A refined prediction model for survival in hepatocellular carcinoma patients treated with transarterial chemoembolization.

Background/Aims: Transarterial chemoembolization (TACE) is widely performed as a major treatment for hepatocellular carcinoma (HCC) patients, and there is a need to stratify patients for whom the most benefit from the treatment. This study aimed to develop a refined prediction model for overall survival (OS) in patients undergoing TACE as a first-line treatment in a large cohort and validate its performance. Methods: A total of 2,632 patients with HCC of Barcelona Clinic Liver Cancer stage A or B who underwent TACE between 2008 and 2017 were enrolled. The patients were randomly assigned to a training cohort (n = 1,304) or a validation cohort (n = 1,328). Independent predictors of OS were used to develop a prediction model. Results: The median age of patients in the entire cohort was 63 years, with the majority having hepatitis B virus (56.6%) and being classified as Child-Pugh class A (82.4%). We developed a new prognostic model, called the TACE-prognostic (TP) score, based on tumor burden (sum of the largest tumor diameter and tumor number), alpha-fetoprotein, and Albumin-Bilirubin grade. Patients were classified into five risk groups according to TP scores, with median survival significantly differentiated in both training and validation cohorts (P < 0.001). The new model consistently outperformed other currently available models in both the training and validation cohorts. Conclusion: This newly developed TP scoring system has the potential to be a useful tool in identifying ideal candidates of TACE and predicting OS with favorable performance and discrimination. However, further external validation is needed to confirm its effectiveness.

A Machine Learning Algorithm Facilitates Prognosis Prediction and Treatment Selection for Barcelona Clinic Liver Cancer Stage C Hepatocellular Carcinoma.

BACKGROUND: Given its heterogeneity and diverse clinical outcomes, precise subclassification of BCLC-C hepatocellular carcinoma (HCC) is required for appropriately determining patient prognosis and selecting treatment. METHODS: We recruited 2,626 patients with BCLC-C stage HCC from multiple centers, comprising training/test (n=1,693) and validation cohorts (n=933). The XGBoost was chosen for maximum performance among the machine learning (ML) models. Patients were categorized into low-/intermediate-/high-/very high-risk subgroups which were based on the estimated prognosis, and this subclassification was named the CLAssification via Machine learning of BCLC-C (CLAM-C). RESULTS: The areas under the receiver operating characteristic curve of the CLAM-C for predicting the 6-/12-/24-month survival of patients with BCLC-C were 0.800/0.831/0.715, respectively-significantly higher than those of the conventional models, which was consistent in the validation cohort. The four subgroups had significantly different median overall survivals, and this difference was maintained among various patient subgroups and treatment modalities. Immune-checkpoint inhibitors and transarterial therapies were associated with significantly better survival than tyrosine kinase inhibitors (TKIs) in the low- and intermediate-risk subgroups. In cases with first-line systemic therapy, the CLAM-C identified atezolizumab-bevacizumab as the best therapy particularly in the high-risk group. In cases with later-line systemic therapy, nivolumab had better survival than TKIs in the low-to-intermediate-risk subgroup, whereas TKIs had better survival in the high-to-very high-risk subgroup. CONCLUSIONS: ML modeling effectively subclassified patients with BCLC-C HCC, potentially aiding treatment allocation. Our study underscores the potential utilization of ML modeling in terms of prognostication and treatment allocation in patients with BCLC-C HCC.

Differential liver function at cessation of atezolizumab-bevacizumab versus lenvatinib in HCC: a multicenter, propensity-score matched comparative study.

Background: Atezolizumab+bevacizumab (AB) and lenvatinib have been proposed as first-line treatment options for patients with advanced hepatocellular carcinoma (HCC), but comparative efficacy and associated factors are controversial. Materials and methods: This real-world multicenter study analysed patients with HCC who received AB (n=169) or lenvatinib (n=177). Results: First, 1:1 propensity score matching (PSM) was performed, resulting in 141 patients in both the AB and lenvatinib groups. After PSM, overall survival (OS) was better in the AB group than in the lenvatinib group [hazard ratio (HR)=0.642, P=0.009], but progression-free survival (PFS) did not vary between the two groups (HR=0.817, P=0.132). Objective response rate (ORR) was also similar between AB and lenvatinib (34.8% vs. 30.8%, P=0.581). In a subgroup of patients with objective responses (OR, n=78), OS (HR=0.364, P=0.012) and PFS (HR=0.536, P=0.019) were better in the AB group (n=41) than in the lenvatinib group (n=37). Time-to-progression from time of OR was also better in the AB group (HR=0.465, P=0.012). Importantly, residual liver function was a significant factor related to OS in both treatments. Child-Pugh score following cessation of the respective treatments was better in the AB group (n=105) than in the lenvatinib group (n=126) (median 6 versus 7, P=0.008), and proportion of salvage treatment was also higher in the AB group (52.4% versus 38.9%, P=0.047). When we adjusted for residual liver function or salvage treatment, there was no difference in OS between the two treatments. Conclusion: Our study suggests that residual liver function and subsequent salvage treatments are major determinants of clinical outcomes in patients treated with AB and lenvatinib; these factors should be considered in future comparative studies.

