Is There Really a Difference in Outcomes between Men and Women with Hepatocellular Cancer?

Hepatocellular carcinoma (HCC) is a male-dominated disease. Currently, gender differences remain incompletely defined. Data from the state tumor registry were used to investigate differences in demographics, comorbidities, treatment patterns, and cancer-specific survival (HSS) among HCC patients according to gender. Additional analyses were performed to evaluate racial differences among women with HCC. 2627 patients with HCC were included; 498 (19%) were women. Women were mostly white (58%) or African American (39%)-only 3.8% were of another or unknown race. Women were older (65.1 vs. 61.3 years), more obese (33.7% vs. 24.2%), and diagnosed at an earlier stage (31.7% vs. 28.4%) than men. Women had a lower incidence of liver associated comorbidities (36.1% vs. 43%), and more often underwent liver-directed surgery (LDS; 27.5% vs. 22%). When controlling for LDS, no survival differences were observed between genders. African American women had similar HSS rates compared to white women (HR 1.14 (0.91,1.41), p = 0.239) despite having different residential and treatment geographical distributions. African American race and age >65 were predictive for worse HSS in men, but not in women. Overall, women with HCC undergo more treatment options-likely because of the earlier stage of the cancer and/or less severe underlying liver disease. However, when controlling for similar stages and treatments, HCC treatment outcomes were similar between men and women. African American race did not appear to influence outcomes among women with HCC as it did in men.

Antithymocyte Globulin Antibody Titer Congruent With Kidney Transplantation: Analysis of Incidence, Outcomes, Cost, and Alternative Targets.

Rabbit antithymocyte globulin (rATG) use for immunosuppression induction is widespread but is contraindicated by the presence of anti-rATG antibodies. This study reports the incidence of positive anti-rATG antibody titers in patients before and after renal transplant and evaluates associated outcomes and costs. In addition, it will correlate CD40L and interleukin (IL)-21 with anti-rATG antibody titers. METHODS: Clinical and billing records from the Indiana University Transplant Laboratory were reviewed for positive versus negative anti-rATG antibody titers, graft survival, and 7-day readmission costs between 2004 and 2018. Serum from patients with positive and negative rATG antibody titers were quantitated for CD40L and IL-21 by enzyme-linked immunosorbent assay. RESULTS: On average, between 2004 and May 2018, 163 kidney transplants per year were performed. Anti-rATG antibody titers were ordered for 17 patients/year, of which 18.2% were positive at 1:100 titer either pre- or post-transplant. Time to graft loss correlated with a positive rATG titer at time of readmission. Moreover, second kidney transplant increased the anti-rATG positive rate. A weak correlation was observed between anti-rATG titer and recipient age. Seven-day readmission treatment costs were significantly lower in patients with positive anti-rATG titer. IL-21 and CD40L were significantly greater in patients with positive anti-rATG titers after transplant when compared with negative anti rATG patients. CONCLUSIONS: Positive anti-rATG antibody titer is associated with a significant negative impact on outcomes. Monitoring of anti-rATG antibody titer is recommended to optimize treatment options in patients, especially in the setting of second transplants. Elucidation of the mechanisms associated with positive anti-rATG antibody is required. IL-21 and CD40L are potential targets for future study.

Specialized care improves outcomes for patients with cirrhosis who require general surgical operations.

