Prediction of Hepatocellular Carcinoma by On-Therapy Response of Noninvasive Fibrosis Markers in Chronic Hepatitis B.

INTRODUCTION: Antiviral therapy improves hepatic fibrosis and reduces hepatocellular carcinoma (HCC) incidence. This study aimed to evaluate whether on-therapy changes in scores for fibrosis index based on 4 factors and aspartate aminotransferase-to-platelet ratio index are associated with HCC development and establish an HCC risk score model incorporating noninvasive fibrosis marker (NFM) response. METHODS: This multicenter study recruited 5,147 patients with chronic hepatitis B (4,028 for derivation cohort and 1,119 for validation cohort) who were given entecavir/tenofovir for >12 months between 2007 and 2018. A risk prediction model for HCC was developed using predictors based on multivariable Cox models, and bootstrapping was performed for validation. RESULTS: The 10-year cumulative HCC incidence rates were 12.6% and 13.7% in the derivation and validation cohorts, respectively. The risk of HCC significantly differed with early NFM response, with a marked reduction in HCC risk in patients achieving a significant decrease in NFM by 12 months (P < 0.001). NFM response, sex, age, and cirrhosis were independently predictive of HCC. We developed the Fibrosis marker response, Sex, Age, and Cirrhosis (FSAC) score based on regression coefficients of each variable. For the 10-year prediction of HCC, FSAC showed higher C-index values than PAGE-B, modified PAGE-B, CU-HCC, and REACH-B (0.84 vs 0.77, 0.80, 0.77, and 0.67, respectively; all P < 0.005). The predictive performance of FSAC was corroborated in the validation cohort, with higher C-index than other models (all P < 0.050). DISCUSSION: On-therapy changes in NFM are an independent indicator of HCC risk. FSAC incorporating NFM response is a reliable risk score for risk estimation for HCC with better performance than other models.

Effects of Positive Hepatitis B Core Antibody and Metabolic Disorders in Hepatocellular Carcinoma in an Endemic Area of Hepatitis B Virus.

BACKGROUND AND AIMS: This retrospective study aimed to investigate the impact of positive hepatitis B core antibody (anti-HBc) and metabolic disorders on clinical characteristics of hepatocellular carcinoma (HCC) patients in an HBV-endemic area. METHODS: A total of 1950 consecutive patients newly diagnosed with HCC between 2002 and 2015 were included. Patient records were reviewed. We compared non-viral and non-alcoholic HCC patients with other etiological groups for HCC. In addition, we compared HCC patients with negative hepatitis B surface antigen (HBsAg) and positive anti-HBc to those with negative HBsAg and negative anti-HBc, and to those with HBV. RESULTS: The prevalence of non-viral and non-alcoholic HCC increased from 7% in 2002-2011 to 12% in 2012-2015. The proportion of non-viral and non-alcoholic HCC gradually increased with age. Patients with non-viral and non-alcoholic HCC exhibited higher rates of metabolic disorders and preserved liver function. The rate of anti-HBc positivity was similarly high in all HCC etiological groups. The clinical features of HCC patients with negative HBsAg and positive anti-HBc were similar to those with negative HBsAg and negative anti-HBc, but significantly different from those with HBV HCC. Regarding tumor characteristics, patients in the non-viral and non-alcoholic HCC group had more advanced stages of tumors (mUICC stage III-V and BCLC stage C/D). There was no significant difference in overall survival among the patient groups. The presence of anti-HBc did not affect patient survival. CONCLUSION: Patients with non-viral and non-alcoholic HCC had a relatively high prevalence of metabolic disorders and preserved liver function. However, they had advanced tumor stage compared to patients from other etiological groups. Anti-HBc positivity did not affect the clinical characteristics or prognosis of non-HBV HCC patients in this study.

Comparison of tenofovir and entecavir on the risk of hepatocellular carcinoma and mortality in treatment-naïve patients with chronic hepatitis B in Korea: a large-scale, propensity score analysis.