Brn3b regulates the formation of fear-related midbrain circuits and defensive responses to visual threat.

Defensive responses to visually threatening stimuli represent an essential fear-related survival instinct, widely detected across species. The neural circuitry mediating visually triggered defensive responses has been delineated in the midbrain. However, the molecular mechanisms regulating the development and function of these circuits remain unresolved. Here, we show that midbrain-specific deletion of the transcription factor Brn3b causes a loss of neurons projecting to the lateral posterior nucleus of the thalamus. Brn3b deletion also down-regulates the expression of the neuropeptide tachykinin 2 (Tac2). Furthermore, Brn3b mutant mice display impaired defensive freezing responses to visual threat precipitated by social isolation. This behavioral phenotype could be ameliorated by overexpressing Tac2, suggesting that Tac2 acts downstream of Brn3b in regulating defensive responses to threat. Together, our experiments identify specific genetic components critical for the functional organization of midbrain fear-related visual circuits. Similar mechanisms may contribute to the development and function of additional long-range brain circuits underlying fear-associated behavior.

A Real-World Comparative Analysis of Atezolizumab Plus Bevacizumab and Transarterial Chemoembolization Plus Radiotherapy in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis.

This study aimed to compare the treatment outcomes of atezolizumab-plus-bevacizumab (Ate/Bev) therapy with those of transarterial chemoembolization plus radiotherapy (TACE + RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) and without metastasis. Between June 2016 and October 2022, we consecutively enrolled 855 HCC patients with PVTT. After excluding 758 patients, 97 patients (n = 37 in the Ate/Bev group; n = 60 in the TACE + RT group) were analyzed. The two groups showed no significant differences in baseline characteristics and had similar objective response and disease control rates. However, the Ate/Bev group showed a significantly higher one-year survival rate (p = 0.041) compared to the TACE + RT group, which was constantly displayed in patients with extensive HCC burden. Meanwhile, the clinical outcomes were comparable between the two groups in patients with unilobar intrahepatic HCC. In Cox-regression analysis, Ate/Bev treatment emerged as a significant factor for better one-year survival (p = 0.049). Finally, in propensity-score matching, the Ate/Bev group demonstrated a better one-year survival (p = 0.02) and PFS (p = 0.01) than the TACE + RT group. In conclusion, Ate/Bev treatment demonstrated superior clinical outcomes compared to TACE + RT treatment in HCC patients with PVTT. Meanwhile, in patients with unilobar intrahepatic HCC, TACE + RT could also be considered as an alternative treatment option alongside Ate/Bev therapy.

The efficacy of treatment for hepatocellular carcinoma in elderly patients.

BACKGROUND/AIM: Despite the increasing proportion of elderly patients with hepatocellular carcinoma (HCC) over time, treatment efficacy in this population is not well established. METHODS: Data collected from the Korean Primary Liver Cancer Registry, a representative cohort of patients newly diagnosed with HCC in Korea between 2008 and 2017, were analyzed. Overall survival (OS) according to tumor stage and treatment modality was compared between elderly and non-elderly patients with HCC. RESULTS: Among 15,186 study patients, 5,829 (38.4%) were elderly. A larger proportion of elderly patients did not receive any treatment for HCC than non-elderly patients (25.2% vs. 16.7%). However, OS was significantly better in elderly patients who received treatment compared to those who did not (median, 38.6 vs. 22.3 months; P<0.001). In early-stage HCC, surgery yielded significantly lower OS in elderly patients compared to non-elderly patients (median, 97.4 vs. 138.0 months; P<0.001), however, local ablation (median, 82.2 vs. 105.5 months) and transarterial therapy (median, 42.6 vs. 56.9 months) each provided comparable OS between the two groups after inverse probability of treatment weighting (IPTW) analysis (all P>0.05). After IPTW, in intermediate-stage HCC, surgery (median, 66.0 vs. 90.3 months) and transarterial therapy (median, 36.5 vs. 37.2 months), and in advanced-stage HCC, transarterial (median, 25.3 vs. 26.3 months) and systemic therapy (median, 25.3 vs. 26.3 months) yielded comparable OS between the elderly and non-elderly HCC patients (all P>0.05). CONCLUSIONS: Personalized treatments tailored to individual patients can improve the prognosis of elderly patients with HCC to a level comparable to that of non-elderly patients.