BACKGROUND: General surgical operations on patients with cirrhosis have historically been associated with high morbidity and mortality rates. This study examines a contemporary series of patients with cirrhosis undergoing general surgical procedures. METHODS: A retrospective evaluation of 358 cirrhotic patients undergoing general surgical operations at a single institution between 2004-2015 was performed. Thirty- and 90-day mortality along with complications and subsequent transplantation rates were examined. RESULTS: 358 cirrhotic patients were identified. The majority were Child-Turcotte-Pugh class (CTP) A (55.9%) followed by class B (32.4%) and class C (11.7%). Mean MELD score differed significantly between the groups (8.7 vs. 12.1 vs. 20.1; p<0.001). The most common operations were herniorrhaphy (29.9%), cholecystectomy (19.3%), and liver resection (14.5%). The majority of cases were performed semi-electively (68.4%), however, within the CTP C patients most cases were performed emergently (73.8%). Thirty and 90-day mortality for all patients were 5% and 6%, respectively. Mortality rates increased from CTP A to CTP C (30 day: 3.0% vs. 5.2% vs. 14.3%; p = 0.01; 90 day: 4.5% vs. 6.9% vs. 16.7%; p = 0.016). Additionally, 30-day mortality (12.8% vs. 2.3%; p<0.001), 90 day mortality (16.0% vs. 3.4%; p<0.001) were higher for emergent compared to elective cases. A total of 13 (3.6%) patients underwent transplantation ≤ 90 days from surgery. No elective cases resulted in an urgent transplantation. CONCLUSION: Performing general surgical operations on cirrhotic patients carries a significant morbidity and mortality. This contemporary series from a specialized liver center demonstrates improved outcomes compared to historical series. These data strongly support early referral of cirrhotic patients needing general surgical operation to centers with liver expertise to minimize morbidity and mortality.

Financial Burden of Liver Transplant vs Resection for Hepatocellular Carcinoma.

BACKGROUND: Liver transplant and liver resection are surgical treatments for hepatocellular carcinoma (HCC) performed with curative intent. While liver transplant provides longer survival when compared to resection, the financial burden on patients and payors is significantly greater. With the increase in health care costs and the emergence of high deductible insurance policies that increase out of pocket deductibles for patients, assessment of value-based treatment is warranted. METHODS: We compiled total billable events from diagnosis of HCC through resection (N = 20) or transplant (N = 24) to death or last reported encounter from January 2011 to December 2012. RESULTS: Patients with HCC receiving resection had a model of end stage liver disease of 10.2 ± 1.2, survival 652 days (3-1, 167 days), and billable encounters of $316,873 ($2904/day). HCC patients receiving a liver transplant had a greater liver injury (model of end stage liver disease of 19.2 ± 3.7), longer survival (1579 days), and higher billable encounters, $740,714 ($2889/day). The surgical procedure represented the largest cost category (28% and 26% resection vs transplant, respectively). The cost effectiveness of treatment was directly proportional to length of survival. In resection, patients who survived >30 days (85%) cost per day dropped to $432. Transplant patients who survived >2 years (75%) saw the cost per day drop to $462. CONCLUSION: The relative financial burdens of liver resection vs liver transplant for treating HCC are comparable in patients who survive beyond a certain threshold. Transplant patients survived longer, and survival beyond 2 years makes this approach cost effective. In a health care climate aiming to contain costs and evaluate value-based treatment paradigms, expected survival and financial burden should be included in the treatment decision analysis.

Long-term safety and efficacy of stereotactic body radiation therapy for hepatic oligometastases.

PURPOSE: To evaluate long-term outcome and toxicity of stereotactic body radiation therapy (SBRT) for hepatic oligometastases from solid tumors. METHODS AND MATERIALS: Eligible patients had 1 to 3 liver metastases, maximum sum diameter 6 cm, without extrahepatic progression. We treated 106 lesions in 81 patients; 67% with colorectal primaries. Median dose was 5400 cGy in 3 to 5 fractions. RESULTS: At median follow-up of 33 months (2.5-70 months), overall local control was 94% (95% confidence interval, not estimable); Kaplan-Meier estimated 96% at 1 year and 91% at 2, 3, and 4 years. Partial/complete response was observed in 69% of lesions with less than 3% progressing. Median survival time was 33.6 months (95% confidence interval, 29.1-38.4); Kaplan-Meier survival estimates at 1, 2, 3, and 4 years were 89.9%, 68.6%, 44.0%, and 28.0%, respectively. Grade 3 or greater liver toxicity was 4.9%. CONCLUSION: SBRT is effective for selected patients with hepatic oligometastases with limited toxicities. A phase 3 trial comparing SBRT with "gold-standard" surgical resection is warranted.

Prognosis after recurrence of hepatocellular carcinoma in liver transplantation: predictors for successful treatment and survival.

