A combination of hepatic encephalopathy and body mass index was associated with the point of no return for improving liver functional reserve after sofosbuvir/velpatasvir treatment in patients with hepatitis C virus-related decompensated cirrhosis.

AIMS: The real-world efficacy of sofosbuvir/velpatasvir treatment for patients with hepatitis C virus-related decompensated cirrhosis is unclear. We aimed to identify factors that improve liver functional reserve after treatment. METHODS: This was a multicenter retrospective study of 12-week sofosbuvir/velpatasvir treatment. A total of 48 patients with Child-Pugh (CP) class B or C were enrolled at 11 institutions. We evaluated changes in liver functional reserve at 24 weeks post-treatment. RESULTS: At baseline, 40 and eight patients were CP class B and C, respectively. The overall rate of sustained virologic response 12 weeks post-treatment was 95.8% (46/48). Serum albumin, alanine aminotransferase and α-fetoprotein levels, and the FIB-4 index were significantly improved post-treatment (P < 0.05). Among patients who achieved sustained virologic response 12 weeks post-treatment, those with CP class A increased from 0 to 24 patients (56%) at 24 weeks post-treatment. In multivariate analysis, body mass index (BMI) ≥25 was an independent factor that inhibited CP class improvement (P < 0.05). In decision tree analysis, after treatment, the initial divergent variable for CP class improvement was hepatic encephalopathy, followed by serum sodium level and BMI. CONCLUSION: Sofosbuvir/velpatasvir treatment improved the liver functional reserve in patients with hepatitis C virus-related decompensated cirrhosis at 24 weeks post-treatment. However, BMI ≥25 inhibited improvement in CP class. Additionally, decision tree analysis revealed that a combination of hepatic encephalopathy, serum sodium levels, and BMI were diversity profiles associated with no improvement in liver functional reserve after the treatment.

Diffusion-weighted magnetic resonance imaging predicts malignant potential in small hepatocellular carcinoma.

BACKGROUND: Poor differentiation and microvascular invasion are indicators of poor outcome after hepatectomy for patients with small hepatocellular carcinoma (HCC). AIMS: We investigated whether gadoxetic acid-enhanced and diffusion-weighted magnetic resonance imaging (MRI) could predict these factors before hepatectomy. METHODS: Between July 2008 and April 2012, 75 patients who underwent hepatectomy for small HCCs (diameter: ≤3cm, tumor number: ≤3) were consecutively enrolled. In gadoxetic acid-enhanced MRI, the signal intensity in the tumor was corrected to that in the paraspinous muscles, and the relative enhancement was calculated. In diffusion-weighted imaging, we measured the apparent diffusion coefficient (ADC). We then investigated the correlations between relative enhancement or ADC and histological grade, microvascular invasion and recurrence-free survival. RESULTS: Poorly differentiated HCCs showed significantly lower ADC than well-differentiated and moderately differentiated HCCs. There was no significant difference in the hepatobiliary phase. Only ADC was an independent predictor of microvascular invasion, and the best cut-off point of its prediction was 1.175×10(-3)mm(2)/s. Additionally, the recurrence-free survival was significantly shorter in low-ADC group than in high-ADC group. CONCLUSION: ADC is useful for predicting poorly differentiated HCCs and microvascular invasion, and low ADC is associated with increased recurrence risk for small HCCs after hepatectomy.

The systemic inflammatory response as a prognostic factor for advanced hepatocellular carcinoma with extrahepatic metastasis.