OBJECTIVE: The use of tenofovir (TDF) and entecavir (ETV) in patients with chronic hepatitis B (CHB) has led to a decrease in the incidence of hepatocellular carcinoma (HCC) and liver-related events. However, whether there is a difference between the two agents in the extent of improving such outcomes has not been clarified thus far. Therefore, we aimed to compare TDF and ETV on the risk of HCC and mortality. DESIGN: A total of 7015 consecutive patients with CHB who were treated with TDF or ETV between February 2007 and January 2018 at the liver units of the Catholic University of Korea were screened for study eligibility and 3022 patients were finally analysed. Study end points were HCC and all-cause mortality or liver transplantation (LT) within 5 years after the initiation of antiviral therapy. Propensity score matching (PSM) and inverse probability of treatment weighting methods were used. RESULTS: No difference was observed between TDF and ETV in the incidence rates of HCC in the entire cohort (HR 1.030; 95% CI 0.703 to 1.509, PSM model, p=0.880) and subgroups of patients with chronic hepatitis and cirrhosis. Also, no difference was observed between TDF and ETV in the incidence rates of all-cause mortality or LT in the entire cohort (HR 1.090; 95% CI 0.622 to 1.911, PSM model, p=0.763), and patients with chronic hepatitis and cirrhosis. CONCLUSION: This study has demonstrated the clinical outcomes in patients with CHB who received TDF or ETV treatment. There was no difference in the intermediate-term risk of HCC and mortality or LT between the two drugs.

Clinical outcomes after the introduction of direct antiviral agents for patients infected with genotype 1b hepatitis C virus depending on the regimens: A multicenter study in Korea.

BACKGROUND: A real-life study is essential outside clinical trials. The aim is to evaluate the clinical outcomes of direct acting agents (DAA) for patients with chronic hepatitis C (CHC) in real practice. METHODS: We analyzed 590 consecutively enrolled patients with CHC-1b who received DAAs since 2015, when DAAs were introduced in Korea. The patients were checked for resistance-associated variants (RAV) against nonstructural protein 5A inhibitors and then daclatasvir/asunaprevir or sofosbuvir based regimens were chosen. RESULTS: The frequency of patients with cirrhosis and prior hepatocellular carcinoma (HCC) was 29.2% and 4.7%, respectively. For the RAV test, 10% were positive and in 3.6% the result was "indeterminate." Overall, 518 patients were treated with a 24-week regimen of daclatasvir/asunaprevir, 72 patients (RAV positive 75%) were treated with 12 weeks regimen of ledipasvir/sofosbuvir or daclatasvir/sofosbuvir. The SVR12 was 94.0% in the daclatasvir/asunaprevir, 98.2% in the ledipasvir/sofosbuvir, and 100% in the daclatasvir/sofosbuvir group. A total of 93.3% of SVR12 in the RAV-"indeterminate" patients was not difference 95.0% in the RAV-negative patients. Up to 1 year, de novo HCC occurrence and recurrence developed in 2.6% and 17.8%, respectively. HCC was more frequent in cirrhotic patients than in noncirrhotic patients (P = 0.000). α Fetoprotein (AFP) level at the end of treatment was a predicting factor for de novo HCC. CONCLUSIONS: Optimizing the choice of DAAs according to RAV test resulted in high SVR among CHC-1b Korean patients. This real practice multicenter cohort study suggests the importance of AFP and HCC surveillance in cirrhotic patients even after successful HCV therapy.

Early Hepatitis B Surface Antigen Seroclearance Following Antiviral Treatment in Patients with Reactivation of Resolved Hepatitis B.

BACKGROUND AND AIMS: Long-term results on hepatitis B virus (HBV) reactivation in patients with resolved infection during anti-cancer therapy are unknown. This study investigated long-term risk and therapeutic endpoints including hepatitis B surface antigen (HBsAg) seroclearance following antiviral therapy in patients developing reactivation of resolved HBV. METHODS: The study included 528 consecutive HBsAg-negative/hepatitis B core antibody-positive patients who underwent rituximab treatment or hematopoietic stem cell transplantation (HSCT) between 2006 and 2016. Long-term outcomes of patients with reactivation after antiviral therapy were examined in comparison with 37 HBsAg-positive chronic carriers under the same medical settings. RESULTS: The 7-year cumulative rate of HBV reactivation was 10.8% and 57.9% in patients receiving rituximab treatment and HSCT, respectively. After antiviral initiation, patients with reactivation of resolved HBV showed significantly higher 1-year cumulative rates of hepatitis B e antigen seroconversion (69.2% vs. 22.6%, P = 0.008) and HBsAg seroclearance (61.8% vs. 3.3%, P < 0.001) than chronic HBsAg carriers. Reactivation of resolved HBV was independently predictive of HBsAg seroclearance in a combined group of reactivated patients and chronic HBsAg carriers. Low viral load at reactivation was predictive of HBsAg seroclearance in reactivated patients. The majority of patients with HBsAg seroclearance developed anti-HBs. None of the reactivated patients who achieved HBsAg seroclearance relapsed after cessation of antiviral therapy. CONCLUSIONS: HBsAg seroclearance rapidly occurs following antiviral therapy for reactivation of resolved HBV infection, suggesting distinct clinical phenotypes as well as shorter duration of HBV infection associated with this particular disease setting-HBV reactivation.

