Pretransplant Functional Status Predicts Postoperative Morbidity and Mortality after Liver Transplantation in Patients with Cirrhosis

Background/Aims@#This study aimed to investigate whether pretransplant frailty can predict postoperative morbidity and mortality after liver transplantation (LT) in patients with cirrhosis. @*Methods@#We retrospectively reviewed 242 patients who underwent LT between 2018 and 2020 at a tertiary hospital in Korea. @*Results@#Among them, 189 patients (78.1%) received LT from a living donor. Physical frailty at baseline was assessed by the Short Physical Performance Battery (SPPB), by which patientswere categorized into two groups: frail (SPPB <10) and non-frail (SPPB ≥10). Among the whole cohort (age, 55.0±9.2 years; male, 165 [68.2%]), 182 patients were classified as non-frail and 60 patients were classified as frail. Posttransplant survival was shorter in the frail group than the non-frail group (9.3 months vs 11.6 months). Postoperative intensive care unit stay was longer in the frail group than in the non-frail group (median, 6 days vs 4 days), and the 30-day complication rate was higher in the frail group than in the non-frail group (78.3% vs 59.3%). Frailty was an independent risk factor for posttransplant mortality (adjusted hazard ratio, 2.38; 95% confidence interval, 1.02 to 5.57). In subgroup analysis, frail patients showed lower posttransplant survival regardless of history of hepatocellular carcinoma and donor type. @*Conclusions@#Assessment of pretransplant frailty, as measured by SPPB, provides important prognostic information for clinical outcomes in cirrhotic patients undergoing LT.

Clinical Outcomes and Validation of Ursodeoxycholic Acid Response Scores in Patients with Korean Primary Biliary Cholangitis: A Multicenter Cohort Study

Background/Aims@#The ursodeoxycholic acid (UDCA) response score (URS) was developed to identify poor responders to UDCA before treatment, in order to offer timely and proactive intervention. However, validation of the URS in Asian population is warranted. @*Methods@#A total of 173 Asian patients diagnosed with primary biliary cholangitis (PBC) between 2007 and 2016 at seven academic institutions in Korea who started UDCA treatment were analyzed to validate the performance of URS. UDCA response was defined as an alkaline phosphatase level less than 1.67 times the upper limit of normal after 1-year of UDCA treatment. In addition, prognostic performance of URS for liver-related events, defined as newly developed hepatic decompensation or hepatocellular carcinoma was evaluated. @*Results@#After 1 year of UDCA treatment, 133 patients (76.9%) achieved UDCA response. UDCAresponse rate was 98.7% for those with URS ≥1.41 (n=76) and 58.8% for those with URS <1.41(n=97). The area under the receiver operating characteristic curve of URS in predicting UDCAresponse was 0.84 (95% confidence interval, 0.78 to 0.88). During a median follow-up of 6.5years, liver-related events developed in 18 patients (10.4%). Among 117 patients with PBC stage I-III by histological evaluation, the 5-year liver-related event-free survival rate differed accordingto the URS; 100% for URS ≥1.41 and 86.5% for URS <1.41 (p=0.005). @*Conclusions@#URS demonstrated good performance in predicting a UDCA treatment response in Asian PBC patients. In addition, the risk of liver-related events differed according to the URS for the PBC stage. Thus, URS can be used to predict the response and clinical outcome in patients with PBC.

Prognostic Value of Alpha-Fetoprotein in Patients Who Achieve a Complete Response to Transarterial Chemoembolization for Hepatocellular Carcinoma

