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CCR Translation for This Article from Number of Target Lesions for EASL and Modified RECIST to Predict Survivals in Hepatocellular Carcinoma Treated with Chemoembolization

Purposes: To date, most studies about the optimal number of target lesions for enhancement criteria for hepatocellular carcinoma (HCC) have focused on cross-sectional analyses of concordance. We investigated the optimal number of target lesions for European Association for the Study of the Liver (EASL) and modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines in predicting overall survival (OS).Experimental Design: We analyzed 254 consecutive treatment-naïve patients with HCC having at least 2 measurable target lesions undergoing transarterial chemoembolization. Kappa values for intermethod agreement of treatment responses were calculated for comparisons between use of maximum of 1, 2, 3, 4, or 5 targets versus use of all target lesions. Prognostic values of radiologic assessments according to number of target lesions for predicting OS were expressed as C-index.Results: By EASL and mRECIST guidelines, κ values between responses assessing the longest 2, 3, 4, or 5 targets and assessing all targets were 0.924, 0.977, 1.000, or 1.000 and 0.907, 0.959, 1.000, or 1.000, respectively, whereas those between responses assessing only one target and assessing all target lesions were 0.723 and 0.666, respectively. C-index when measuring the longest 1, 2, 3, 4, 5, and all targets was similar, ranging from 0.739 to 0.749 for EASL criteria and from 0.750 to 0.759 for mRECIST. From Cox regression analyses, radiologic response from each calculation method showed independently significant effects on OS for both guidelines, regardless of number of target lesions.Conclusions: Prognostic values for predicting OS were similar regardless of number of target lesions. Assessing the 2 largest targets rather than only 1 index lesion could be recommended considering high concordances from cross-sectional analyses. Clin Cancer Res; 19(6); 1503–11. ©2012 AACR.

PDF file - 136K, Univariate analysis for parameters influencing overall survival

PDF file - 125K, Inter-observer agreements according to radiological methods regarding treatment responses (CR, PR, SD, and PD)

PDF file - 107K

PDF file - 52K, Intra-individual agreement rates for target (A) and overall (B) response using EASL criteria and intra-individual agreement rates for target (C) and overall (D) response using mRECIST

PDF file - 30K, Flowchart describing the selection of the study population

PDF file - 111K, Detailed agreement rates in subgroups according to tumor numbers

Purpose Due to the seroepidemiological shift in hepatitis A (HA), its severity, mortality, and complications have increased in recent years. Thus, the aim of this study was to identify predictive factors associated with poor prognosis among patients with HA. Materials and Methods A total of 304 patients with HA admitted to our institution between July 2009 and June 2011 were enrolled consecutively. Patients with complications defined as acute liver failure (ALF) were evaluated, and mortality was defined as death or liver transplantation. Results The mean age of patients (204 males, 100 females) was 32 years. Eighteen (5.9%) patients had progressed to ALF. Of the patients with ALF, 10 patients (3.3%) showed spontaneous survival while 8 (2.6%) died or underwent liver transplantation. Multivariate regression analysis showed that Model for End-Stage Liver Disease (MELD) and systemic inflammatory response syndrome (SIRS) scores were significant predictive factors of ALF. Based on receiver operating characteristics (ROC) analysis, a MELD ≥23.5 was significantly more predictive than a SIRS score ≥3 (area under the ROC: 0.940 vs. 0.742, respectively). In addition, of patients with a MELD score ≥23.5, King's College Hospital criteria (KCC) and SIRS scores were predictive factors associated with death/transplantation in multivariate analysis. Conclusion MELD and SIRS scores ≥23.5 and ≥3, respectively, appeared to be related to ALF development. In addition, KCC and SIRS scores ≥3 were valuable in predicting mortality of patients with a MELD ≥23.5.

We investigated whether liver stiffness (LS) values can predict liver-related events (LREs) development in patients with chronic hepatitis B (CHB).LS values using transient elastography provides accurate assessment of liver fibrosis in patients with chronic liver disease.Between June 2007 and May 2010, a total of 162 patients with CHB who completed 2-year entecavir (ETV) treatment were evaluated. The primary endpoint was LRE development (hepatic decompensation, hepatocellular carcinoma, or liver-related death) during the 2-year ETV treatment.The median age of the patients (99 men, 63 women) was 51 years, and the median LS value was 14.8 kPa. During the 2-year ETV treatment, 15 (9.3%) patients experienced LREs. On univariate analysis, age, the proportion of patients with liver cirrhosis, platelet counts, and baseline LS values were significantly associated with LRE development (all P0.05). Together with age, multivariate analysis identified baseline LS values as an independent predictor of LRE development (P=0.046; hazard ratio, 1.040; 95% confidence interval, 1.101-1.084). The cutoff LS value maximizing the sum of sensitivity and specificity was 12.0 kPa (area under the receiver operating characteristics curve, 0.736; P=0.003; sensitivity, 93.3%; specificity, 42.2%). In addition, the changes in LS values between baseline and 1-year ETV treatment showed significant correlations with LRE development (P=0.030).Our data suggest that LS values are predictive of LRE development during 2-year ETV treatment in patients with CHB. The potential role of LS value as a monitoring tool for predicting dynamic changes in the risk of LRE development during long-term ETV treatment should be investigated further.