Safety and effectiveness of direct-acting antivirals in patients with chronic hepatitis C and chronic kidney disease.

BACKGROUND/AIMS: To evaluate the effectiveness and safety of direct acting antivirals (DAAs) available in chronic kidney disease (CKD) patients with hepatitis C virus (HCV) infection in Korea. METHODS: In a retrospective, multicenter cohort study, 362 patients were enrolled from 2015 to 2019. The effectiveness and safety of DAAs including glecaprevir/pibrentasvir, sofosubvir/ribavirin, ledipasvir/sofosbuvir, and daclatasvir/asunaprevir were analyzed for patients according to CKD stage. We evaluated sustained virologic response at week 12 after treatment (SVR12) as primary endpoint. The effectiveness and safety were also evaluated according to CKD stage. RESULTS: Among 362 patients, 307 patients completed DAAs treatment and follow-up period after end of treatment. The subjects comprised 87 patients (62 with CKD stage 3 and 25 with CKD stage (4-5), of whom 22 were undergoing hemodialysis). HCV patients with CKD stage 1 and 2 (estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m2) showed SVR12 of 97.2% and 95.4% respectively. SVR12 of CKD stage 3 and 4-5 (eGFR < 60 mL/min/1.73 m2) patients was 91.9% and 91.6% respectively. Patients undergoing hemodialysis achieved SVR12 (90.9%). Treatment failure of DAAs in stage 1, 2, 3, and 4-5 was 2.8%, 2.7%, 1.6%, and 4%. DAAs showed good safety profile and did not affect deterioration of renal function. CONCLUSION: DAAs shows comparable SVR12 and safety in CKD patients (stage 3, 4, and 5) with HCV compared with patients with stage 1 and 2. The effectiveness and safety of DAAs may be related to the treatment duration. Therefore, it is important to select adequate regimens of DAAs and to increase treatment adherence.

Real-life experience of ledipasvir and sofosbuvir for HCV infected Korean patients: a multicenter cohort study.

BACKGROUND/AIMS: To evaluate the efficacy and safety of ledipasvir/sofosbuvir (LDV/SOF) therapy in hepatitis C virus (HCV)-infected Korean patients in a real clinical setting. METHODS: A total of 273 patients who received LDV/SOF therapy between May 2016 and February 2021 were consecutively enrolled and analyzed. A per-protocol analysis was performed to evaluate the virologic response. RESULTS: Seventy-five percent were infected with genotype 1, and 25% were infected with genotype 2. A hundred eightyone (66.3%) patients had chronic hepatitis, 74 (27.1%) had compensated cirrhosis, eight (2.9%) had decompensated cirrhosis, and 10 (3.7%) had undergone liver transplantation. Undetectable HCV RNA at week 4 was achieved in 90.2% (231/256) of patients, 99.2% (250/252) achieved the end of treatment response, and 98.1% (202/206) achieved sustained virologic response at 12 weeks post-treatment (SVR12). According to liver function, the SVR12 rates were 99.3% (135/136) in chronic hepatitis, 96.4% (53/55) in compensated cirrhosis, and 100% (6/6) in decompensated cirrhosis. The SVR12 rates according to the genotype were 98.2% (167/170) for genotype 1 and 97.2% (35/36) for genotype 2. An 8-week LDV/SOF treatment in treatment-naïve chronic hepatitis patients with HCV RNA < 6,000,000 IU/mL at baseline resulted in 100% (23/23) SVR12 rates. Overall, LDV/SOF was tolerated well, with a 0.7% (2/273) discontinuation rate due to adverse events that were unrelated to LDV/SOF. CONCLUSION: LDV/SOF is effective and safe for treating HCV-infected Korean patients with high SVR12 rates.

A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance.