Purpose@#Alpha-fetoprotein (AFP) is a prognostic marker for hepatocellular carcinoma (HCC). We investigated the prognostic value of AFP levels in patients who achieved complete response (CR) to transarterial chemoembolization (TACE) for HCC. @*Materials and Methods@#Between 2005 and 2018, 890 patients with HCC who achieved a CR to TACE were recruited. An AFP responder was defined as a patient who showed elevated levels of AFP (>10 ng/mL) during TACE, but showed normalization or a >50% reduction in AFP levels after achieving a CR. @*Results@#Among the recruited patients, 569 (63.9%) with naïve HCC and 321 (36.1%) with recurrent HCC after complete resection were treated. Before TACE, 305 (34.3%) patients had multiple tumors, 219 (24.6%) had a maximal tumor size >3 cm, and 22 (2.5%) had portal vein tumor thrombosis. The median AFP level after achieving a CR was 6.36 ng/mL. After a CR, 473 (53.1%) patients experienced recurrence, and 417 (46.9%) died [median progression-free survival (PFS) and overall survival (OS) of 16.3 and 62.8 months, respectively]. High AFP levels at CR (>20 ng/mL) were independently associated with a shorter PFS [hazard ratio (HR)=1.403] and OS (HR=1.284), together with tumor multiplicity at TACE (HR=1.518 and 1.666, respectively). AFP non-responders at CR (76.2%, n=359 of 471) showed a shorter PFS (median 10.5 months vs. 15.5 months, HR=1.375) and OS (median 41.4 months vs. 61.8 months, HR=1.424) than AFP responders (all p=0.001). @*Conclusion@#High AFP levels and AFP non-responders were independently associated with poor outcomes after TACE. AFP holds clinical implications for detailed risk stratification upon achieving a CR after TACE.

Radiation-induced abscopal effect and its enhancement by programmed cell death 1 blockade in the hepatocellular carcinoma: A murine model study

Background/Aims@#The abscopal effect, a rare phenomenon induced by radiation, can be reinforced by immunotherapy. Although radiation therapy and immunotherapy are increasingly being utilized for the treatment of hepatocellular carcinoma (HCC), whether immunotherapy could boost the abscopal effect remains unclear. In this study, we aimed to elucidate the immunological mechanisms underlying the abscopal effect induced by the combination of irradiation and immunotherapy in a murine HCC model. @*Methods@#A syngeneic HCC mouse model was established by transplanting murine Hepa 1–6 HCC cells into both hind legs of immunocompetent C57BL/6 mice. The tumors on the right hind legs were irradiated, and abscopal effects were observed in the non-irradiated tumors on the left hind leg with or without the coadministration of anti-programmed cell death 1 (PD-1) antibodies. Flow cytometric analyses were performed to analyze the distributions of immune cells infiltrating both irradiated and non-irradiated tumors and the tumor-draining lymph nodes (TDLNs). @*Results@#Administration of 16 Gy in two fractions more effectively inhibited the growth of both irradiated and nonirradiated tumors with higher tumor infiltration of cytotoxic T cells than 8 Gy did in a single fraction. The higher dose also increased activated dendritic cells in TDLNs, which had higher expression of the programmed cell death ligand 1. Coadministration of anti-PD-1 antibodies significantly enhanced the abscopal effect and increased infiltration of activated cytotoxic T cells in both irradiated and non-irradiated tumors. @*Conclusions@#Our findings show that adding anti-PD-1 therapy to radiation enhanced the abscopal effect in a syngeneic murine model of HCC.

Proton Pump Inhibitor Use Increases Pyogenic Liver Abscess Risk: A Nationwide Cohort Study

Background/Aims@#Proton pump inhibitors (PPIs) increase gastric pH and alter the gut microbiome. An increased risk for infectious diseases has been reported in PPI users. However, little is known about the association of PPI use with pyogenic liver abscess (PLA) incidence risk. @*Methods@#We conducted a population-based cohort study using data from a nationwide representative sample of the Korean general population followed up for 10 years (January 1, 2003 to December 31, 2013). We identified PPI prescriptions and considered PPI as a timevarying variable. Proportional hazards regression model was used for incident PLA comparing PPI use versus non-use. Propensity score matching was also conducted. @*Results@#During the 4 209 229 person-years of follow-up, 58 595 participants had at least 1 PPI prescription and 541 patients developed liver abscess. The age-, sex-, residential area-, and income-adjusted hazard ratio for PLA incidence with PPI use was 4.19 (95% CI, 2.54-6.92). The association was observed in fully adjusted models (hazard ratio 3.88; 95% CI, 2.33-6.44). The positive association between PPI use and PLA was consistent in all subgroups analyzed and in propensity score matching group. @*Conclusion@#The present data indicate that PPI use is associated with an increased PLA risk. Therefore, it is necessary to prescribe PPIs with clear indication and to avoid improper use of PPIs.