Background & Aims We examined the durability of the virological response after discontinuing lamivudine (LVD) in chronic hepatitis B (CHB) patients with LVD-resistant hepatitis B virus (HBV), who responded to LVD plus adefovir (ADV) combination therapy, and the outcome of switching to ADV monotherapy compared to maintaining combination therapy. Methods This study enrolled 72 patients with undetectable viral loads (≤12 IU/ml) and normal alanine aminotransferase levels after ADV add-on therapy for at least 6 months in LVD-resistant CHB patients. The enrolled patients were randomly assigned to continue with LVD–ADV combination therapy or switch to ADV monotherapy (n = 36 per group). Virological rebound was defined as HBV DNA detection at more than 12 IU/ml by quantitative polymerase chain reaction determined on two consecutive measurements. Results During 96 weeks of follow-up, 100% (36/36) of the patients in the LVD–ADV combination maintained group had persistently undetectable HBV DNA, compared with 94.4% (34/36) patients in the ADV monotherapy switched group. These two patients had undetectable HBV DNA after switching back to LVD–ADV combination therapy. There were no significant differences in the HBsAg levels between the two treatment groups during the 96-week follow-up period. Conclusions In our study, switching to ADV monotherapy resulted in sustained HBV DNA suppression in 94.4% of the patients for 96 weeks. Prior complete viral suppression with LVD–ADV combination therapy conferred a significant advantage in patients who switched to ADV monotherapy. LVD may be discontinued in patients who show a complete virological response to LVD–ADV combination therapy for at least 6 months.

To compare hepatocellular carcinoma (HCC) stage, treatment modality, and survival between groups submitted to different surveillance interval.It is not clear if surveillance interval affects patient survival with HCC.Clinical data from 10,307 patients at risk for HCC were prospectively collected from 1990 to 2005. The characteristics of cancer and 5-year survival in patients diagnosed as HCC during follow-up were compared between surveillance interval of6 months and beyond 6 months.A total of 400 patients were diagnosed with HCC, with a mean tumor size of 3.5 cm and an annual detection rate of 2.4%. The tumor sizes detected in patients with surveillance interval ≤ 6 months were significantly smaller than those detected in patients with interval of6 months (n=219; 3.0 ± 1.7 cm vs. n=181; 4.0 ± 2.6 cm, P0.001). The survival benefit in patients with surveillance interval of ≤ 6 months was significant compared with those with interval of6 months even after considering lead time with assumed tumor doubling time of 60 days. The 5-year survival of HCC patients surveyed between 2000 and 2004 was significantly higher compared with those surveyed between 1990 and 1994 or between 1995 and 1999 (41% vs. 17% and 19%, respectively, P0.0001). Using a Cox regression model, Child-Pugh class, Japanese tumor-node-metastasis stage, and α-fetoprotein levels were independently associated with patient survival.Our data show that surveillance ≤ 6 months might be associated with early detection of HCC and improved survival in a hepatitis B endemic area.

We herein report a patient with advanced hepatitis B virus-related hepatocellular carcinoma (HCC) beyond the Milan criteria. He underwent orthotopic liver transplantation after successful HCC downstaging that satisfied the University of California, San Francisco criteria, using concurrent chemoradiation therapy with a combination of repeated hepatic arterial infusion chemotherapy (HAIC) and sorafenib. A 52-year-old male was diagnosed with advanced hepatitis B virus-related HCC beyond the Milan criteria. He underwent concurrent chemoradiation therapy (50 Gy with 20 fractions over 5 weeks with HAIC using 5-fluorouracil at a dose of 500 mg/day, which was administered during the first and fifth weeks of radiation therapy) as an initial treatment modality. This was followed by the combined use of HAIC using 5-fluorouracil (500 mg/m(2) for 5 hours on days 1-3) and cisplatin (60 mg/m(2) for 2 hours on day 2) every 4 weeks (twelve cycles) and sorafenib (from the third to the twelfth cycle of HAIC) to treat the remaining HCC. Because a remarkable decrease in the tumor burden that satisfied the University of California, San Francisco criteria was observed after these combination treatments, the patient underwent orthotopic liver transplantation with curative aim and survived for 11 months without evidence of HCC recurrence.

