transgastric endolumenal cystogastrostomy and pancreatic debridement.

BACKGROUND: Cystogastrostomy is commonly performed for internal drainage of pancreatic pseudocysts (PP) and concomitant debridement of walled-off pancreatic necrosis (WOPN). While an open approach to cystogastrostomy is well established, an optimal minimally invasive technique continues to evolve. This laparoscopic transgastric endolumenal cystogastrostomy presented here allows for a large cystogastrostomy with complete debridement of necrosis and internal drainage through a minimally invasive approach. METHODS: We performed a retrospective review of 22 patients with symptomatic PP/WOPN treated with attempted laparoscopic transgastric endolumenal cystogastrostomy (Lap-TEC) and pancreatic debridement. Short- and long-term outcomes were assessed. RESULTS: From November 2006 to March 2013, a total of 22 Lap-TEC/pancreatic debridement procedures were attempted; 15 were completed laparoscopically. The median age of the cohort was 49.5 ± 12 years (range = 18-71), average body mass index = 29.1 kg/m(2), 77 % had an ASA score ≥ 3, and 10 were female. Gallstones were the most common etiology (50 %), and median time between initial presentation and surgery was 86 days (range = 0-360). Median operative time and estimated blood loss were 213 min and 100 cc, respectively. Forty-one percent of the patients were admitted to the ICU postoperatively and the average length of stay was 14 days (range = 4-50). Median follow-up was 2 months (range = 0-62.5), with one patient having a procedure-related complication. No other reoperations, late complications, or mortalities occurred. All patients had resolution of their symptoms and fluid collections. CONCLUSION: This technique of internal drainage via Lap-TEC and pancreatic debridement has been successful in achieving primary drainage and relieving symptoms of PP/WOPN with no mortality and minimal morbidity.

Hepatocellular carcinoma and cholangiocarcinoma: an update.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer worldwide and is rising in incidence. Ultrasound is the preferred modality for screening high-risk patients for HCC because it detects clinically significant nodules, widespread availability and lower cost. HCC does not require a biopsy for diagnosis if specific imaging criteria are fulfilled. Transarterial chemoembolization (TACE) is the most common modality used to treat HCC followed by ablation. Cholangiocarcinoma (CCA) is increasing in incidence and the second most common primary malignancy of the liver. There is no effective screening strategy for CCA although magnetic resonance imaging and carbohydrate antigen 19-9 (CA 19-9) are commonly used without proven benefit. Therapy for CCA is challenging and resection, when possible, is the mainstay of therapy. Gemcitabine in combination with cisplatin or biologics may offer a modest survival benefit. Liver transplantation for CCA is associated with reasonable survival in select cases. Molecular diagnostics offer the potential to develop personalized approaches in the management of HCC and CCA.

Ablation therapy for hepatocellular carcinoma: past, present and future perspectives.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and is most commonly found in the setting of liver cirrhosis. Treatment of HCC must consider both the tumors present, as well as the remaining dysfunctional liver that both hinders treatment and can produce additional HCC over time. Ablation is an evolving part of the multimodality treatment approach to HCC that can effectively destroy tumors while preserving surrounding liver parenchyma. New technologies have made ablation an indispensable tool in the treatment of all stages of HCC. This review presents the history, present technologies and future potential of ablation in the treatment of HCC.

Changes in inferior vena cava filter placement over the past decade at a large community-based academic health center.

OBJECTIVE: A significant increase in the frequency of inferior vena cava (IVC) filter placement at our large community-based academic health center led us to evaluate changes in indications, devices, and providers over the past decade. METHODS: A single-center retrospective review of all filter placements was performed comparing 76 patients in 1995 with 470 patients in 2005. Demographic data, provider data, filter type, and indications for placement were tabulated. Complications, follow-up evaluation, filter removal, and patient outcomes were examined. RESULTS: There was a greater than sixfold increase in the number of filters placed in 2005 vs 1995. There were no significant differences in patient demographics or the extent of venous thromboembolic (VTE) disease during this period except for an increase in median age. Filter placement by interventional radiologists remained approximately 50% of the total whereas placement by vascular/trauma surgeons increased to 24% and placement by cardiologists decreased to 29% (P < .001). In 2005, a smaller percentage of filters were placed for absolute indications, while filter placements for relative and prophylactic indications increased over the same time period, especially among cardiologists (P = .02). Potentially retrievable filters are increasingly being used for prophylaxis; however, only 2.4% were retrieved. An increasing number of filters were placed in patients with only infrapopliteal deep venous thrombosis (P = .07). A shift was seen to lower profile and removable filter types. Long-term patient follow-up showed little change in disease progression or in morbidity and mortality of filter insertion. CONCLUSIONS: Technological and practice pattern changes have led to an increase in filters inserted by vascular and trauma surgeons in the operating room and intensive care units. Increased diagnosis of VTE disease and newer low profile delivery systems in patients may also have contributed to the significant increase in filter placement. A shift in indications for placement from absolute toward relative indications and prophylaxis is evident over time and across providers, indicating the need for consensus development of appropriate criteria.