Proton Pump Inhibitor Use Increases Pyogenic Liver Abscess Risk: A Nationwide Cohort Study

Background/Aims@#Proton pump inhibitors (PPIs) increase gastric pH and alter the gut microbiome. An increased risk for infectious diseases has been reported in PPI users. However, little is known about the association of PPI use with pyogenic liver abscess (PLA) incidence risk. @*Methods@#We conducted a population-based cohort study using data from a nationwide representative sample of the Korean general population followed up for 10 years (January 1, 2003 to December 31, 2013). We identified PPI prescriptions and considered PPI as a timevarying variable. Proportional hazards regression model was used for incident PLA comparing PPI use versus non-use. Propensity score matching was also conducted. @*Results@#During the 4 209 229 person-years of follow-up, 58 595 participants had at least 1 PPI prescription and 541 patients developed liver abscess. The age-, sex-, residential area-, and income-adjusted hazard ratio for PLA incidence with PPI use was 4.19 (95% CI, 2.54-6.92). The association was observed in fully adjusted models (hazard ratio 3.88; 95% CI, 2.33-6.44). The positive association between PPI use and PLA was consistent in all subgroups analyzed and in propensity score matching group. @*Conclusion@#The present data indicate that PPI use is associated with an increased PLA risk. Therefore, it is necessary to prescribe PPIs with clear indication and to avoid improper use of PPIs.

Advanced Stage Hepatocellular Carcinoma Successfully Treated with Transarterial Radioembolization and Multi-tyrosine Kinase Inhibitor Therapy

Transarterial radioembolization (TARE) with yttrium-90 microspheres has become widely utilized in managing hepatocellular carcinoma (HCC). The utility of TARE is expanding with new insights through experiences from real-world practice and clinical trials, and recently published data suggest that TARE in combination with sorafenib may improve the overall survival in selected patients. Here, we report a case of advanced stage HCC that was successfully treated with TARE and sorafenib. The patient achieved complete response (CR) at 12 months after the initial treatment with TARE and sorafenib, followed by additional transarterial chemoembolization and proton beam therapy for local tumor recurrence at 19-month post-TARE. The patient was followed up every 3 months thereafter and still achieved CR both biochemically and radiologically for the following 12 months. A combination strategy of TARE and systemic therapy may be a useful alternative treatment option for selected patients with advanced stage HCC.

Substantial risk of recurrence even after 5 recurrence-free years in early-stage hepatocellular carcinoma patients

Background/Aims@#Although hepatocellular carcinoma (HCC) is notorious for its high recurrence rate, some patients do not experience recurrence for more than 5 years after resection or radiofrequency ablation for early-stage HCC. For those with five recurrence-free period, the risk of HCC recurrence within the next 5 years remains unknown. @*Methods@#A total of 1,451 consecutive patients (median, 55 years old; males, 79.0%; hepatitis B virus-related, 79.3%) with good liver function (Child-Pugh class A) diagnosed with early-stage HCC by Barcelona Clinic Liver Cancer Staging and received radiofrequency ablation or resection as an initial treatment between 2005 and 2010 were analyzed. @*Results@#During a median follow-up period of 8.1 years, 961 patients (66.2%) experienced HCC recurrence. The cumulative recurrence rates increased to 39.7%, 60.3%, and 71.0% at 2, 5, and 10 years, respectively, and did not reach a plateau. Five years after HCC diagnosis, 487 patients were alive without experiencing a recurrence. Among them, during a median of 3.9 additional years of follow-up (range, 0.1–9.0 years), 127 patients (26.1%) experienced recurrence. The next 5-year cumulative recurrence rate (5–10 years from initial diagnosis) was 27.0%. Male sex, higher fibrosis-4 scores, and alpha-fetoprotein levels at 5 years were associated with later HCC recurrence among patients who did not experience recurrence for more than 5 years. @*Conclusions@#The HCC recurrence rate following 5 recurrence-free years after HCC treatment was high, indicating that HCC patients warrant continued HCC surveillance, even after 5 recurrence-free years.