Efficacy and Safety of Tenofovir Disoproxil Fumarate in Treatment-Naïve Patients with Chronic Hepatitis B in Korea.

AIMS: To evaluate the efficacy and safety of 144-week tenofovir disoproxil fumarate (TDF) therapy in treatment-naïve chronic hepatitis B (CHB) patients in Korean. METHODS: In total, 579 treatment-naïve CHB patients at 11 medical centers were enrolled retrospective and prospective from September 2015 to January 2016 by design (NCT02533544). We evaluated the complete virologic response (CVR) rate and the renal safety of TDF. RESULTS: The overall CVR rate was 69.4%, 87.0%, and 89.7% at weeks 48, 96, and 144, respectively. In the HBeAg-positive CHB patients, the CVR rate at weeks 48, 96, and 144 was 61.4%, 83.1%, and 89.6%, respectively. The rates of HBeAg loss and seroconversion at weeks 48, 96, and 144 were 16.6%, 23.5%, 34.1%, and 7.6%, 8.9%, 13.3%, respectively. In HBeAg-negative CHB patients, the CVR rate at weeks 48, 96, and 144 was 82.5%, 93.2%, and 90.0%, respectively. The rate of alanine aminotransferase normalization was 36.9%, 45.4%, and 46.8% at weeks 48, 96, and 144, respectively. Of the CHB patients, 0.9% showed an elevated creatinine (> 0.5 mg/dL from baseline). Age (≥ 60 years) was significantly associated with a decline in renal function at week 144 (P < 0.0001). Comorbidities (diabetes or hypertension) showed the tendency to reduce renal function (P = 0.0624). Hepatocellular carcinoma developed in 10 (1.7%) patients and was related to cirrhosis. CONCLUSIONS: TDF therapy induced sustained viral suppression and had a favorable safety profile over a 3-year period. However, close monitoring of renal function should be mandatory in treating CHB patients receiving TDF, particularly older patients.

A pilot study of autologous CD34-depleted bone marrow mononuclear cell transplantation via the hepatic artery in five patients with liver failure.

BACKGROUND AIMS: Many rodent experiments and human studies on stem cell therapy have shown promising therapeutic approaches to liver diseases. We investigated the clinical outcomes of five patients with liver failure of various causes who received autologous CD34-depleted bone marrow-derived mononuclear cell (BM-MNC) transplantation, including mesenchymal stromal cells, through the hepatic artery. METHODS: CD34-depleted BM-MNCs were obtained from five patients waiting for liver transplantation by bone marrow aspiration and using the CliniMACS CD34 Reagent System (Miltenyi Biotech, Bergisch Gladbach, Germany), and autologous hepatic artery infusion was performed. The causes of hepatic decompensation were hepatitis B virus (HBV), hepatitis C virus (HCV), propylthiouracil-induced toxic hepatitis and Wilson disease. RESULTS: Serum albumin levels improved 1 week after transplantation from 2.8 g/dL, 2.4 g/dL, 2.7 g/dL and 1.9 g/dL to 3.3 g/dL, 3.1 g/dL, 2.8 g/dL and 2.6 g/dL. Transient liver elastography data showed some change from 65 kPa, 33 kPa, 34.8 kPa and undetectable to 46.4 kPa, 19.8 kPa, 29.1 kPa and 67.8 kPa at 4 weeks after transplantation in a patient with Wilson disease, a patient with HCV, and two patients with HBV. Ascites decreased in two patients. One of the patients with HBV underwent liver transplantation 4 months after the infusion, and the hepatic progenitor markers (cytokeratin [CD]-7, CD-8, CD-9, CD-18, CD-19, c-Kit and epithelial cell adhesion molecule [EpCAM]) were highly expressed in the explanted liver. CONCLUSIONS: Serum albumin levels, liver stiffness, liver volume, subjective healthiness and quality of life improved in the study patients. Although these findings were observed in a small population, the results may suggest a promising future for autologous CD34-depleted BM-MNC transplantation as a bridge to liver transplantation in patients with liver failure.