Background The enhanced liver fibrosis (ELF) value is a non-invasive serum marker used for assessing liver fibrosis in chronic liver disease. To use the ELF value for the purpose of screening the general population and selecting subpopulations at high risk, it is important to know the normal range of ELF values as a prerequisite. Aims We aimed to define the normal range of ELF values by recruiting apparently healthy subjects and investigating factors influencing ELF values in subjects with minimal fibrotic burden. Methods ELF values were determined in a cohort of healthy subjects who underwent a health check-up and in healthy living liver donors who were screened for transplantation. None of subjects suffered from chronic heart disease, diabetes mellitus, metabolic syndrome, hepatitis B, hepatitis C, or human immunodeficiency virus infection, systemic autoimmune disease or liver dysfunction. Results Among 183 subjects analyzed, the normal ELF 5th through 95th percentile range was 5.95–8.73. Body mass index (P = 0.014) and male gender (P = 0.015) showed significant positive correlations with ELF value, whereas age did not. In multivariate linear regression analysis, platelet count was identified as the only independent factor influencing the ELF value (β=−0.006, P = 0.016). When considering the difference in ELF values between genders, the normal range of men was defined to be 6.72–8.93, this was slightly higher than that of women, 5.69–8.67. Conclusions We identified the normal range of ELF values and found that it can be significantly influenced by platelet count even in the healthy population.

European Association for the Study of the Liver (EASL) and modified Response Evaluation Criteria in Solid Tumours (mRECIST) guidelines, which measure changes in arterialised hepatocellular carcinoma (HCC), differ in terms of number of target lesions (all versus ≤2) and calculation method (bidimensional versus unidimensional). We compared prognostic values of mRECIST for predicting overall survival (OS) with reference to EASL criteria in treatment-naïve HCC undergoing trans-arterial chemoembolisation (TACE).The ability to predict OS during longitudinal follow-up was expressed as C-index, and a sample size of 292 patients was required to validate its equivalence between each criteria. Treatment responses were assessed using both guidelines 4weeks after the first TACE, using dynamic computed tomography or magnetic resonance imaging. Kaplan-Meier and Cox regression analyses were used to explore differences in OS between responders (complete or partial) and non-responders (stable or progressive disease), defined by each method.C-index for EASL and mRECIST guidelines was 0.753 and 0.759, respectively, demonstrating equivalence between two methods. Differences in median OS between responders and non-responders were statistically significant for both EASL (30.1 versus 18.7 months, p0.001) and mRECIST (33.8 versus 17.1 months, p0.001) guidelines. In addition to radiological response, α-fetoprotein (p0.001), tumour number (p0.001) and tumour size (p=0.048) were significant predictors of OS. In multivariate analysis, radiological criteria, tumour number and α-fetoprotein were identified as independent predictors (all p0.05).mRECIST, a simpler method, provided prognostic values for predicting OS equivalent to EASL criteria in patients with HCC undergoing TACE as an initial treatment modality.

Although mortality after liver resection has declined, posthepatectomy liver failure (PHLF) remains a major cause of operative mortality. To date there is not consensus on a definition for PHLF. However, there have been many efforts to define PHLF causing operative mortality. In the present study we sought to identify early predictors of death from irreversible PHLF.We retrospectively analyzed the medical records of 359 patients with hepatocellular carcinoma who underwent liver resection between March 2000 and December 2010. Various biochemical parameters from postoperative days (POD) 1, 3, 5, and 7 were analyzed and compared with the "50-50" criterion.Operative mortality was 4.7 %. Prothrombin time (PT)65 % and bilirubin ≥ 38 μmol/L on POD 5 showed the only significant difference as compared with "50-50" criterion. The new combination of bilirubin level and the international normalized ratio showed higher sensitivity, area under the curve, as well as similar accuracy (sensitivity 78.6 vs. 28.6 %; p = 0.002; area under the curve 0.8402 vs. 0.6396; p = 0.00176; accuracy 88.6 vs. 93.4 %; p = 0.090). Multivariate analysis revealed the combination of PT65 % and bilirubin ≥ 38 μmol/L on POD 5 to be the only independent predictive factor of mortality (odds ratio, 82.29; 95 % confidence interval 8.69-779.64; p0.001).In patients with chronic liver disease who will undergo liver resection the combination of PT65 % and bilirubin ≥ 38 μmol/L on POD 5 may be a more sensitive predictor than the "50-50" criterion of mortality from PHLF. Although it needs to validated by prospective study, this measure may be applied to select patients receiving artificial liver supports or liver transplantation.

Background/Aims: In patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB) receiving adefovir (ADV) add-on LAM therapy, insufficient viral suppression or the appearance of additional ADV resistance has remained unresolved. This study determined the partial virological response (PVR) criteria to predict a virological response (VR) at week 96 in these patients. Methods: 96 patients with LAM-resistant CHB (ADV add-on LAM therapy >2 years) were analyzed. For predicting VR at week 96, the area under the receiver operating characteristic curve values at different time points were compared to establish the optimal time point, and the maximal Youden index was calculated to determine the optimal cut-off hepatitis B virus (HBV) DNA level. Results: 50 (52.1%) patients achieved VR at 2 years after ADV add-on LAM therapy. The optimal PVR criteria were determined to be HBV DNA 500 IU/ml at week 48. 44 (45.8%) patients who met optimal PVR criteria showed a significantly higher risk for detectable HBV DNA levels at week 96 than those with a favorable VR (HBV DNA Conclusions: This study suggested optimal PVR criteria in patients with LAM-resistant CHB receiving ADV add-on LAM therapy. Modification of the antiviral agent regimen should be considered if the serum HBV DNA level exceeds 500 IU/ml at week 48.