Real world data on follicular lymphoma patients treated by rituximab-containing immunochemotherapy and rituximab maintenance

Background/Aims@#Real-world data about the treatment outcomes of patients receiving rituximab-containing immunochemotherapy followed by rituximab maintenance are required to understand better the treatment for follicular lymphoma (FL). @*Methods@#A cross-sectional study analyzed FL patients who were treated with R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab maintenance. @*Results@#Of 139 patients, 85 patients received R-CVP and 54 received R-CHOP. The characteristics did not differ significantly between the groups. Only grade 3 of FL was more common in R-CHOP. The complete response rate did not differ significantly between R-CHOP (50/54, 92.6%) and R-CVP (77/85, 90.6%). The number of disease relapses during rituximab maintenance did not differ significantly between the groups (p = 0.798). Therefore, the comparison of progression-free survival (PFS) showed no significant difference: the 3-year PFS rates for R-CVP and R-CHOP were 77% and 85%, respectively (p = 0.567). Although five of 56 hepatitis B virus (HBV) core antibody (anti-HBc)-positive patients experienced HBV reactivation, all cases of HBV reactivation were identified during regular monitoring for HBV DNA in blood, and were successfully managed with antiviral treatment. @*Conclusions@#The survival outcomes of FL patients on rituximab maintenance after responding to R-CVP or R-CHOP were similar. Rituximab-containing immunochemotherapy followed by rituximab maintenance can be safely used for anti-HBc-positive patients if HBV DNA titer in blood can be regularly monitored.

Potential etiology, prevalence of cirrhosis, and mode of detection among patients with non-B non-C hepatocellular carcinoma in Korea

Background/Aims@#We systematically evaluated the clinical characteristics, prevalence of cirrhosis, and mode of detection in virus-unrelated (non-B non-C, NBNC) hepatocellular carcinoma (HCC) patients in Korea. @*Methods@#A total of 447 consecutive treatment-naïve NBNC-HCC adult patients who were registered at the Samsung Medical Center HCC registry in Korea from 2010 to 2013 were analyzed. NBNC was defined as negative hepatitis B surface antigen and negative anti-hepatitis C virus antibody. Presence of cirrhosis was determined based on histological, radiological, endoscopic, and serologic results. Mode of detection was classified as either under surveillance, incidental, or symptomatic. @*Results@#Heavy alcohol use was the most common potential etiology in NBNCHCC (NBNC-A, alcohol) (59.7%). Ten patients had other identifiable causes (NBNC-O, other identifiable cause) such as autoimmune hepatitis. The rest (38.0%) had no-identifiable cause (NBNC-NA-NO, non-alcohol, no-other identifiable cause). In NBNC-NA-NO group, 83.5% (96/115) of patients with available hepatitis B core immunoglobulin G antibody (HBcIgG) showed HBcIgG positivity, and 80.6% (137/170) had metabolic risk factors (diabetes, obesity, hypertension, and/ or dyslipidemia). Cirrhosis was present in 90.0%, 70.4%, and 60.0% of NBNC-O, NBNC-A, and NBNC-NA-NO patients, respectively. The proportion of patients diagnosed under surveillance was 25.5% across all patients, with specific proportions being 80.0%, 27.7%, and 18.8% for NBNC-O, NBNC-A, and NBNC-NA-NO, respectively. @*Conclusions@#Among NBNC-HCC patients, heavy alcohol use or any other identifiable cause was not found in 38.0%. These NBNC-NA-NO HCC patients showed a high prevalence of HBcIgG positivity and metabolic risk factors, suggesting that prior hepatitis B virus infection and metabolic risk factors may be major contributing factors in the hepatocarcinogenesis in NBNC-NA-NO patients.

Comparison of outcome between liver resection, radiofrequency ablation, and transarterial therapy for multiple small hepatocellular carcinoma within the Milan criteria

Purpose@#Although surgical resection is usually considered for a single tumor, several reports have suggested that resection can be considered for multiple tumors. The objective of this study was to determine whether resection could provide better long-term outcome for patients with multiple hepatocellular carcinomas (HCCs) within Milan criteria. @*Methods@#A total of 276 patients with multiple HCCs within Milan criteria with liver function preserved who underwent resection, radiofrequency ablation (RFA), or transarterial chemoembolization (TACE) between 2009 and 2013 were analyzed. Propensity-score (PS) matching was conducted. @*Results@#Five-year overall survival (OS) and recurrence-free survival (RFS) were better in the resection group than that in the RFA or TACE group. Patients who underwent resection had more preserved liver function and different tumor characteristics compared to those received RFA or TACE. With similar baseline characteristics generated in the PS model, there was no difference in 5-year OS among 3 groups (79.5% vs. 72.3% or 62.0%, P = 0.232), but the 5-year RFS was better for patients who received resection than those who received RFA or TACE (51.9% vs. 22.0% or 0.0%, P < 0.001). Although the major complication rate was slightly higher than RFA or TACE, there was no significant difference between the 3 groups before and after PS matching. @*Conclusion@#Resection was associated with better RFS than RFA or TACE and showed comparable OS in multiple HCC patients within the Milan criteria, but at a cost of slightly increased risk of complication. Resection can be considered as a first-line option if selected appropriately.