RPL36 as a prognostic marker in hepatocellular carcinoma.

Ribosomal proteins (RP) play key roles in the regulation of apoptosis, multidrug resistance and carcinogenesis. The aim of this study was to investigate the expression of ribosomal protein L36 (RPL36) in hepatocellular carcinoma (HCC) and to correlate it with clinicopathological parameters and clinical outcome. Liver specimens were obtained from 60 HCC patients who had undergone a partial hepatectomy. Expression of RPL36 in tumor tissue and surrounding non-tumorous tissues was evaluated on a tissue microarray by immunohistochemistry. RPL36 was expressed in 45 of 60 (75%) HCC by immunohistochemistry, but was not detected in corresponding non-tumors. RPL36 expression correlated significantly with serum levels of albumin (P= 0.044) and prothrombin time (P= 0.026), which reflect liver synthetic function. Moreover, expression of RPL36 was found to be higher in patients with early tumor stages (I/II) (P= 0.038) or without portal vein thrombosis (P= 0.005). In univariate analysis, patients with RPL36 expression revealed better overall survival (P= 0.037). By multivariate survival analysis, RPL36 expression was found to be an independent prognostic factor for overall survival (P= 0.026). Our data suggest that RPL36 may be involved in the early stage of hepatocarcinogenesis, and it can be used as an independent and potential prognostic marker for resected HCC.

Frequency of killer cell immunoglobulin-like receptors (KIRs) in Korean patients with chronic HCV infection.

Natural killer (NK) cells play an important role in innate immunity, especially in the response to viral infections, such as hepatitis C virus (HCV). Killer cell immunoglobulin-like receptors (KIRs) are the primary receptors of NK cells that mediate innate immunity. KIRs are also involved in acquired immunity, because some KIRs are expressed on the surface of certain subsets of T cells. In this study, the frequency of KIR genes, HLA-C allotypes, and combinations of KIR genes with their HLA-C ligands were evaluated in two different groups of the Korean population: controls and patients with chronic HCV infection. The study population consisted of 147 Korean patients with chronic HCV infection. The frequency of KIR2DS2 in patients with chronic HCV infection was 9.5% which was significantly lower than 19.5% of the control (P < 0.01). However, there were no significant differences in the frequency of other KIR genes, HLA-C allotypes or different combinations of KIR genes with their HLA-C ligands. This study can contribute to the further prospective study with a larger scale, suggesting the assumption that KIR2DS2 might aid in HCV clearance by enhancing both the innate and acquired immune responses of people in Korea.

Hepatitis B virus load in serum does not reflect histologic activity in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Little is known about whether histologic data can predict which patients with hepatitis B virus (HBV)-related decompensated cirrhosis will respond to antiviral therapies. We assessed the relationship between serum HBV DNA load and histologic activity by analyzing liver specimens from patients with decompensated cirrhosis. METHODS: The study included 72 consecutive patients who underwent liver transplantation for HBV-related decompensated cirrhosis between November 2000 and March 2008. None of the patients had received nucleoside or nucleotide analogues more than 2 weeks before transplantation. Serum HBV DNA levels at the time of transplantation were compared with histologic activity in explanted liver specimens. RESULTS: The median HBV DNA level of the 72 patients was 5.40 log(10) copies/mL (range, 1.45-8.00 log(10) copies/mL). There were no differences in HBV DNA level between patients grouped according to lobular or portoperiportal activity (P = .678, P = .291, respectively). Of 16 patients (22.2%) with HBV DNA levels less than 2000 copies/mL, 8 patients (50.0%) had moderate or severe portoperiportal activity; their median alanine aminotransferase level was 30.5 U/L (range, 12-135 U/L). CONCLUSIONS: HBV DNA load does not reflect histologic activity in patients with HBV-related decompensated cirrhosis. Although patients with decompensated cirrhosis might have normal levels of alanine aminotransferase and a low level of viremia (<2000 copies/mL), they still can have significant portoperiportal activity.

Impact of serial hepatitis B virus DNA on hepatocellular carcinoma development in patients with liver cirrhosis.