There are no established prognostic factors or standardized therapies for hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT). The aim of this study was to investigate impact of underlying patient condition on treatment and outcomes of recurrence of HCC after LT. The medical records of 268 LT patients with HCC were evaluated. Potential prognostic factors for survival after recurrence were evaluated, including recurrent tumor characteristics, medical/radiological/surgical therapies for recurrence, and an inflammatory marker (neutrophil/lymphocyte ratio). Laboratory tests at recurrence, including albumin, absolute lymphocyte count (ALC), prognostic nutritional index (PNI: ALC(/µL) × 0.005 + Albumin(g/dL) × 10), were evaluated as surrogate markers for underlying patient conditions. A total of 51 (19%) patients developed HCC recurrence. The use of sirolimus and sorafenib significantly improved outcome (p = 0.007 and 0.04), and better nutritional status (PNI ≥ 40) enhanced their efficacy. On multivariate analysis, low ALC (<500/µL) and albumin (<2.8 g/L) remained independent prognostic factors (p = 0.03 and 0.02; hazard ratio = 3.61 [Ref. >1000/µL] and 4.97 [Ref. >3.5 g/dL], respectively). Low PNI (<40) showed significantly lower survival rate after adjusting the risk (p = 0.006, hazard ratio = 3.29). Underlying patient conditions and nutritional status, represented by ALC and albumin, are important to successful cancer treatment and strong prognostic markers for survival after HCC recurrence.

Thalidomide ameliorates portal hypertension via nitric oxide synthase independent reduced systolic blood pressure.

AIM: Portal hypertension is a common complication of liver cirrhosis and significantly increases mortality and morbidity. Previous reports have suggested that the compound thalidomide attenuates portal hypertension (PHT). However, the mechanism for this action is not fully elucidated. One hypothesis is that thalidomide destabilizes tumor necrosis factor α (TNFα) mRNA and therefore diminishes TNFα induction of nitric oxide synthase (NOS) and the production of nitric oxide (NO). To examine this hypothesis, we utilized the murine partial portal vein ligation (PVL) PHT model in combination with endothelial or inducible NOS isoform gene knockout mice. METHODS: Wild type, inducible nitric oxide synthase (iNOS)(-/-) and endothelial nitric oxide synthase (eNOS)(-/-) mice received either PVL or sham surgery and were given either thalidomide or vehicle. Serum nitrate (total nitrate, NOx) was measured daily for 7 d as a surrogate of NO synthesis. Serum TNFα level was quantified by enzyme-linked immunosorbent assay. TNFα mRNA was quantified in liver and aorta tissue by reverse transcription-polymerase chain reaction. PHT was determined by recording splenic pulp pressure (SPP) and abdominal aortic flow after 0-7 d. Response to thalidomide was determined by measurement of SPP and mean arterial pressure (MAP). RESULTS: SPP, abdominal aortic flow (Qao) and plasma NOx were increased in wild type and iNOS(-/-) PVL mice when compared to sham operated control mice. In contrast, SPP, Qao and plasma NOx were not increased in eNOS(-/-) PVL mice when compared to sham controls. Serum TNFα level in both sham and PVL mice was below the detection limit of the commercial ELISA used. Therefore, the effect of thalidomide on serum TNFα levels was undetermined in wild type, eNOS(-/-) or iNOS(-/-) mice. Thalidomide acutely increased plasma NOx in wild type and eNOS(-/-) mice but not iNOS(-/-) mice. Moreover, thalidomide temporarily (0-90 min) decreased mean arterial pressure, SPP and Qao in wild type, eNOS(-/-) and iNOS(-/-) PVL mice, after which time levels returned to the respective baseline. CONCLUSION: Thalidomide does not reduce portal pressure in the murine PVL model by modulation of NO biosynthesis. Rather, thalidomide reduces PHT by decreasing MAP by an undetermined mechanism.

Long-term outcomes comparing surgery to embolization-ablation for treatment of solitary HCC<7 cm.