Lamivudine resistance develops in up to 80% of patients with chronic hepatitis B (CHB) after 5 years of treatment. Cross-resistance between nucleoside/nucleotide analogues limits management options in these patients. To investigate the role of pegylated interferon-α2a as rescue therapy in these patients, the efficacy and safety of pegylated interferon-α2a between treatment-naive patients and lamivudine-resistant patients with hepatitis B e antigen (HBeAg)-positive CHB were compared.A total of 150 HBeAg-positive CHB patients were stratified according to prior treatment. Lamivudine-resistant patients (n=64) and treatment-naive patients (n=86) received pegylated interferon-α2a once-weekly for 48 weeks and were followed-up for an additional 24 weeks. Primary end points were HBeAg loss and HBV DNA100,000 copies/ml at end of follow-up.A total of 65 (76%) treatment-naive patients and 49 (77%) lamivudine-resistant patients completed treatment and 24 weeks of follow-up. Rates of HBeAg loss were comparable at end of follow-up between treatment-naive patients and lamivudine-resistant patients (20.9% and 23.4%, respectively; P=0.8423). Similarly, rates of HBV DNA100,000 copies/ml were comparable at end of follow-up between treatment-naive patients and lamivudine-resistant patients (20.9% and 21.9%, respectively; P=1.000). There was no statistically significant difference in alanine aminotransferase normalization rates between treatment-naive patients and lamivudine-resistant patients (36.0% and 29.7%, respectively; P=0.4848). A total of one patient in each group achieved hepatitis B surface antigen (HBsAg) loss and seroconversion. The most common adverse events were those known to occur with pegylated interferon-α2a therapy, and safety profiles were similar between both patient populations.Pegylated interferon-α2a may be effective as a rescue therapy in patients with lamivudine-resistant HBeAg-positive CHB.

Background and Aim: Little information is available about the antiviral efficacy of lamivudine (LAM) and entecavir (ETV) in patients with hepatitis B virus (HBV)-related advanced hepatocellular carcinoma (HCC). Thus, we compared the antiviral efficacy of LAM and ETV in these patients. Methods: The medical records of 134 antiviral therapy-naive patients with HBV-related advanced HCC (modified Union for International Cancer Control [UICC] Tumor, Nodes, and Metastases [TNM] stages III–IV) treated between January 2005 and September 2009 were reviewed. After HCC diagnosis, 87 (64.9%) and 47 (35.1%) patients received LAM and ETV, respectively. Results: The mean age of patients (115 men, 19 women) was 53 years. Sixty-five (48.5%) and 69 (51.5%) patients had TNM stages III and IV HCC, respectively. Treatment outcomes during follow-up, including virologic, biochemical, and serologic responses and appearance of antiviral resistance, were similar in the LAM and ETV groups (all P > 0.05). Multivariate analysis identified Child–Pugh class, α-fetoprotein, and TNM stage as independent predictors of overall survival (all P

BACKGROUND/AIMS Liver stiffness measurement (LSM) using transient elastography (FibroScan) is influenced by major changes in aminotransferase. We aimed to determine the optimal time for restoring the reliability of LSM for assessing liver fibrosis in patients with chronic hepatitis B experiencing acute exacerbation. METHODS Twenty-one patients with acute exacerbation of chronic hepatitis B [alanine aminotransferase (ALT)>5× upper limit of normal (ULN)] were prospectively recruited. Serial LSM and biochemical tests were performed at the time of admission and after 1, 3, 6, 9, and 12 months. The ULN of ALT was defined as 40 IU/L. The cutoff LSM value for cirrhosis was defined as 10.3 kPa. RESULTS The median age (9 male) was 49 years. The median ALT and LSM in the baseline were 522 IU/L and 15.1 kPa, respectively. Three months after acute exacerbation, ALT had decreased significantly below 2× ULN and stabilized (median: 522, 43, 21, 19, 18, and 16 IU/L at baseline, 1, 3, 6, 9, and 12 mo, respectively). However, LSM needed 3 more months (6 mo after exacerbation) for stabilization (median: 15.1, 10.0, 7.4, 7.1, 6.3, and 5.8 kPa at baseline, 1, 3, 6, 9, and 12 mo, respectively). CONCLUSIONS LSM should be postponed for at least 3 months after stabilization of ALT below 2× ULN to restore the reliability of LSM in assessing liver fibrosis.