Initial clinical outcomes of proton beam radiotherapy for hepatocellular carcinoma

PURPOSE: This study aimed to evaluate the initial outcomes of proton beam therapy (PBT) for hepatocellular carcinoma (HCC) in terms of tumor response and safety. MATERIALS AND METHODS: HCC patients who were not indicated for standard curative local modalities and who were treated with PBT at Samsung Medical Center from January 2016 to February 2017 were enrolled. Toxicity was scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Tumor response was evaluated using modified Response Evaluation Criteria in Solid Tumors (mRECIST). RESULTS: A total of 101 HCC patients treated with PBT were included. Patients were treated with an equivalent dose of 62–92 GyE10. Liver function status was not significantly affected after PBT. Greater than 80% of patients had Child-Pugh class A and albumin-bilirubin (ALBI) grade 1 up to 3-months after PBT. Of 78 patients followed for three months after PBT, infield complete and partial responses were achieved in 54 (69.2%) and 14 (17.9%) patients, respectively. CONCLUSION: PBT treatment of HCC patients showed a favorable infield complete response rate of 69.2% with acceptable acute toxicity. An additional follow-up study of these patients will be conducted.

Noninvasive Diagnostic Criteria of the Revised 2014 the Korean Liver Cancer Study Group and the National Cancer Center Guideline for Subcentimetersized Hepatocellular Carcinoma: Is It Too Strict?

BACKGROUND/AIMS: Noninvasive diagnostic criteria for hepatocellular carcinoma (HCC) differ between guidelines, especially for subcentimeter-sized nodules. This study aimed to analyze clinical and radiological characteristics of subcentimeter-sized HCC, and assess the validity of noninvasive diagnostic criteria of the revised 2014 the Korean Liver Cancer Study Group and the National Cancer Center (KLCSG-NCC) guideline for subcentimeter-sized HCC. METHODS: A total of 33 consecutive patients (median age, 58.6 years; men, 60.6%; hepatitis B virus-infected, 87.9%) who were diagnosed with HCC between January 2009 and December 2013 and had a maximum tumor diameter less than 1 cm were retrospectively included. RESULTS: Among 33 subcentimeter-sized HCC cases, 6 cases were histologically proven and the remaining 27 patients were diagnosed by radiologically and/or serologically. Initial detection modality was dynamic contrast-enhanced computed tomography (CT) (66.7%, 22/33) or dynamic contrast-enhanced magnetic resonance imaging (MRI) (33.3% 11/33). No case was identified by surveillance ultrasonography. Typical radiological feature of HCC, which is arterial enhancement with delayed washout, was present in 51.7% (15/29 patients) in dynamic contrast-enhanced CT, and 90.9% (30/33 patients) in dynamic contrast-enhanced MRI. When these 33 cases were re-assessed by the revised 2014 KLCSG-NCC guideline, no one has fulfilled the noninvasive diagnostic criteria. CONCLUSIONS: None of the cases that were diagnosed as subcentimeter-sized HCC including histologically confirmed cases did not fulfill the noninvasive diagnostic criteria of the revised 2014 KLCSG-NCC guideline. Refinement of the current noninvasive diagnostic criteria for subcentimeter-sized HCC may be required.

The role of scheduled second TACE in early-stage hepatocellular carcinoma with complete response to initial TACE

BACKGROUND/AIMS: We investigated the outcomes of early-stage hepatocellular carcinoma (HCC) patients who showed a complete response (CR) to initial transarterial chemoembolization (TACE), with a focus on the role of scheduled TACE repetition. METHODS: A total of 178 patients with early-stage HCC who were initially treated with TACE and showed a CR based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria on one month follow-up computed tomography (CT) were analyzed. Among them, 90 patients underwent scheduled repetition of TACE in the absence of viable tumor on CT. RESULTS: During a median follow-up period of 4.6 years (range: 0.4-8.8 years), mortality was observed in 71 patients (39.9%). The overall recurrence-free and local recurrence-free survival rates at 1 year were 44.4% and 56.2%. In the multivariable model, scheduled repetition of TACE was an independent factor associated with survival (hazard ratio [95% confidence interval]: 0.56 [0.34-0.93], P=0.025). When stratified using Barcelona clinic liver cancer (BCLC) stage, scheduled repetition of TACE was associated with a favorable survival rate in BCLC stage A patients, but not in BCLC 0 patients. CONCLUSIONS: Scheduled repetition of TACE was associated with better survival for early-stage HCC patients showing a CR after initial TACE, especially in BCLC stage A patients.