BACKGROUND: Resection has been the standard of care for patients with solitary hepatocellular carcinoma (HCC). Transarterial embolization and percutaneous ablation are alternative therapies often reserved for suboptimal surgical candidates. Here we compare long-term outcomes of patients with solitary HCC treated with resection versus combined embo-ablation. METHODS: We previously reported a retrospective comparison of resection and embo-ablation in 73 patients with solitary HCC<7 cm after a median follow-up of 23 months. This study represents long-term updated follow-up over a median of 134 months. RESULTS: There was no difference in survival among Okuda I patients who underwent resection versus embo-ablation (66 vs 58 months, p=.39). There was no difference between the groups in the rate of distant intrahepatic (p=.35) or metastatic progression (p=.48). Surgical patients experienced more complications (p=.004), longer hospitalizations (p<.001), and were more likely to require hospital readmission within 30 days of discharge (p=.03). CONCLUSION: Over a median follow up of more than 10 years, we found no significant difference in overall survival of Okuda 1 patients with solitary HCC<7 cm who underwent surgical resection versus embo-ablation. Our data suggest that there may be a greater role for primary embo-ablation in the treatment of potentially resectable solitary HCC.

Lysophospholipid variants in hepatocellular carcinoma.

BACKGROUND: The U.S. incidence of hepatocellular carcinoma (HCC) is increasing and is linked to hepatitis C (HepC) infection, alcohol toxicity, and obesity. This manuscript examines lysophosphatidic acid (LPA) variant biosynthesis as a biomarker and potential therapeutic target for HCC. METHODS: Serum LPA variant levels were determined in patients with HepC ± HCC, alcoholic cirrhosis ± HCC, or nonalcoholic steatohepatitis ± HCC by mass spectroscopy. To clarify the relationship between cancer and LPA variant profiles, LPA variants were evaluated in HepC + HCC patients before and after liver transplantation. Moreover, LPA variant modification of gene expression was also determined in vitro by real-time polymerase chain reaction. RESULTS: In patients diagnosed with HCC, 18:2 LPA biosynthesis was decreased, whereas 20:4 LPA biosynthesis and 20:4 LPA:18:2 LPA ratio were increased. Three days after liver transplantation, serum LPA levels and 18:2 LPA:20:4 LPA ratio were significantly reduced in patients with cancer. The 20:4 LPA selectively stimulated LPA receptor and tumor necrosis factor α expression in Hep3B cells, whereas 18:2 LPA did not. CONCLUSIONS: Serum LPA variant profiles are unique in patients with HCC allowing for the stratification of patients. Moreover, LPA variants impart individual mitogenic properties associated with tumorigenesis that may provide a potential therapeutic target. We envision that LPA profiling may accelerate diagnosis, help stratify patients at high risk of developing cancer, and provide potential targets for chemoprevention.

Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is increasing in incidence due to hepatitis C. Stereotactic body radiotherapy (SBRT) is a noninvasive, effective therapy in the management of liver malignancies. The authors evaluated radiological response in 26 patients with HCC treated with SBRT at Indiana University. METHODS: Between March 2005 and June 2008, 26 patients with HCC who were not surgical candidates were enrolled in a phase 1 to 2 trial. Eligibility criteria included solitary tumors ≤ 6 cm or up to 3 lesions with sum diameters ≤ 6 cm, and well-compensated cirrhosis. All patients had imaging before, at 1 to 3 months, and every 3 to 6 months after SBRT. RESULTS: Patients received 3 to 5 fractions of SBRT. Median SBRT dose was 42 Gray (Gy) (range: 24-48 Gy). Median follow-up was 13 months. Per Response Evaluation Criteria in Solid Tumors (RECIST), 4 patients had a complete response (CR), 15 had a partial response (PR), and 7 achieved stable disease (SD) at 12 months. One patient with SD experienced progression marginal to the treated area. The overall best response rate (CR + PR) was 73%. In comparison, by European Association for the Study of the Liver (EASL) criteria, 18 of 26 patients had ≥ 50% nonenhancement at 12 months. Thirteen of 18 demonstrated 100% nonenhancement, being > 50% in 5 patients. Kaplan-Meier 1- and 2-year survival estimates were 77% and 60%, respectively. CONCLUSIONS: SBRT is effective therapy for patients with HCC with an overall best response rate (CR + PR) of 73%. Nonenhancement on imaging, a surrogate for ablation, may be a more useful indicator than size reduction in evaluating HCC response to SBRT in the first 6 to 12 months, supporting EASL criteria.

Hepatocellular carcinoma associated lipid metabolism reprogramming.