Liver stiffness measurement (LSM) using transient elastography (FibroScan) can accurately assess the degree of liver fibrosis and predict the development of hepatocellular carcinoma (HCC) and variceal bleeding in patients with chronic hepatitis B (CHB).We compared the accuracy of noninvasive liver fibrosis prediction methods in predicting the development of HCC or hepatic decompensation in patients with CHB.A total of 1126 patients with CHB who underwent LSMs and attended regular follow-ups to detect the development of HCC and hepatic decompensations (variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, or hepatorenal syndrome) were enrolled. Noninvasive liver fibrosis prediction methods included, age-spleen-to-platelet ratio index, LSM, LSM-spleen diameter-to-platelet ratio index (LSPI), P2/MS, and FIB-4.During follow-up (median, 30.7 mo), HCC and hepatic decompensation developed in 63 and 68 patients, respectively. The accuracy of LSM and LSPI in predicting the development of HCC or hepatic decompensation was higher than that of aspartate aminotransferase-to-platelet ratio index, age-spleen-to-platelet ratio index, P2/MS, or FIB-4 (areas under the receiver operating characteristic curve=0.789 and 0.788 vs. 0.729, 0.756, 0.696, and 0.744 for HCC development; areas under the receiver operating characteristic curve=0.820 and 0.848 vs. 0.787, 0.799, 0.812, and 0.784 for hepatic decompensation). On multivariate analyses, LSM and LSPI were identified as independent predictors of the development of HCC [hazard ratio (HR), 1.040 (LSM); HR, 1.001 (LSPI)] and hepatic decompensation [HR, 1.033 (LSM); HR, 1.002 (LSPI)].Our results suggest that LSM or LSPI may be useful predictors of the development of HCC and hepatic decompensation in patients with CHB.

Summary Background It remains unclear whether initial compact lipiodol uptake after transarterial chemoembolisation (TACE) is associated with improved survival in patients with hepatocellular carcinoma (HCC). Aim To reveal the clinical relevance of compact lipiodolisation after TACE. Methods We studied 490 patients with unresectable HCC who had first been treated with TACE. Compact lipiodolisation was defined as the absence of an arterial enhancing lesion, reflecting complete lipiodol uptake, as assessed by dynamic computed tomography (CT) 1 month after treatment. The rate of initial compact lipiodolisation was analysed according to multiplicity and size of tumour, and survival of patients who achieved compact lipiodolisation was compared to that of patients who did not. Results Of the 490 patients, 409 (83.5%) were in Child–Pugh class A and 81 (16.5%) in class B. The rate of initial compact lipiodolisation in single HCCs was higher than that in multinodular HCCs (33.7% vs. 14.6%, P 10 cm was 46.6%, 13.6%, and 0% respectively. The 1-, 3- and 5-year survival rates of patients with compact uptake were 92.7%, 70.7% and 52.4% compared to 60.8%, 28.0% and 16.9% in patients with noncompact lipiodolisation. Multivariate analysis revealed that Child–Pugh class, alpha-fetoprotein level, tumour node metastasis stage, portal vein thrombosis and initial compact lipiodolisation were independent predictors of survival. Conclusions Initial compact lipiodol uptake after transarterial chemoembolisation is associated with improved survival in patients with unresectable hepatocellular carcinoma. Accordingly, initial complete lipiodolisation should be considered a relevant therapeutic target.

Alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) are widely used complementary tumor markers for hepatocellular carcinoma (HCC). In this study, we investigated whether preoperative AFP and DCP levels predict recurrence after curative resection in patients with hepatitis B virus (HBV)-related HCC. Records for 267 patients who were diagnosed with HBV-related HCC and who underwent curative resection for HCC were retrospectively reviewed. Patients were divided into two preoperative groups: pre-op I (AFP ≥ 20 ng/dL and DCP ≥ 40 mAU/mL) and pre-op II (AFP ≥ 20 ng/dL and DCP

BACKGROUND AND AIMS Few studies have adequately examined the efficacy of lamivudine plus adefovir (LAM+ADV) combination therapy vs. entecavir (ETV) monotherapy in HBeAg-positive hepatitis B patients who fail to respond to sequential treatment with LAM and ADV. We compared directly the efficacy of LAM+ADV vs. ETV in such patients and assessed prognostic factors associated with a virologic response at month 12. METHODS In total, 72 HBeAg-positive patients who showed resistance (n = 33) or a suboptimal virologic response (n = 39) to ADV monotherapy with resistance to LAM therapy underwent rescue therapy (31 LAM+ADV and 41 ETV). All patients were followed for at least 12 months. RESULTS Following 12 months of treatment, in the LAM+ADV and ETV groups, a virologic response was observed in 7/31 (22.6%) and 8/41 (19.5%; P = 0.777) patients; ALT normalization occurred in 11/13 (84.6%) and 16/18 (88.9%; P = 0.566); HBeAg seroconversion in 1/31 (2.3%) and 4/41 (9.8%; P = 0.341) and a virologic breakthrough in 3/31 (9.0%) and 5/41 (12.1%; P = 0.452) respectively. Independent prognostic factors associated with a virologic response were the baseline HBV-DNA level (OR = 0.37; 95% CI 0.17-0.80; P = 0.011) and the duration of prior ADV monotherapy (OR = 0.89; 95% CI 0.83-0.95; P = 0.044). CONCLUSIONS Neither LAM+ADV nor ETV was adequately effective in patients with sequential LAM and ADV treatment failure. Thus, when chronic hepatitis B patients show resistance or suboptimal response to ADV monotherapy, early modification of treatment should be considered.