Several indices have been proposed to evaluate the systemic inflammatory response (SIR), which has been reported to be a useful prognostic factor in various types of cancer. We investigated the usefulness of the Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic factors in patients with advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis (stage IVB). Between April, 1997 and March, 2013, a total of 434 HCC patients who developed extrahepatic metastasis were enrolled in the present study. The GPS was defined on the basis of pretreatment C-reactive protein (CRP) and albumin (Alb) levels, and the subjects were grouped according to GPS 0-2. The NLR was calculated as the neutrophil count/lymphocyte count, and the PLR was calculated as the platelet count/lymphocyte count. A comparative examination was performed using a survival analysis with approximate median values to determine the cut-off value for both ratios. The median survival time (MST) of the 434 patients overall was 7.3 months, with cumulative survival rates of 31.8, 14.5 and 7.7% at 1, 2 and 3 years, respectively. The patient backround was as follows: The male:female ratio was 363:71, with a median age of 67.0 years (range, 15.0-92.0 years). Hepatitis B virus patients:hepatitis C virus patients:non-B, non-C hepatitis patients = 75:303:56. Child-Pugh class A:B:C = 218:153:63. As regards T stage, ≤T2:T3:T4 = 60:190:181. The median white blood cell count was 4,650/l (range, 1,400-20,500/l); the platelet count was 11.1×104/µl (range, 3.1×104-45.5×104/µl); the aspartate aminotransferase level was 40.0 U/l (range, 7.0-338.0 U/l) and the alanine aminotransferase level 64.5 U/l (range, 16.0-407.0 U/l); the α-fetoprotein level was 622.1 ng/ml (range, 1.5-3,311,794.0 ng/ml); and the des-gamma-carboxyprothrombin level was 1,285.0 mAU/ml (range, 8.0->75,000 mAU/ml). The principal sites of metastasis included the lungs (53.9%), bone (38.9%), lymph nodes (21.4%) and adrenal glands (10.1%). The survival analysis revealed that hepatic functional reserve [Child-Pugh class B+C; hazard ratio (HR)=2.055; 95% confidence interval (CI): 1.592-2.651, P<0.001], T stage (T3; HR=2.359; 95% CI: 1.648-3.376, P<0.001), AFP (≥200 ng/ml; HR=1.416; 95% CI: 1.125-1.783, P=0.003), NLR (≥3; HR=1.569; 95% CI: 1.253-1.963, P<0.001) and GPS (1+2; HR=1.410; 95% CI: 1.060-1.874, P=0.018) were independent risk factors. A total of 136 patients were included in the GPS 0 group, 169 patients in the GPS 1 group and 129 patients in the GPS 2 group. The low together with the high NLR groups comprised 217 patients. The MST was 480 days in the GPS 0 group, 154 days in the GPS 1 and 2 groups, 115 days in the high NLR group and 321 days in the low NLR group; a significant difference in survival was observed for the GPS and NLR groups. Therefore, we consider GPS and NLR to be useful prognostic factors in patients with stage IVB HCC.

Hepatic arterial infusion chemoembolization therapy for advanced hepatocellular carcinoma: multicenter phase II study.

PURPOSE: Portal vein tumor thrombosis is a critical complication in patients with hepatocellular carcinoma (HCC). This prospective multicenter trial assessed the efficacy of hepatic arterial infusion chemoembolization therapy with cisplatin suspended in lipiodol combined with 5-fluorouracil for HCC patients with portal vein tumor thrombosis. METHODS: We enrolled 52 HCC patients with portal vein tumor thrombosis. They received hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol and 5-fluorouracil. The primary efficacy endpoint was progression-free survival (PFS), while the secondary endpoints were overall survival (OS), tumor response rate, safety, and tolerability. Independent factors for survival were also evaluated. RESULTS: The median PFS and OS were 8.6 and 27.0 months, respectively. Ten patients showed complete response, while 29 had partial response (response rate, 75.0 %). The median survival time of 10 patients with complete response and 29 with partial response was 32 months, while that of 15 patients with partial response who later showed disappearance of HCC following additional therapies was 50 months. Multivariate analysis identified response to treatment and disappearance of viable HCC as independent predictors of survival. The treatment was well tolerated, and the only encountered Grade 3 toxicities were thrombocytopenia and hyperbilirubinemia. CONCLUSIONS: Hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol combined with 5-fluorouracil is effective treatment for unresectable HCC with portal vein tumor thrombosis.