BACKGROUND: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with a high worldwide prevalence and poor prognosis. Previous data, by Affymetrix microarray analysis, has shown a decrease in genes involved in phospholipid catabolism, fatty acid catabolism, choline metabolism, and bile acid metabolism in HCC compared with control tissue. The aim of this study was to better understand metabolic processes in relation to the development of HCC. MATERIALS AND METHODS: Tumor, plasma, and bile samples were collected at the time of hepatic resection for HCC. All bile specimens were collected from the gallbladder at the beginning of the case. Normal bile and plasma were collected from patients undergoing cholecystectomy for non-neoplastic disease. Liver biopsy samples were taken from both tumor and adjacent normal tissue. Phospholipid levels were evaluated by enzyme-linked immunosorbent assay (ELISA) and high performance thin layer chromatography (HPTLC). RESULTS: Targeted phospholipid analysis by HPTLC and ELISA showed a modified choline metabolic profile within the liver, bile, and serum, culminating in an increased synthesis of lysophosphatidic acid (LPA). Choline was significantly increased in tumor tissue; lysophosphatidylcholine (LPC) was increased within bile while LPA was increased in all three biological samples of HCC patients compared with controls. Phosphatidylcholine was not significantly changed. CONCLUSIONS: HCC is congruent with a reprogramming of choline catabolism and phospholipid metabolism. Increased LPA may provide a potent mitogenic and proliferative microenvironment via autocrine/paracrine activation of high-affinity G-protein-coupled receptors. Additional research is required to better understand the role of these pathways in HCC development.

Evidence of aberrant lipid metabolism in hepatitis C and hepatocellular carcinoma.

OBJECTIVES: Lipids are linked to many pathological processes including hepatic steatosis and liver malignancy. This study aimed to explore lipid metabolism in hepatitis C virus (HCV) and HCV-related hepatocellular carcinoma (HCC). METHODS: Serum lipids were measured in normal, HCV and HCV-HCC patients. Whole-genome microarray was performed to identify potential signature genes involved in lipid metabolism characterizing normal vs. HCV vs. HCV-HCC conditions. RESULTS: Serum cholesterol was significantly reduced in HCV and HCV-HCC patients compared with normal controls, whereas there was no difference in glucose and triglycerides. Microarray analysis identified 224 probe sets with known functional roles in lipid metabolism (anova, 1.5-fold, P ≤ 0.001). Gene-mediated fatty acid (FA) de novo synthesis and uptake were upregulated in HCV and this upregulation was further enhanced in HCC. Genes involved in FA oxidation were downregulated in both the HCV and HCC groups. The abnormality of cholesterol metabolism in HCV was associated with downregulation of genes involved in cholesterol biosynthesis, absorption and transportation and bile acid synthesis; this abnormality was further intensified in HCC. CONCLUSIONS: Our data support the notion that HCV-related lipid metabolic abnormalities may contribute to hepatic steatosis and the development of cancer. Identification of these aberrations would stratify patients and improve treatment algorithms.

Autotaxin expression and its connection with the TNF-alpha-NF-kappaB axis in human hepatocellular carcinoma.

BACKGROUND: Autotaxin (ATX) is an extracellular lysophospholipase D that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been shown to be involved in many cancers. However, the functional role of ATX and the regulation of ATX expression in human hepatocellular carcinoma (HCC) remain elusive. RESULTS: In this study, ATX expression was evaluated in tissues from 38 human HCC and 10 normal control subjects. ATX was detected mainly in tumor cells within tissue sections and its over-expression in HCC was specifically correlated with inflammation and liver cirrhosis. In addition, ATX expression was examined in normal human hepatocytes and liver cancer cell lines. Hepatoma Hep3B and Huh7 cells displayed stronger ATX expression than hepatoblastoma HepG2 cells and normal hepatocytes did. Proinflammtory cytokine tumor necrosis factor alpha (TNF-alpha) promoted ATX expression and secretion selectively in Hep3B and Huh7 cells, which led to a corresponding increase in lysophospholipase-D activity. Moreover, we explored the mechanism governing the expression of ATX in hepatoma cells and established a critical role of nuclear factor-kappa B (NF-kappaB) in basal and TNF-alpha induced ATX expression. Further study showed that secreted enzymatically active ATX stimulated Hep3B cell invasion. CONCLUSIONS: This report highlights for the first time the clinical and biological evidence for the involvement of ATX in human HCC. Our observation that links the TNF-alpha/NF-kappaB axis and the ATX-LPA signaling pathway suggests that ATX is likely playing an important role in inflammation related liver tumorigenesis.