Background and Aim: Liver stiffness (LS) measurement can distinguish individuals with potential liver disease (LD) from the general population. However, if LS is sex-sensitive, prevalence of LD may be incorrectly estimated when the same reference LS value is applied irrespective of sex. Here, we evaluated whether normal ranges of LS differ between healthy men and women. Methods: LS was measured in a cohort of healthy living liver and kidney donors, none of whom suffered from diabetes mellitus, hypertension, hepatitis B or C virus infection, heart or liver dysfunction, or metabolic syndrome. Patients with abnormal laboratory findings related to potential LD (platelet count 40 IU/L; alanine aminotransferase [ALT] > 40 IU/L; albumin 1.2 mg/dL; gamma-glutamyl transpeptidase > 54 IU/L; alkaline phosphatase > 115 IU/L) were excluded. Results: Among 242 patients analyzed, the mean age was 34.1 for men (n = 121) and 40.5 years for women (n = 121) (P

Acoustic radiation force impulse (ARFI) elastography can be used to assess the degree of liver fibrosis. We evaluated the performance of ARFI elastography in assessment of liver fibrosis and compared it with the performance of aspartate aminotransferase-to-platelet ratio index (APRI) and transient elastography with Fibroscan (FS). We prospectively analyzed 250 consecutive patients who underwent liver biopsy and ARFI from June 2010 to May 2011. Reliable FS values were obtained for 97 (38.8%) patients. The mean age of patients (147 male and 103 female) was 46.6 years. Liver stiffness values obtained by use of ARFI elastography significantly correlated with histological fibrosis stage (R = 0.575, P

Background and Aim: The clinical utility of alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) as a predictor of treatment outcome in patients with advanced hepatocellular carcinoma (HCC) receiving hepatic artery infusional chemotherapy (HAIC) or concurrent chemoradiation therapy (CCRT) has been poorly defined. Methods: Between January 2003 and December 2007, we enrolled 127 treatment-naive patients who received HAIC (n = 60) or CCRT (n = 67) as an initial treatment modality. An AFP or DCP response was defined as a reduction of more than 20% from the baseline level. Results: AFP responders showed significantly better overall survival (OS) than non-responders among patients with HAIC (median 17.3 vs 6.4 months, P

Background/Aim: Periodic endoscopy for esophageal varices (EVs) and prophylactic treatment of high-risk EVs, i.e. medium/large EVs, small EVs with the red-color sign or decompensation, are recommended in cirrhotic patients. We assessed the cumulative risks for future EV bleeding using the following simple P2/MS index: (platelet count)2/[monocyte fraction (%) × segmented neutrophil fraction (%)]. Methods: We enrolled 475 consecutive B-viral cirrhosis patients for 4 years, none of whom experienced EV bleeding. All underwent laboratory work-ups, endoscopy and ultrasonography. Those with EV bleeding took a nonselective β-blocker as prophylaxis. The major endpoint was the first occurrence of EV bleeding, analyzed using the Kaplan-Meier and Cox regression methods. Results: Among patients with EV bleeding (n = 131), 25 experienced their first EV bleeding during follow-up. To differentiate the risk for EV bleeding, we divided them into two subgroups according to their P2/MS value (subgroup 1: P2/MS ≥9 and subgroup 2: P2/MS Conclusions: The P2/MS is a reliable predictor for the risk of EV bleeding among patients with EV bleeding. According to risk stratification, different prophylactic treatments should be considered for the subgroup with a P2/MS