The Clinical Significance of Serum Alpha-fetoprotein in Diagnosing Hepatocellular Carcinoma in a Health Screening Population / 대한소화기학회지

BACKGROUND/AIMS: Serum alpha-fetoprotein (AFP) measurement is commonly included in a health check-up program in Korea. However, its benefits remain uncertain. We analyzed whether AFP measurement should be included in a general health check-up program to screen for hepatocellular carcinoma (HCC). METHODS: A total of 36,552 adults aged 18 years or older—who participated in a routine health examination including AFP determination between January 2009 and December 2009 at the Health Promotion Center, Samsung Medical Center, South Korea—were analyzed. High risk of HCC was defined as positivity for hepatitis B surface antigen, anti-hepatitis C virus antibody or having liver cirrhosis. RESULTS: AFP level >10 ng/mL was observed in 27 participants (0.1%) and primary liver cancer was diagnosed in 9 patients (6 HCC and 3 cholangiocarcinoma). Among 1,619 participants with high risk factors of HCC, AFP level >10 ng/mL was observed in 16 participants, of which, 4 diagnoses were made. Sensitivity, specificity, positive predictive value, and negative predictive value of AFP for HCC was 0.66, 0.99, 0.25 and 0.99, respectively, for high risk participants. Among 34,933 participants without risk factors for HCC, 11 patients (<0.1%) showed elevated AFP levels above 10 ng/mL, and no case was diagnosed with primary liver cancer during a median follow-up period of 36 months (range: 0-48 months). CONCLUSIONS: AFP elevation was rare in participants without risk factors for HCC, and was unable to screen for HCC in this population. We discourage routine AFP measurements for asymptomatic adults without risk factors of HCC.

A Novel Model for Predicting Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B and Normal Alanine Aminotransferase Levels

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) can develop in chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels. Therefore, methods that can stratify an individual's HCC risk are needed. METHODS: A simple HCC risk score was developed from 971 patients with CHB who had elevated hepatitis B virus DNA levels (>2,000 IU/mL) with normal or mildly elevated ALT levels (<80 U/L). The score was validated from an independent cohort of 507 patients. RESULTS: A 4-point risk scale was developed, with HCC risk ranging from 0% to 17.8% at 5 years for the lowest and highest risk scores. The D2AS score had high area under the receiver operating curves (AUROCs) for predicting development of HCC at 3/5 years (0.895/0.884). The calculated AUROCs to predict the development of HCC at 3/5 years were 0.889/0.876 in the validation cohort, with 5-year HCC incidence rates ranging from 0% to 13.8% at 5 years for the lowest and highest risk scores. CONCLUSIONS: The D2AS risk score can play a valuable role in risk stratification and may be useful for guiding clinical decisions for enhanced surveillance or treatment to reduce the HCC risk in CHB patients with normal or mildly elevated ALT levels.

Cause of Mortality for Hepatocellular Carcinoma Patients who were Diagnosed within the Milan Criteria

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a unique condition where the cause of death might not only be due to progressive cancer, but also from liver failure. We evaluated specific causes of death for HCC patients who were initially diagnosed within the Milan criteria. METHODS: A retrospective cohort of 147 patients with mortality who were initially diagnosed with HCC within the Milan criteria between January 2008 and December 2012 at a single institution was reviewed. RESULTS: During follow-up, 104 patients (70.7%) experienced one or more cirrhotic complications, such as ascites, variceal bleeding, or hepatic encephalopathy. Near mortality, cancer progression (exceeding the Milan criteria) was recorded for 102 patients (69.3%), while cirrhosis progression (greater than two-point increase in Child-Pugh score) was noted in 110 (74.8%) patients. Alpha-fetoprotein, protein-induced by vitamin K antagonist-II levels and treatment modality were associated with cancer progression, while age and Child-Pugh class were associated with cirrhosis progression. There were 61 patients with in-hospital mortality; cancer progression plus liver failure was noted in 34 patients (55.7%), liver failure without cancer progression was seen in 20 patients (32.8%), and only four patients (6.6%) showed mortality from extrahepatic metastasis without liver failure. CONCLUSIONS: Among HCC patients who were diagnosed within the Milan criteria, most of them had cirrhosis progression near mortality, and significant proportion died without uncontrolled cancer growth, mainly due to liver failure. These findings show the importance of liver function that should be considered in managing HCC patients.