BACKGROUND & AIMS: After hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains, and the optimal surveillance strategy has yet to be determined. Herein, we aimed to evaluate incidence and risk factors for HCC and establish a novel prediction model for HCC development after HBsAg seroclearance. METHODS: A total of 1,443 patients with chronic hepatitis B who achieved HBsAg seroclearance between 1991 and 2020 were retrospectively screened for study eligibility. The data from 831 of these patients were included in the final analysis. A prediction model was developed based on multivariable Cox models. Harrell's C-index and a time-dependent AUROC were used for discrimination. Bootstrap analysis was performed for internal validation. RESULTS: Overall, 40 patients (4.8%) developed HCC after HBsAg seroclearance during a follow-up of 4,644 person-years (0.86%/year). Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently predictive of HCC, and these 4 independent variables were used to develop the prediction model. The C-index of the model was 0.804. The time-dependent AUROCs of the score for HCC prediction at 5, 10, and 15 years were 0.799, 0.835, and 0.817, respectively. The score also showed good discrimination in the internal validation and sensitivity analysis. CONCLUSIONS: The novel prediction model based on age, cirrhosis, family history of HCC, and alcohol consumption enables reliable risk estimation of HCC after HBsAg seroclearance and may serve as a useful reference for decision-making in HCC surveillance for HBsAg-cleared patients. LAY SUMMARY: After spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the risk of hepatocellular carcinoma (HCC) remains. Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently associated with HCC development after HBsAg seroclearance. The novel prediction model using these 4 variables enables reliable risk estimation of HCC and serves as a useful reference for decision-making in HCC surveillance and management for HBsAg-cleared patients.

Effect of Combined Exercise Program on Lower Extremity Alignment and Knee Pain in Patients with Genu Varum.

This study aimed to assess the effect of a combined exercise program on lower-extremity alignment and knee pain in patients with genu varum. Forty-seven middle-aged women with knee pain and genu varum were randomly divided into the exercise (EG, n = 24) and control (CG, n = 23) groups. The exercise group underwent a combined exercise program lasting 60 min in one session, three times a week for 12 weeks. Knee-to-knee length (KTKL), hip-knee-ankle angle (HKAA), hip inclination angle (HIA), and medial proximal tibial angle (MPTA) were assessed to evaluate lower-extremity alignment. To evaluate knee pain, the short form-McGill Pain Questionnaire (SF-MPQ) were used. There was a significant difference between the groups, and a decrease of 16% in KTKL (from 6.48 ± 1.26 cm to 5.47 ± 1.21 cm) was shown in EG. Other variables, including HKAA, HIA, and MPTA on the right side, showed significant differences between pre- and post-intervention in EG (p < 0.01, p < 0.01, and p < 0.01, respectively). SF-MPQ score improved with 45% from 18.75 ± 1.64 to 10.33 ± 2.47 after exercise intervention in EG. These results suggest that the combined exercise program, including strength and neuromuscular exercises, is an effective intervention for improving lower-extremity alignment and knee pain in middle-aged women with genu varum.

Anti-fibrotic effects of branched-chain amino acids on hepatic stellate cells.

BACKGROUND/AIMS: Patients with liver cirrhosis (LC) have low levels of branched-chain amino acids (BCAAs). There is accumulating evidence that BCAAs have anti- fibrotic effects in cirrhosis. This study is aimed to evaluate the effect of BCAAs on the function and phenotype of activated hepatic stellate cells (HSCs). METHODS: LX-2, an immortalized human stellate cell line, was used in in vitro experiments. LX-2 cells were exposed to transforming growth factor ß1 (TGF-ß1) and BCAAs or to valine, leucine, and isoleucine, which are components of BCAAs. Activation of the TGF-ß signaling pathway in LX-2 cells was observed using real-time quantitative polymerase chain reaction and Western blotting. RESULTS: The increased expression of snail family transcriptional repressor 1 (SNAI1) was observed in LX-2 cells activated by TGF-ß1. After BCAA treatment, its expression was significantly decreased at the mRNA level. The increased expression of Col1α1 and TIMP2 at the mRNA level and alpha smooth muscle actin at the protein level in activated LX-2 cells decreased after BCAA treatment. Among the BCAA components, leucine and valine significantly abrogated TGF-ß-induced activation of LX-2 cells. BCAA treatment led to the decreased phosphorylation of Smad2 and p38 proteins, which are markers for Smad and Smad-independent p38 mitogen-activated protein kinase signaling pathways, respectively. CONCLUSION: BCAA treatment can improve hepatic fibrosis by directly affecting the activated state of hepatic stellate cells through inhibition of the TGF-ß signaling pathway. Among BCAA components, leucine and valine mainly abrogated TGF-ß-induced activation of HSCs. Our results suggest that BCAA may be used to attenuate the progression of liver fibrosis.