OBJECTIVES: We investigated the pattern of serial HBV DNA levels in known cirrhosis patients and its impact on the development of hepatocellular carcinoma (HCC). METHODS: We analyzed a retrospective case/control study based on 352 HCC patients associated with HBV between 2005 and 2007. Prior to HCC development, 49 cirrhosis patients were tested for HBV DNA levels more than once a year (median 4 times) during the follow-up period. Ninety-eight consecutive cirrhosis patients without HCC, matched for age, sex and HBe Ag status were included as controls. Eighty-three patients in both groups had undergone antiviral therapy. RESULTS: In cirrhosis, the most common HBV DNA pattern was fluctuating (33.3%), followed by persistently high (> or =10(4) copies/ml, 23.8%). Compared to a persistently low pattern (<10(4) copies/ml), the relative risks of HCC in patients with persistently high and fluctuating patterns were 2.650 and 1.475. At multivariate analysis, a persistently high pattern was an independent risk factor for HCC (hazard ratio 3.135). Patients with sustained HBV DNA suppression during antiviral therapy were less likely to develop HCC than those with viral breakthrough/nonresponse. CONCLUSIONS: This study showed that persistent suppression of HBV DNA is also important to prevent the development of HCC in known cirrhosis patients.

Real-World Outcomes of Nivolumab in Patients With Unresectable Hepatocellular Carcinoma in an Endemic Area of Hepatitis B Virus Infection.

Real-world results of nivolumab monotherapy against HCC are lacking in the hepatitis B virus (HBV)-endemic, Asia-Pacific regions. Moreover, heterogeneous responses to immune checkpoint inhibitors have rarely been described in advanced HCC. The aim of this study is to evaluate the efficacy and safety of nivolumab monotherapy in a real-world setting in 33 Korean patients with unresectable HCC. In our cohort, twenty-nine patients (88%) showed HBsAg positivity. At the time of nivolumab initiation, 4 among 33 patients (12%) were classified as Barcelona Clinic Liver Cancer (BCLC)-B stage and 29 (88%) as BCLC-C stage, respectively. Prior sorafenib treatment was given to 31 (94%) patients, and 13 (39%) received prior regorafenib treatment. For the liver reserve, patients were classified as Child-Pugh class A (79%) and B (21%), respectively. Grade 3 toxicities occurred in one patient, who developed pneumonitis after 5 cycles of nivolumab treatment. Best overall responses were complete response in 2 patients out of the 33 enrolled patients (6%), partial response in 4 patients (12%) and stable disease in 4 patients (12%). With 29 patients having images for the response evaluation, the objective response rate was 21.4%. The median overall survival (OS) of the cohort was 26.4 weeks (range 2.3-175.1). Achieving objective responses, pre-treatment small tumors (maximal diameter <5 cm) and favorable liver function as assessed by Albumin-Bilirubin grade were significant factors for the favorable OS. Interestingly, differential responses to nivolumab among multiple tumors in a single patient were noted in 6 patients (18%). In these patients, small metastatic tumors were regressed, although their larger tumors did not respond to nivolumab monotherapy. In summary, nivolumab treatment seems clinically efficacious in treating unresectable HCC in an endemic area of HBV infection. Further prospective evaluation is required to overcome the heterogeneous efficacy of nivolumab monotherapy according to the baseline tumor burden.

[A case of rhabdomyolysis during hospitalization for acute hepatitis A].

A 29-year-old man was admitted to hospital with fever, myalgia, and sore throat. Initial laboratory findings were compatible with acute hepatitis; he was positive for the serologic marker for acute hepatitis A. On the 3rd day of admission, in spite of normalization of body temperature and a reduction in serum liver enzyme levels, serum levels of creatinine phosphokinase had increased up to 16,949 U/L. The patient recovered with supportive therapy and was discharged on the 12th day. We report a case of acute hepatitis A complicated by rhabdomyolysis during hospitalization.

Inflammatory cytokines and change of Th1/Th2 balance as prognostic indicators for hepatocellular carcinoma in patients treated with transarterial chemoembolization.

Tumor-associated immune response plays a critical role in cancer pathogenesis. This study evaluated clinical implications of T cell cytokines and regulatory T cells (Tregs) in HCC patients treated with TACE. Whole blood was obtained for analysis of T cell cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-22, IFN-γ, and TNF-α) and Tregs from 142 HCC patients. Patients with CTP class A had a significantly lower proportion of detectable IL-4 or IL-6, but a higher proportion of detectable IL-22 than patients with CTP class B/C. IL-6 level was well correlated with tumor stage and undetectable IL-17A was associated with extrahepatic metastasis. The overall survival rate was significantly higher in patients who had undetectable IL-6 or detectable IL-22 than patients who did not. IL-6 among cytokines remained independently predictive factor for survival. Increased IFN-γ/IL-10 ratio and no increase in IL-6 level following TACE were associated with prolonged survival, and baseline Tregs could affect Th1/Th2 balance. T cell cytokines are associated with a variety of clinical aspects of HCC, and IL-6 is the most significant predictor of survival. A shift toward increased Th1 response and no increase in IL-6 level exert favorable immunologic effects on HCC prognosis.