Background and Aim: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing in Korea as the dietary pattern and lifestyle become more Westernized and the obese population increases. The spectrum of NAFLD ranges from asymptomatic steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. Schwimmer et al. divided NASH into three types according to the histological characteristics, such as adult type, pediatric type and overlap type. We investigated clinical and histologic features of NAFLD patients in Korean young men. Methods: A total of 64 male patients under age 30 years, diagnosed as NAFLD by a liver biopsy, were reviewed retrospectively. NASH was diagnosed by NAFLD activity score (NAS), and NASH patients were classified with Schwimmer's histological classification. Results: Pathological features of liver biopsy revealed NASH in most cases (59 cases, 92.2%) including 29 cases (45.3%) of borderline NASH and 30 cases (46.9%) of definite NASH. The definite NASH group showed significantly high aspartate aminotransferase/alanine aminotransferase levels compared to the borderline NASH group. There were four cases (6.8%) of pediatric type, 17 cases (28.8%) of adult type, and 38 cases (64.4%) of overlap type in the NASH group. NAS was 3.75 ± 0.05 in the pediatric type, 4.29 ± 1.16 in the adult type and 4.87 ± 1.21 in the overlap type, and the overlap type showed a higher NAS than the pediatric type. The fibrosis stage was significantly higher in the overlap type than the other types. Conclusion: Most Korean young men with NAFLD turned out to have borderline or definite NASH. More than half of the NASH cases showed overlap type in Korean young men.

Background and Aim: Although several studies have investigated the normal range of liver elasticity using acoustic radiation force impulse (ARFI) elastography in healthy volunteers, they could not strictly exclude the morphological and functional liver abnormalities. The aim of this study was to identify the normal range of ARFI velocity by recruiting healthy living liver and kidney donors who passed the full laboratory tests and imaging studies. Methods: The study prospectively enrolled 108 healthy living liver (n = 42) and kidney donors (n = 66) who were admitted for transplantation between July 2010 to April 2011. None of the subjects had abnormal liver function test and imaging findings including conventional ultrasonography, computed tomography or magnetic resonance imaging. Results: The mean age of the study population (58 men and 50 women) was 35.5 years, and the mean ARFI velocity was 1.07 ± 0.11 m/s (range: 0.79–1.27). ARFI velocity was not significantly different between subjects with body mass index (BMI)

Hepatitis B virus surface antigen (HBsAg) quantification has been suggested to discriminate inactive carriers from hepatitis e antigen (HBeAg) negative chronic hepatitis, but it could be genotype-dependent. We studied the predictive value of HBsAg quantification in genotype C HBeAg-negative hepatitis B virus (HBV) carriers.We recruited 104 HBeAg-negative HBV carriers with HBV DNA levels 2,000 IU/ml and normal alanine aminotransferase (ALT) levels for at least 12 months and prospectively followed them for 36 months. Patients were classified into two groups: inactive carriers (IC) who showed HBV DNA levels 2,000 IU/ml and persistently ALT ≤ 40 IU/ml throughout the follow-up period and patients with HBeAg-negative chronic hepatitis (ENH).After follow-up, 73 patients were categorized into the IC group and 31 patients into the ENH group. HBsAg levels were significantly lower in the IC group than in the ENH group. The diagnostic accuracy of single-point HBsAg levels for predicting viral activation was favourable (AUROC = 0.710, P 0.001). Diagnostic accuracy improved when HBsAg was combined with baseline HBV DNA levels (AUROC = 0.750, P 0.001). The combination of HBsAg levels 850 IU/ml and HBV DNA 850 IU/ml predicted the reactivation of HBV replication with 84.6% diagnostic accuracy.Although it is inferior to other genotypes and to serum HBV DNA alone, single-point HBsAg level has a favourable diagnostic accuracy in genotype C HBeAg-negative HBV carriers and is expected to provide additional information for managing chronic hepatitis B.

Background/Aims In 2009, the American Joint Committee on Cancer (AJCC) published the 7th edition of the hepatocellular carcinoma (HCC) staging system. We investigated the prognostic value of the 7th AJCC staging system as a clinical staging system in patients with HCC. Methods We retrospectively applied the 6th and 7th AJCC systems to 877 patients who were diagnosed with HCC between January 2004 and December 2006 using radiological findings and compared the performance of the AJCC systems to that of the Barcelona Clinic Liver Cancer (BCLC) system. The prognostic power was quantified using a linear trend χ2 test and –2 log likelihood. Results The median age was 57 years and males predominated (n = 701, 79.9%). There was no significant difference in survival between adjoining advanced stages of the 6th and 7th AJCC systems (⩾stage IIIA in the 6th and ⩾stage IIIB in the 7th; all p > 0.05), although a significant difference between adjoining early stages was identified. The 7th AJCC system had greater prognostic power than the 6th (linear trend χ2 test, 168.195 versus 160.293; -2 log likelihood, 7366.347 versus 7396.380), but not greater than that of the BCLC system (linear trend χ2 test = 207.013, -2 log likelihood = 7320.726). Conclusions The 7th AJCC staging system provided better prognostic power than the 6th for patients with HCC, but not better than that of the BCLC system. Thus, the 7th AJCC staging system should be applied cautiously in patients with advanced HCC because of its low prognostic power in advanced stages.