Immunoproteasome induction is suppressed in hepatitis C virus-infected cells in a protein kinase R-dependent manner

By changing the relative abundance of generated antigenic peptides through alterations in the proteolytic activity, interferon (IFN)-γ-induced immunoproteasomes influence the outcome of CD8⁺ cytotoxic T lymphocyte responses. In the present study, we investigated the effects of hepatitis C virus (HCV) infection on IFN-γ-induced immunoproteasome expression using a HCV infection cell culture system. We found that, although IFN-γ induced the transcriptional expression of mRNAs encoding the β1i/LMP2, β2i/MECL-1 and β5i/LMP7 immunoproteasome subunits, the formation of immunoproteasomes was significantly suppressed in HCV-infected cells. This finding indicated that immunoproteasome induction was impaired at the translational or posttranslational level by HCV infection. Gene silencing studies showed that the suppression of immunoproteasome induction is essentially dependent on protein kinase R (PKR). Indeed, the generation of a strictly immunoproteasome-dependent cytotoxic T lymphocyte epitope was impaired in in vitro processing experiments using isolated 20S proteasomes from HCV-infected cells and was restored by the silencing of PKR expression. In conclusion, our data point to a novel mechanism of immune regulation by HCV that affects the antigen-processing machinery through the PKR-mediated suppression of immunoproteasome induction in infected cells.

A Case of Autoimmune Hepatitis Combined with Graves' Disease / 대한소화기학회지

A 25-year-old woman presented with jaundice, palpitation, and weight loss of 5 kg during a period of 2 weeks. Laboratory tests showed elevated levels of liver enzymes (AST 1,282 IU/L, ALT 1,119 IU/L) and total bilirubin (6.4 mg/dL); negative for hepatitis virus infection; elevated serum levels of triiodothyronine (T3, 3.60 ng/dL), free thyroxine (fT4, 3.82 ng/dL), and lowered serum level of thyroid stimulating hormone (TSH, <0.025 microIU/mL); and positive for thyroid stimulating antibody and anti-mitochondrial antibody (AMA). The liver biopsy findings were consistent with autoimmune hepatitis (AIH). Accordingly, oral steroid therapy was started with 60 mg of prednisolone under the impression of AIH associated with Graves' disease. After a week of steroid therapy, the clinical manifestation showed significant improvement, with normalization of both liver and thyroid functions. Diagnosis of the liver condition of patients who present with hyperthyroidism and liver dysfunction is important, so that appropriate therapy can be promptly initiated.

Spontaneous Neoplastic Remission of Hepatocellular Carcinoma / 대한소화기학회지

We report on a case of a 57-year-old male who underwent a curative resection for hepatocellular carcinoma (HCC) with histological confirmation of a spontaneously necrotized tumor. Initial serum AFP level was 4,778 ng/mL. A 3.7 cm hyperechoic mass in segment 6 of the liver was observed on ultrasonography and dynamic contrast-enhanced liver MRI showed a 3.7x3.1 cm sized HCC. He was scheduled to undergo curative surgical resection under the clinical diagnosis of an early stage HCC (Barcelona Clinic Liver Cancer stage A). Without treatment, the serum AFP level declined rapidly to 50 ng/mL over five weeks. He underwent curative wedge resection of segment 6 of the liver. Histology revealed complete necrosis of the mass rimmed by inflamed fibrous capsule on a background of HBV-related cirrhosis with infiltration of lymphoplasma cells. Exact pathophysiology underlying this event is unknown. Among the proposed mechanisms of spontaneous neoplastic remission of HCC, circulatory disturbance and activation of host immune response offer the most scientific explanation for the complete histologic necrosis of HCC in the resected mass seen in our patient.