Role of long-term lamivudine treatment of hepatitis B virus recurrence after liver transplantation.

In this study, the long-term (>3 years) efficacy of combination therapy for hepatitis B virus (HBV) recurrence and the associated factors were investigated. One hundred and sixty-five consecutive HBsAg-positive patients (92 with liver cirrhosis, 73 with hepatocellular carcinoma; HCC) who underwent liver transplantation were assessed with a median follow-up time of 40 months. One hundred and twenty-one patients (121/165, 73.3%) were treated with lamivudine before transplantation for a mean of 8.4 months (range 0.1-72 months). The post-transplantation treatment protocol consisted of a high dose intravenous hepatitis B immunoglobulin (HBIg) followed by a low dose intramuscular HBIg and lamivudine combination therapy. Seven (4.2%, 7/165) recipients experienced HBV recurrence at a median time of 19 months (range 5-36 months) following transplantation. Six of seven cases of HBV recurrence were treated with lamivudine before transplantation for a median period of 15 months (range 0.6-30 months). Eighteen (24.6%, 18/73) patients had HCC recurrences after transplantation. Of the four patients with both HCC and HBV recurrence, three experienced HBV recurrence after recurrence of HCC. The clinical factor associated with HBV recurrence in the total cohort (n = 165) was the duration of antiviral treatment (over 6 months) before transplantation (P = 0.004). In the HCC group, HCC recurrence after transplantation (P = 0.002), tumor burden before transplantation (P = 0.005), and postoperative adjuvant chemotherapy (P = 0.002), were additional factors for HBV recurrence. Combination therapy of HBIg and antiviral drugs was effective over 3 years regardless of the pretransplantation viral load. However, the possible recurrence of HBV needs to be monitored cautiously in patients treated with long-term (over 6 months) lamivudine.

Transarterial infusion of epirubicin and cisplatin combined with systemic infusion of 5-fluorouracil versus transarterial chemoembolization using doxorubicin for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a retrospective analysis.

BACKGROUND: More than one-third of hepatocellular carcinoma (HCC) patients are diagnosed at advanced stage with portal vein tumor thrombosis (PVTT) or extrahepatic metastasis. However, the outcomes of current therapeutic approaches are unsatisfactory. As a novel therapeutic strategy for unresectable HCC with PVTT, we analyzed the outcomes of transarterial infusion of epirubicin and cisplatin combined with systemic infusion of 5-fluorouracil (TAC-ECF) and compared its therapeutic effects and toxicity with transarterial chemoembolization (TACE) using doxorubicin (DOX). METHODS: A total of 540 consecutive HCC patients who received TACE at the Catholic Medical Center between January 2007 and November 2013 were enrolled. Of these patients, we retrospectively analyzed 129 Barcelona clinic liver cancer stage C HCC patients with PVTT who received either TAC-ECF or TACE using DOX. RESULTS: The objective tumor response rate was higher in the TAC-ECF group, with 31.3% objective response rate after TAC-ECF compared to 10% after DOX treatment (p = 0.004). Median follow-up period was 7 months (range, 1-57 months). The overall survival rate was also significantly higher in the TAC-ECF group compared to the DOX group (median 9.3 versus 4.6 months, p < 0.0001). Multivariate analysis revealed that TAC-ECF and extrahepatic metastasis were independent predictive factors for overall survival (p < 0.0001 and p = 0.002 respectively). No serious adverse effects developed in both groups. CONCLUSIONS: TAC-ECF therapy was tolerable and showed higher overall survival rate and tumor response compared to the conventional TACE DOX in advanced stage HCC patients with PVTT. Therefore, TAC-ECF may be considered as an effective treatment option for patients with unresectable HCC.

Early treatment response to transcatheter arterial chemoembolization is associated with time to the development of extrahepatic metastasis and overall survival in intermediate-stage hepatocellular carcinoma.