Effect of pioglitazone on outcome following curative treatment for hepatocellular carcinoma in patients with hepatitis C virus infection: A prospective study.

Pioglitazone is an insulin sensitizer used for the treatment of diabetes mellitus (DM). DM with insulin resistance is a risk factor for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection. We aimed to investigate the effects of pioglitazone on HCC recurrence following treatment in HCV-infected patients. Between 2009 and 2011, 85 HCV-infected HCC patients who underwent curative treatment were enrolled in this prospective study. Among 45 patients with type 2 DM, 27 were administered pioglitazone (pioglitazone group) following treatment. The remaining 58 patients were assigned to the control group. The primary outcome was recurrence-free survival. Changes in insulin resistance and serum adiponectin levels resulting from pioglitazone treatment were also assessed. In the whole analysis (n=85), no significant difference in recurrence-free survival was observed between the pioglitazone and control groups. However, in a spline model analysis of DM patients, a decreased risk of HCC recurrence was associated with increased body weight in patients with a body mass index (BMI) ≥23; this association became significant at BMI ≥24 (hazard ratio=0.17; 95% confidence interval: 0.03-0.95). In addition, significantly decreased homeostasis model assessment for insulin resistance values (P=0.002) and significantly increased serum high-molecular-weight adiponectin levels (P<0.001) were observed following pioglitazone treatment. Although pioglitazone did not suppress HCC recurrence in the whole analysis, it inhibited HCC recurrence in overweight HCV-infected diabetic patients. Moreover, pioglitazone improved insulin resistance and adipocytokine levels. Thus, pioglitazone may suppress HCC recurrence, which is associated with glucose and fat metabolism disorders.

Usefulness of short-term eltrombopag treatment as a supportive treatment in hepatocellular carcinoma patients with cirrhosis and severe thrombocytopenia: A report of two cases.

Eltrombopag is an oral thrombopoietin (TPO) receptor agonist that increases platelet counts in patients with idiopathic thrombocytopenic purpura and in patients with liver cirrhosis. When cirrhotic patients with thrombocytopenia undergo elective invasive procedures, eltrombopag treatment reduces the requirement for platelet transfusions. However, TPO is known to have proliferative effects on hepatic progenitor cells and hepatic sinusoidal endothelial cells, which indicates that eltrombopag may accelerate tumor progression. Thus, the effect of eltrombopag on hepatocellular carcinoma (HCC) progression is an important issue. The current study describes two cases of HCC with cirrhosis-related thrombocytopenia. A two-week administration of eltrombopag increased platelet counts from 4.8 to 11.3×104 /µl in case 1 and 4.5 to 23.2×104 /µl in case 2. However, no changes were identified in the serum levels of tumor markers or HCC size following eltrombopag administration in the two cases. These HCCs were curatively treated by radiofrequency ablation without platelet transfusions or serious bleeding. Thus, short-term eltrombopag administration may not accelerate HCC proliferation and may be beneficial for invasive HCC treatment in cirrhotic patients with thrombocytopenia.

Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The aim of this study was to evaluate whether there are differences in the clinical characteristics and survival between patients with advanced HCC with extrahepatic metastasis who received and those who did not receive previous treatment. Between April, 1998 and April, 2012, a total of 419 HCC patients with extrahepatic metastasis (81 previously untreated and 338 previously treated) were enrolled in this study. The differences in the clinical characteristics, including metastatic sites, were compared between the two groups. In addition, the prognostic predictors among all the patients and among the 81 previously untreated patients were analyzed. The distribution of the major metastatic sites was similar in the two groups; the most frequent site of extrahepatic metastasis was the lungs, followed by the bones, lymph nodes and adrenal glands. The median survival time (MST) among the 419 patients was 6.8 months. The 1-, 2-, 3- and 5-year survival rates were 31.6, 15.3, 9.5 and 2.3%, respectively. No significant differences in survival were observed between patients who received and those who did not receive previous treatment. The multivariate analysis revealed that the Child-Pugh classification, white blood cell count, neutrophil-lymphocyte ratio (NLR) and primary tumor stage were independent predictors of survival for all the patients and for the 81 previously untreated patients. Differences in the clinical characteristics of patients with advanced HCC with extrahepatic metastasis were identified between patients who received and those who did not receive previous treatment. Furthermore, intrahepatic tumor status, Child-Pugh classification, white blood cell count and NLR were demonstrated to be independent predictors of survival in HCC patients with extrahepatic metastasis.