Few studies have reported on the clinical characteristics of hepatocellular carcinoma (HCC) at the time of diagnosis with regard to pre-S and basal core promoter (BCP) mutations. In this study, the clinical features and prognosis of 126 Korean HCC patients were examined with respect to pre-S deletion and BCP mutations of hepatitis B virus. The proportion of HCC patients according to tumor-node-metastasis stage are as follows: 8.7% in stage I, 31% in stage II, 30.2% in stage III, 21.4% in stage IV-A, and 8.7% in stage IV-B. Overall, 40.5% of HCC patients were treated by surgery or ablation, 59.5% by other methods. Patients were divided according to pre-S deletion and BCP mutations (103 without pre-S deletion, 23 with pre-S deletion; 44 without BCP mutation, 82 with BCP mutation). The tumor characteristics and prognosis were evaluated between the groups, including size, number, type, vessel invasion, portal vein thrombosis, and metastasis. No significant difference in tumor characteristics between the HCC patients with pre-S deletion was observed, compared with the HCC patients without pre-S deletion. In contrast, the survival rate was lower in those with pre-S deletion than in those without it (P = 0.024). No difference in tumor characteristics was found in non-BCP and BCP mutation patients. Unlike the pre-S deletion group, no difference was observed in survival rate between the non-BCP and BCP patients. In conclusion, pre-S deletion and BCP mutations did not affect the initial tumor features. However, pre-S deletion was an independent risk factor affecting HCC survival.

Risk Assessment of Esophageal Variceal Bleeding in B-Viral Liver Cirrhosis by a Liver Stiffness Measurement-Based Model

Aim: Liver transplantation (LT) is a curative treatment for localized hepatocellular carcinoma (HCC), but the recurrence rate after LT is about 10–20%, with a dismal prognosis. Little data exist as to the natural history, treatment outcome and optimal treatment of recurrent HCC after LT. We reviewed various treatment modalities given to patients with recurrent HCC after LT. Methods: Among 132 patients who underwent LT for localized HCC, we retrospectively reviewed medical records of 39 of the 132 patients who developed recurrent HCC after LT. We analyzed the clinical outcome of various treatment modalities and treatment-related adverse events. Results: A total of 39 (29%) of the original 132 patients had recurrent HCC, most recurrences (82%) having occurred within 1 year after LT and involved extrahepatic lesions. Only seven patients had recurrent disease limited to the liver. The median overall survival from the initial treatment of all relapsed patients was 6.9 months. There were various initial treatment modalities, namely palliative systemic chemotherapy, trans-catheter arterial chemo-embolization/infusion (TACE/I), radiation therapy (RT), surgical resection and no treatment. The median overall survival was 9.5 months for first-line chemotherapy, including those who had prior local therapy, 6.3 months TACE/I and 6.9 months for RT. Conclusion: Various clinical approaches have been used to treat patients with recurrent HCC after LT in a clinical setting. More effective strategies and clinical guidelines for recurrent HCC following LT must be established.

BACKGROUND/AIMS Prediction of significant fibrosis (F=2) using non-invasive methods for chronic hepatitis C (CHC) patients with persistently normal alanine aminotransferase (PNALT) levels remains a challenging problem. We aimed to develop a novel non-invasive model for predicting the presence of significant fibrosis in CHC patients with PNALT. METHODOLOGY We prospectively enrolled 40 treatment-naive CHC patients with PNALT who underwent liver biopsy and liver stiffness measurements (LSM). Age-platelet index (API), aspartate aminotransferase to platelet ratio index (APRI), LSM and LSM to platelet ratio index (LPRI) were compared with liver histology results. RESULTS Significant fibrosis was diagnosed in 17 patients (42.5%). The diagnostic accuracy of LPRI was the highest for the prediction of significant fibrosis (AUROC = 0.859) when compared to that of APRI (0.770), LSM (0.769) and API (0.703). Using a cutoff value of LPRI =37, the significant fibrosis could be correctly identified with high accuracy (100% PPV) in 6 (15.0%) patients. While, using an LPRI cutoff value

The incidence of acute viral hepatitis A (AHA) in Korea is increasing rapidly. Additionally, we are encountering more cases with acute kidney injury (AKI), which was once regarded as a rare complication of AHA. Thus, we investigated recent aspects of the incidence and clinical characteristics of AHA complicated by AKI.Patients diagnosed with AHA at 2 referral hospitals in Seoul during the period January 2006 to December 2009 were enrolled.Of 1025 patients, 71 (6.9%) had AKI. The incidence of AKI was 3.1% in 2006, 6.0% in 2007, 8.9% in 2008, and 6.9% in 2009. Patients with AKI were predominantly male, heavy alcohol drinkers, and smokers, and also had a higher rate of underlying hypertension than patients without AKI. At admission, patients with AKI had significantly higher white blood cell counts, prolonged prothrombin times, and elevated liver enzymes, including total and direct bilirubin, gamma-glutamyltransferase, and C-reactive protein. Additionally, patients with AKI had a higher peak total bilirubin level and lower initial serum albumin level than patients without AKI.Although most patients with AHA complicated by AKI recover with conservative treatment, we should pay particular attention to patients who have risk factors for AKI.