PURPOSE: Transcatheter arterial chemoembolization (TACE) is the treatment of choice for intermediate-stage hepatocellular carcinoma (HCC). The absence of an early response to TACE might indicate alternative therapeutic strategies early in the course of the disease, thus improving outcomes. Therefore, our purpose was to identify the relationship between treatment response after two sessions of TACE and the time to the development of extrahepatic metastasis and overall survival. METHODS: In total, 108 treatment-naïve intermediate-stage HCC patients who received at least two consecutive sessions of TACE as the first-line treatment were analyzed. RESULTS: The median follow-up duration was 28.5 months. Extrahepatic metastasis developed in 32 patients (29.6%). Patient age >60 years (P = 0.027), alpha-fetoprotein (AFP) >200 ng/ml (P = 0.039), and objective response after two TACE treatments (P = 0.001) were the predictive factors for time to the development of metastasis. The median survival time for the patients who achieved objective response after two sessions of TACE was 45.9 and 14.4 months for the patients who failed to achieve objective response (P = 0.0001). Objective response after two TACE treatments (P = 0.0001) and the occurrence of extrahepatic metastasis (P = 0.002) were associated with overall survival. CONCLUSIONS: Early objective tumor response after two sessions of TACE was associated with prolonged time to metastasis and improved survival. Therefore, surveillance for metastasis should be performed more frequently when an objective response is not obtained after two sessions of TACE and in younger intermediate-stage HCC patients with high AFP levels.

Reactivation of Hepatitis C Virus and Its Clinical Outcomes in Patients Treated with Systemic Chemotherapy or Immunosuppressive Therapy.

BACKGROUND/AIMS: According to the results of several studies, the outcome of hepatitis C virus (HCV) reactivation is not as severe as the outcome of hepatitis B virus reactivation. The aim of this study was to evaluate the effect of pharmacological immunosuppression on HCV reactivation. METHODS: The medical records of patients who underwent systemic chemotherapy, corticosteroid therapy, or other immunosuppressive therapies between January 2008 and March 2015 were reviewed. Subsequently, 202 patients who were seropositive for the anti-HCV antibody were enrolled. Exclusion criteria were: unavailability of data on HCV RNA levels, a history of treatment for chronic hepatitis C, and the presence of liver diseases other than a chronic HCV infection. RESULTS: Among the 120 patients enrolled in this study, hepatitis was present in 46 patients (38%). None of the patients were diagnosed with severe hepatitis. Enhanced replication of HCV was noted in nine (27%) of the 33 patients who had data available on both basal and follow-up HCV RNA loads. Reappearance of the HCV RNA from an undetectable state did not occur after treatment. The cumulative rate of enhanced HCV replication was 23% at 1 year and 30% at 2 years. CONCLUSIONS: Although enhanced HCV replication is relatively common in HCV-infected patients treated with chemotherapy or immunosuppressive therapy, it does not lead to serious sequelae.

[Clinical and biochemical parameters of nutrition to predict hepatic encephalopathy in cirrhotic patients].

BACKGROUND/AIMS: Protein-calorie malnutrition is a common complication in cirrhosis. Protein restriction for the treatment of hepatic encephalopathy (HE) may cause disease progression and poor prognosis. Therefore, we evaluated important clinical parameters for nutritional state in cirrhotic patients with or without HE to predict the development of HE. METHODS: Twenty-two cirrhotic patients were divided into two groups; group A-13 patients without HE and group B-9 patients with HE. Clinical and biochemical parameters, serum proteins {serum albumin, insulin-like growth factor-1 (IGF-1), transferrin, leptin, etc}, immunologic parameters and anthropometry were measured. RESULTS: Child-Pugh score and Model for End-stage Liver Disease (MELD) scale were higher in group B (p<0.01). After correction of various factors affecting nutritional assessment, especially of Child-Pugh score and MELD scale, leptin was higher in group B (p<0.05). There was no difference in anthropometric measurements. Transferrin correlated inversely with MELD scale in group A (p<0.01). IGF-1 correlated inversely with total lymphocyte count in group B (p<0.05). Leptin correlated with Child-Pugh scores, total lymphocyte count and mid-arm muscle circumference in group A (p<0.05, p<0.05 and p<0.05, respectively), and correlated inversely with CD8 in group B (p<0.05). CONCLUSIONS: Leptin level is higher in patients with HE, and further studies for parameters of nutrition to predict HE in many cirrhotic patients will be needed.