CD34(+) cell therapy is safe and effective in slowing the decline of hepatic reserve function in patients with decompensated liver cirrhosis.

BACKGROUND AND AIM: Preclinical studies in rodent models of chronic liver fibrosis have shown that transplantation of peripheral blood (PB) CD34(+) cells leads to hepatic regeneration and a reduction of liver fibrosis by suppressing hepatic stellate cell activity and increasing matrix metalloproteinase activity. The aim of this study was to examine the safety and clinical efficacy of intrahepatic transplantation of autologous granulocyte colony-stimulating factor (G-CSF)-mobilized PB-CD34(+) cells in patients with decompensated liver cirrhosis. METHODS: PB-CD34(+) cells were isolated from G-CSF-mobilized apheresis products. Ten patients were treated with G-CSF-mobilized PB-CD34(+) cells (treatment group) and seven patients were treated with standard medical therapy. For mobilization, patients in the treatment group received subcutaneous injections of 10 µg G-CSF/kg/day for 5 days. The cells were then injected at three different doses (5 × 10(5) , 1 × 10(6) and 2 × 10(6) cells/kg) through the hepatic artery. Thereafter, all patients were followed up for 24 months. RESULTS: G-CSF treatment and leukapheresis were well tolerated, and no serious adverse events were observed. Patients in the treatment group had a significant but transient splenomegaly. After 24 weeks, serum albumin was significantly increased in patients who had received middle or high doses of CD34(+) cells compared with baseline. Doppler ultrasound showed a significant increase in hepatic blood flow velocity and blood flow volume after CD34(+) cell therapy. The hepatic vein pressure gradient decreased in two patients who received high-dose CD34(+) cells at week 16. CONCLUSIONS: CD34(+) cell therapy is feasible, safe and effective in slowing the decline of hepatic reserve function.

Usefulness of magnifying endoscopy with narrow-band imaging for diagnosis of depressed gastric lesions.

The usefulness of magnifying endoscopy with narrow-band imaging (ME-NBI) for the diagnosis of early gastric cancer is well known, however, there are no evaluation criteria. The aim of this study was to devise and evaluate a novel diagnostic algorithm for ME-NBI in depressed early gastric cancer. Between August, 2007 and May, 2011, 90 patients with a total of 110 depressed gastric lesions were enrolled in the study. A diagnostic algorithm was devised based on ME-NBI microvascular findings: microvascular irregularity and abnormal microvascular patterns (fine network, corkscrew and unclassified patterns). The diagnostic efficiency of the algorithm for gastric cancer and histological grade was assessed by measuring its mean sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Furthermore, inter- and intra-observer variation were measured. In the differential diagnosis of gastric cancer from non-cancerous lesions, the mean sensitivity, specificity, PPV, NPV, and accuracy of the diagnostic algorithm were 86.7, 48.0, 94.4, 26.7, and 83.2%, respectively. Furthermore, in the differential diagnosis of undifferentiated adenocarcinoma from differentiated adenocarcinoma, the mean sensitivity, specificity, PPV, NPV, and accuracy of the diagnostic algorithm were 61.6, 86.3, 69.0, 84.8, and 79.1%, respectively. For the ME-NBI final diagnosis using this algorithm, the mean κ values for inter- and intra-observer agreement were 0.50 and 0.77, respectively. In conclusion, the diagnostic algorithm based on ME-NBI microvascular findings was convenient and had high diagnostic accuracy, reliability and reproducibility in the differential diagnosis of depressed gastric lesions.