Tumor necrosis factor alpha signaling in the development of experimental murine pre-hepatic portal hypertension.

The cytokine tumor necrosis factor alpha (TNFa) has previously been identified in the development of portal hypertension (PHT) by facilitating portal venous and systemic hyperemia. TNFa is reported to contribute to hyperemia via endothelial nitric oxide synthase (eNOS) induction and nitric oxide (NO) production. This study examines this hypothesis by utilizing TNFa receptor knockout mice and a murine model of pre-hepatic PHT. Plasma TNFa and NOx and tissue TNFa mRNA levels were determined in wild-type mice 0-7d post induction of pre-hepatic PHT by partial portal vein ligation (PVL). TNFa receptor knockout mice also received PVL or sham surgery and splenic pulp pressure, abdominal aortic flow and portal-systemic shunting were recorded 7d following. Portal pressure and systemic hyperemia developed rapidly following PVL. Plasma NOx was increased temporarily 2-3 days following PVL and returned to baseline by day 7. Circulating TNFa was below detectable limits of the ELISA used, as such no increase was observed. Hepatic and vascular TNFa mRNA levels were transiently changed after PVL otherwise there was no significant change. TNFa receptor targeted gene deletion did not ameliorate plasma NOx following PVL and had no effect on the development of PHT. TNFa receptor signaling plays no detectable role in the development of systemic hyperemia in the murine model of pre-hepatic PHT. Consequently, increased TNFa observed in intra-hepatic inflammatory models (CCl(4)) and in patients is probably related to inflammation associated with intra-hepatic pathology. Alternatively, TNFa may be signaling via a TNFa receptor independent mechanism.

A comparison of outcomes from treating hepatocellular carcinoma by hepatic artery embolization in patients younger or older than 70 years.

BACKGROUND: : The objective of this study was to compare the morbidity, mortality, and survival of patients aged <70 years and aged > or =70 years who underwent hepatic arterial embolization (HAE) for the treatment of hepatocellular carcinoma (HCC). METHODS: : Between 1997 and 2007, 386 patients underwent HAE for HCC at a single center. Two hundred patients were aged <70 years (153 men; median age, 60 years), and 186 patients were aged > or =70 years (128 men; median age, 75 years). Patients underwent a total 965 embolization procedures (median, 2 procedures per patient). Patient demographics, morbidity, mortality, length of hospital stay, and survival were analyzed. Complications were categorized using Common Terminology Criteria for Adverse Events, version 3.0 guidelines. Survival was calculated by using the Kaplan-Meier method. RESULTS: : There were no significant differences between younger and older groups in the incidence of infectious, hepatobiliary, renal, vascular, or miscellaneous complications (P > or = .05); complication severity (P = .82); procedural mortality (P = .63); length of hospitalization (P = .55); intensive care unit admission (P = .64); or overall survival (P = .30). There were more cardiopulmonary complications in the older group (P = .04), but the association of age and likelihood of a cardiopulmonary complication lost significance after adjusting for the presence of more cardiovascular comorbidities in the older group (P = .08). CONCLUSIONS: : Survival and mortality outcomes of HAE for the treatment of HCC were similar whether patients were aged <70 years or > or =70 years. Although patients aged > or =70 years with cardiovascular comorbidities more often had a cardiopulmonary complication, other morbidity measures, including complication severity, need for intensive care unit admission, and length of hospitalization, were similar between groups. Cancer 2009. (c) 2009 American Cancer Society.

Role of endothelial nitric oxide synthase in the development of portal hypertension in the carbon tetrachloride-induced liver fibrosis model.