The significance of classifying microvascular invasion in patients with hepatocellular carcinoma.

BACKGROUND: Microvascular invasion (MVI) has been recognized as a risk factor for outcome following curative resection in hepatocellular carcinoma (HCC). Because MVI can range from few to many invaded vessels, we evaluated the significance of MVI classification in this study. METHODS: Between January 1995 and December 2010, 207 consecutive patients who underwent curative resection for HCC within Milan criteria were included in this retrospective study. Patients were classified into mild and severe MVI groups based on the number of vessels invaded. This study evaluated whether MVI classification can help to predict recurrence and survival after curative resection. RESULTS: Of the total 207 patients, 103 (50 %) patients had no detectable MVI, whereas 59 (28 %) had mild MVI, and 45 (22 %) had severe MVI. Recurrence-free survival rates at 2 years for patients without MVI, with mild MVI, and severe MVI were 75.9, 47.2, and 32.7 %, respectively. Patients with severe MVI experienced a high frequency of fatal recurrence, such as multiple tumors, macroscopic vascular invasion, and extrahepatic metastasis after curative resection. Multivariate analysis revealed age, number of tumors, mild MVI, and severe MVI as independent predictors of recurrence-free survival. Disease-specific survival rates at 5 years for patients without MVI, with mild MVI, and severe MVI were 91.5, 70.4, and 51.4, respectively. Multivariate analysis also revealed cirrhosis, tumor size, mild MVI, and severe MVI as independent predictors of disease-specific survival. CONCLUSIONS: We demonstrated that MVI classification can stratify HCC patients by different patterns of recurrence and risk of survival after curative resection.

Long-term outcome of elderly patients (75 years or older) with hepatocellular carcinoma.

AIM: The aim of this study was to evaluate the long-term outcome of elderly patients with hepatocellular carcinoma (HCC) aged 75 years or older. METHODS: The study included 422 patients with HCC, who were divided into two age groups: 75 years or older (n = 140) and younger than 75 (n = 282). Outcomes were compared between the two groups. RESULTS: The number of elderly patients treated with supportive care alone (33 patients; 24%) was significantly higher than younger patients (30 patients; 11%, P < 0.01). The 1-, 3-, 5- and 7-year overall survival rates of the elderly patients (81%, 55%, 39% and 23%, respectively) were worse than those of younger patients (85%, 64%, 49% and 36%, respectively, P = 0.042). However, the overall survival rate of the elderly group after excluding 63 patients treated with supportive care alone, was similar to that of the younger group (P = 0.615). Multivariate analysis identified age, total bilirubin levels, albumin levels, serum des-γ-carboxy prothrombin levels, tumor size, number of HCC nodules, vascular invasion, extrahepatic metastasis and treatment modality as independent and significant factors of overall survival. CONCLUSION: Advanced age is a negative prognostic factor in patients with HCC due to the tendency for frequent use of conservative treatment rather than locoregional or surgical treatment.

Serum albumin level is a notable profiling factor for non-B, non-C hepatitis virus-related hepatocellular carcinoma: A data-mining analysis.

AIM: Various factors are underlying for the onset of non-B, non-C hepatitis virus-related hepatocellular carcinoma (NBNC-HCC). We aimed to investigate the independent risk factors and profiles associated with NBNC-HCC using a data-mining technique. METHODS: We conducted a case-control study and enrolled 223 NBNC-HCC patients and 669 controls from a health checkup database (n = 176 886). Multivariate analysis, random forest analysis and a decision-tree algorithm were employed to examine the independent risk factors, factors distinguishing between the case and control groups, and to identify profiles for the incidence of NBNC-HCC, respectively. RESULTS: In multivariate analysis, besides γ-glutamyltransferase (GGT) levels and the Brinkman index, albumin level was an independent negative risk factor for the incidence of NBNC-HCC (odds ratio = 0.67; 95% confidence interval = 0.60-0.70; P < 0.0001). In random forest analysis, serum albumin level was the highest-ranked variable for distinguishing between the case and control groups (98 variable importance). A decision-tree algorithm was created for albumin and GGT levels, the aspartate aminotransferase-to-platelet ratio index (APRI) and the Brinkman index. The serum albumin level was selected as the initial split variable, and 82.5% of the subjects with albumin levels of less than 4.01 g/dL were found to have NBNC-HCC. CONCLUSION: Data-mining analysis revealed that serum albumin level is an independent risk factor and the most distinguishable factor associated with the incidence of NBNC-HCC. Furthermore, we created an NBNC-HCC profile consisting of albumin and GGT levels, the APRI and the Brinkman index. This profile could be used in the screening strategy for NBNC-HCC.

Effect of occult hepatitis B virus infection on the early-onset of hepatocellular carcinoma in patients with hepatitis C virus infection.

Although overt hepatitis B virus (HBV) infection promotes the onset of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients, the effect of occult HBV infection remains unclear. The aim of this study was to investigate the effect of occult HBV infection on the early-onset of HCC in HCV-infected patients. A total of 173 HCC patients with HCV infection were enrolled and classified into 2 groups according to the median age of HCC onset: the early-onset group (n=91; 61.1±5.6 years) and the late-onset group (n=82; 73.8±3.7 years). Independent factors associated with the early-onset of HCC were assessed by multivariate analysis. In the overall analysis, independent risk factors for the early-onset of HCC were the white blood cell count and alanine aminotransferase level, but not the presence of HBV DNA. In a stratification analysis according to albumin levels of ≥3.5 g/dl, the presence of HBV DNA was a significant independent risk factor for the early-onset of HCC (OR 145.18, 95% CI 1.38-15296.61, P=0.036), whereas the presence of antibodies against hepatitis B core antigen was not found to be a risk factor. The presence of HBV DNA was not a risk factor for the early-onset of HCC in the overall analysis. However, its presence was an independent factor for the early-onset of HCC in HCV-infected patients with an albumin level of ≥3.5 g/dl. Thus, occult HBV infection may accelerate hepatocarcino-genesis in HCV-infected patients with relatively low carcinogenic potential.

Efficacy, safety, and survival factors for sorafenib treatment in Japanese patients with advanced hepatocellular carcinoma.

BACKGROUND: Sorafenib, an oral multikinase inhibitor, was approved for the treatment of advanced hepatocellular carcinoma (HCC), but has not been adequately evaluated for safety and effectiveness in Japanese patients with advanced HCC. AIMS: The purpose of this study was to prospectively assess the efficacy, safety, and risk factors for survival in patients with advanced HCC treated with sorafenib. METHODS: Between May 2009 and December 2010, 96 Japanese patients with advanced HCC (76 male, 20 female, mean age: 70.4 years) were treated with sorafenib. Eighty-eight patients had Child-Pugh class A, and 8 patients had Child-Pugh class B liver cirrhosis. Barcelona Clinic Liver Cancer stage B and C were found in 64 and 32 patients, respectively. RESULTS: Twelve patients demonstrated partial response to sorafenib therapy, 43 patients had stable disease, and 33 patients had progressive disease at the first radiologic assessment. The most frequent adverse events leading to discontinuation of sorafenib treatment were liver dysfunction (n = 8), hand-foot skin reaction (n = 7), and diarrhea (n = 4). The median survival time and time to progression were 11.6 and 3.2 months, respectively. By multivariate analysis, des-γ-carboxy prothrombin serum levels and duration of treatment were identified as independent risk factors for survival. CONCLUSIONS: This study showed that sorafenib was safe and useful in Japanese patients with advanced HCC. In addition, this study demonstrated that sorafenib should be administered as a long-term treatment for advanced HCC regardless of therapeutic effect and dosage.