Portal hypertension (PHT) is a complication of liver cirrhosis and directly increases mortality and morbidity by increasing the propensity of venous hemorrhage. There are two main underlying causations for PHT, increased hepatic resistance and systemic hyperdynamic circulation. Both are related to localized aberrations in endothelial nitric oxide synthase (eNOS) function and NO biosynthesis. This study investigates the importance of eNOS and systemic hyperdynamic-associated hyperemia to better understand the pathophysiology of PHT. Wild-type and eNOS(-/-) mice were given the hepatotoxin CCl(4) for 4-12 wk. Hepatic fibrosis was determined histologically following collagen staining. Portal venous pressure, hepatic resistance, and hyperemia were determined by measuring splenic pulp pressure (SPP), hepatic portal-venous perfusion pressure (HPVPP), abdominal aortic flow (Qao), and portal venous flow (Qpv). Hepatic fibrosis developed equally in wild-type and eNOS(-/-) CCl(4)-exposed mice. SPP, Qao, and Qpv increased rapidly in wild-type CCl(4)-exposed mice, but HPVPP did not. In eNOS(-/-) CCl(4) mice, Qao was not increased, SPP was partially increased, and HPVPP and Qpv were increased nonsignificantly. We concluded that the systemic hyperemia component of hyperdynamic circulation is eNOS dependent and precedes increased changes in hepatic resistance. Alternative mechanisms, possibly involving cyclooxygenase, may contribute. eNOS maintains normal hepatic resistance following CCl(4)-induced fibrosis. Consequently, increased portal pressure following chronic CCl(4) exposure is linked to hyperdynamic circulation in wild-type mice and increased hepatic resistance in eNOS(-/-) mice.

NF-kappaB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy.

Nuclear factor-kappaB (NF-kappaB) has been shown to play an important role in the development and progression of cancer. In this study, we systematically examined NF-kappaBp65 signaling pathway in both human hepatocellular carcinoma (HCC) tissue and HCC cell lines. NF-kappaBp65 signaling pathway is aberrantly expressed and activated in both human HCC tissue and HCC Hep3B cells. Inhibition of NF-kappaB activity significantly reduced proliferation and invasion of Hep3B cells as well as down-regulated the expression of invasion-related molecules including matrix metalloproteinase (MMP)-2, MMP-9, membrane type-1 MMP (MT1-MMP), urokinase plasminogen activator (uPA) and vascular endothelial growth factor (VEGF). Hep3B cells exhibited a dose-dependent increase in apoptosis after receiving sorafenib treatment. Inhibition of NF-kappaB activity strongly sensitized Hep3B cells to sorafenib-induced cell death. Mechanistically, combined treatment of sorafenib and NF-kappaB inhibition enhanced inhibition of MAPK signaling and down-regulation of anti-apoptotic protein Mcl-1 expression. These observations indicate that inhibition of NF-kappaB may be a potential antineoplastic therapy for HCC, especially the combination of NF-kappaB inhibition and sorafenib provides a novel therapeutic strategy for patients with advanced-stage HCC.

Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma.

PURPOSE: To determine the survival of patients with hepatocellular carcinoma (HCC) treated with a standardized method of transcatheter arterial embolization (TAE) with small embolic particles intended to impart terminal vessel blockade, and to evaluate prognostic factors that impact overall survival. MATERIALS AND METHODS: A total of 322 patients with HCC who underwent 766 embolizations from January 1997 to December 2004 were retrospectively reviewed. Selective embolization of vessels feeding individual tumors was performed with small (50 microm) polyvinyl alcohol or spherical embolic particles (40-120 microm) intended to cause terminal vessel blockade. Repeat embolization was performed in cases of evidence of persistent viable tumor or development of new lesions. Patient, tumor, and treatment characteristics were prospectively recorded and tested for prognostic significance by univariate and multivariate analysis. RESULTS: The median survival time was 21 months, with 1-, 2-, and 3-year overall survival rates of 66%, 46%, and 33%, respectively. In patients without extrahepatic disease or portal vein involvement by tumor, the overall 1-, 2-, and 3-year survival rates increased to 84%, 66%, and 51%, respectively. Okuda stage, extrahepatic disease, diffuse disease (> or =5 tumors), and tumor size were independent predictors of survival on multivariate analysis. There were 90 complications (11.9%) in 75 patients, including eight deaths (2.5%), within 30 days of embolization. CONCLUSIONS: Hepatic arterial embolization with small particles to cause terminal vessel blockade is an effective treatment method for patients with unresectable HCC. These data support our hypothesis that particles alone may be the critical component of catheter-directed embolotherapy.