Serum vascular endothelial growth factor as a predictor of response and survival in patients with advanced hepatocellular carcinoma undergoing hepatic arterial infusion chemotherapy.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has been recognized as a useful therapeutic modality for patients with advanced hepatocellular carcinoma (HCC). The aim of this study was to investigate the association between serum vascular endothelial growth factor (VEGF) levels and the therapeutic effect of HAIC and the survival of patients undergoing HAIC. METHODS: Seventy-one patients with advanced HCC underwent HAIC through a subcutaneously implanted infusion port. One chemotherapy course consisted of low-dose cisplatin (10 mg/body on days 1-5) and 5-fluorouracil (250 mg/body on days 1-5), and 1 treatment cycle consisted of 2-3 courses of chemotherapy. Serum VEGF levels were measured with the Bio-Plex Suspension Array System (Bio-Rad Laboratories). RESULTS: The median survival time (MST) of all patients was 10.2 months, and the 1-, 2-, 3-, and 5-year survival rates were 46.5, 21.9, 12.8, and 3.7%, respectively. Of the 71 patients, 3 achieved a complete response (CR) and 22 achieved a partial response (PR) [response rate (CR + PR/71) = 35%]. The serum VEGF level (≥100 pg/mL, P = 0.026) was an independent predictor of therapeutic effect, and was positively correlated with the platelet count (r = 0.569, P < 0.001) and tumor size (r = 0.543, P < 0.001). Child-Pugh class (P = 0.046), serum VEGF level (P = 0.004), and therapeutic effect (P = 0.005) were identified by multivariate analysis as independent predictors of survival. CONCLUSIONS: These results demonstrate that the serum VEGF level in patients with advanced HCC undergoing HAIC is an important predictive factor for therapeutic effect and survival.

Total and high molecular weight adiponectin and hepatocellular carcinoma with HCV infection.

BACKGROUND: Adiponectin is shown to be inversely associated with development and progression of various cancers. We evaluated whether adiponectin level was associated with the prevalence and histological grade of hepatocellular carcinoma (HCC), and liver fibrosis in patients with hepatitis C virus (HCV) infection. METHODS: A case-control study was conducted on 97 HCC patients (cases) and 97 patients (controls) matched for sex, Child-Pugh grade and platelet count in patients with HCV infection. The serum total and high molecular weight (HMW) adiponectin levels were measured by enzyme-linked immunosorbent assays and examined in their association with the prevalence of HCC. In addition, the relationship between these adiponectin levels and body mass index (BMI), progression of liver fibrosis, and histological grade of HCC was also evaluated. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI). RESULTS: There were no significant differences in the serum total and HMW adiponectin levels between cases and controls. Moreover, there were no inverse associations between serum total and HMW adiponectin levels and BMI in both cases and controls. On the other hand, serum total and HMW adiponectin levels are positively correlated with APRI in both cases (r = 0.491, P<0.001 and r = 0.485, P<0.001, respectively) and controls (r = 0.482, P<0.001 and r = 0.476, P<0.001, respectively). Interestingly, lower serum total (OR 11.76, 95% CI: 2.97-46.66 [P<0.001]) and HMW (OR 10.24, CI: 2.80-37.40 [P<0.001] adiponectin levels were independent risk factors of worse histological grade of HCC. CONCLUSIONS: Our results suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low these adiponectin levels were significantly associated with worse histological grades.

Insulin resistance and chronic liver disease.

Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes. Distinctive factors including hepatic parenchymal cell damage, portal-systemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes. Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes, retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure, hepatocellular carcinoma and gastrointestinal hemorrhage. Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes. Moreover, exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis. Thus, pathogenesis, cause of death, assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes. In this article, we review features of insulin resistance in relationship to chronic liver disease. We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis.

Adipocytokine involvement in hepatocellular carcinoma after sustained response to interferon for chronic hepatitis C.

AIM: Interferon (IFN) dramatically reduces the risk of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) to chronic hepatitis C (CH-C). However, HCC still develops in some patients after SVR. To evaluate metabolic factors in patients with HCC occurring after SVR and to determine whether insulin resistance and adipocytokines were involved in this etiology. METHODS: We examined clinical and biochemical features, histological findings and serum levels of adipocytokine prior to IFN therapy and at the detection of HCC in nine patients who were diagnosed with HCC. As controls, 27 patients were included who showed SVR but had not been diagnosed with HCC for at least 5 years after SVR. RESULTS: Three of four patients who developed HCC within 5 years after SVR showed liver cirrhosis when HCC was diagnosed. Prior to IFN therapy, four of nine HCC patients were diagnosed as having type 2 diabetes mellitus. Serum levels of leptin and insulin, Homeostatic Model of Assessment of Insulin Resistance and body mass index (BMI) were significantly higher and serum adiponectin was significantly lower in HCC patients at the time of HCC detection than in control patients more than 5 years after SVR. Six HCC patients had increased BMI and one HCC patient had a decreased BMI during the observation period. CONCLUSION: Hepatic fibrosis may be tightly related to the emergence of HCC after SVR. Insulin resistance and adipocytokine disorders may be implicated in hepatocarcinogenesis after SVR, in part by promoting hepatic fibrosis.

Recent progress in the management of hepatocellular carcinoma detected during a surveillance program in Japan.

AIM: This study explored recent improvements in the management of hepatocellular carcinoma (HCC) diagnosed during surveillance. METHODS: The subjects were 1074 patients with HCC, subdivided into three groups. Group A comprised 211 patients for whom HCC was detected during periodic follow-up examinations at Kurume University School of Medicine, Group B comprised 544 patients diagnosed with HCC during periodic follow-up examinations at other institutions, and, Group C comprised 319 patients with HCC detected incidentally or because of symptoms. RESULTS: In 1995-2000 and 2001-2006, 91% and 91% of group A, 68% and 70% of group B, and 27% and 26% of group C patients with HCC, respectively, met the Milan criteria. For groups A and B, the proportions of patients with Child-Pugh class A and use of promising treatment increased in the later periods compared to those diagnosed during the earlier periods (group A, Child-Pugh class A, 72% vs 58% [P = 0.040], receiving treatment, 90% vs 70% [P < 0.0001]; group B, Child-Pugh class A, 71% vs 62% [P = 0.031]; receiving treatment, 72% vs 52% [P < 0.0001], respectively). The cumulative survival rates of the 405 patients with HCC detected in the latter 6 years tended to be better than those for patients diagnosed in the former 6 years (350 patients) (4 years, 58% vs 50% [P = 0.0349]). CONCLUSION: The use of promising treatment and prognosis have improved in the last 6 years for patients with HCC diagnosed through surveillance relative to those identified in 1995-2000.

The pathogenesis, complications and therapeutic strategy for hepatitis C virus-associated insulin resistance in the era of anti-viral treatment.

Recent experimental and clinical studies have shown that chronic hepatitis C virus (HCV) infection causes insulin resistance. Since insulin resistance decreases response to antiviral treatments, promotes inflammatory and fibrogenic reactions and increases a risk of hepatocellular carcinoma (HCC), amelioration of insulin resistance may be a novel therapeutic target, which could improve the prognosis in patients with HCV-related chronic liver disease. Despite the increased awareness of health risk of insulin resistance, there is no common therapeutic strategy for HCV-associated insulin resistance. Indeed, treatments with exogenous insulin or sulfonylureas may be rather harmful because these treatments are associated with the development of HCC in patients with HCV infection. Meanwhile, we, along with others, have found distinctive treatments which improve HCV-associated insulin resistance. Administration of branched-chain amino acids (BCAA), especially as a late evening snack, improves glucose metabolism by improving insulin-signal cascades in insulin resistance patients with HCV infection. In this paper, we discuss the pathogenesis and complications for HCV-associated insulin resistance and further review a recent clinical therapeutic strategy using these agents for the treatment of this devastating disorder. We also discuss therapeutic potentialities of incretin-based therapies, new anti-diabetic agents for HCV-associated insulin resistance and the significance of insulin resistance in the era of new anti-viral treatments.