Anticancer Effect of Statins in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma.

The anticancer effect of statins is drawing attention. However, it is unclear whether statin use reduces the risk of hepatocellular carcinoma (HCC) recurrence in patients who undergo liver transplantation (LT) for HCC. Consecutive patients who underwent LT for HCC between 1995 and 2019 were enrolled. The effects of statins on HCC recurrence and mortality were compared between statin user and statin nonuser groups. We performed the analyses in a variety of ways, including inverse probability treatment weighting (IPTW) methods to balance any confounders and the landmark method to avoid immortal time bias. A total of 430 patients were enrolled, among whom 323 (75.1%) were statin nonusers and 107 (24.9%) were statin users. During a median of 64.9 months (IQR, 26.1-122.6 months) of follow-up, 79 patients (18.4%) had HCC recurrence and 111 (25.8%) died. Among those who died, 53 (47.7%) were identified as HCC-related mortalities. Statin use was a predictor of HCC recurrence (adjusted hazard ratio [HR], 0.3; 95% confidence interval [CI], 0.1-0.6; P = 0.002), all-cause mortality (adjusted HR, 0.3; 95% CI, 0.2-0.5; P < 0.001), and HCC-related mortality (adjusted HR, 0.4; 95% CI, 0.2-0.9; P = 0.03). The effects of statin use on clinical outcomes were also identified through IPTW analysis. There was a dose-dependent relationship between statin use and HCC recurrence. The anticancer effect of statins on HCC recurrence was consistently significant across multivariable-stratified and sensitivity analyses. Statin use significantly reduced the risk of HCC recurrence and improved the survival of patients who underwent LT for HCC.

The role of transjugular intrahepatic portosystemic shunt in patients with portal hypertension: Advantages and pitfalls.

Transjugular intrahepatic portosystemic shunt (TIPS) is an effective interventional procedure to relieve portal hypertension, which is a main mechanism for the development of complications of liver cirrhosis (LC), such as variceal hemorrhage, ascites, and hepatorenal syndrome. However, the high incidence of adverse events after TIPS implementation limits its application in clinical practice. Esophageal variceal hemorrhage is one of the major indications for TIPS. Recently, preemptively performed TIPS has been recommended, as several studies have shown that TIPS significantly reduced mortality as well as rebleeding or failure to control bleeding in patients who are at high risk of treatment failure for bleeding control with endoscopic variceal ligation and vasoactive drugs. Meanwhile, recurrent ascites is another indication for TIPS with a proven survival benefit. TIPS may also be considered as an effective treatment for other LC complications, usually as an alternative therapy. Although there are concerns about the development of hepatic encephalopathy and hepatic dysfunction after TIPS implementation, careful patient selection using prognostic scores can lead to excellent outcomes. Assessments of cardiac and renal function prior to TIPS may also be considered to improve patient prognosis.

Tenofovir disoproxil fumarate directly ameliorates liver fibrosis by inducing hepatic stellate cell apoptosis via downregulation of PI3K/Akt/mTOR signaling pathway.

BACKGROUND: Antifibrotic agent for the treatment of liver fibrosis has not been developed so far. Long term treatment of chronic hepatitis B patients with antiviral drugs tenofovir disoproxil fumarate (TDF) and entecavir (ETV) results in the regression of liver fibrosis, but the underlying mechanism has not been clarified. Therefore, we aimed to investigate the direct impact of TDF and ETV on liver fibrosis. METHODS: Activated hepatic stellate cell (HSC) cell lines were used to evaluate the effects of TDF and ETV. After treatment with each antiviral agent, cell viability, morphology, apoptotic features, autophagy and antifibrosis signalling pathways were examined. Then, collagen deposition, fibrosis markers and activated HSCs were measured in liver tissues of the liver fibrosis model mice. RESULTS: After TDF treatment, the viabilities of LX2 and HSC-T6 cells were decreased, and the cells exhibited apoptotic features, but ETV did not induce these effects. Cleavage of PARP and Caspase-3 and the inhibition of the antiapoptotic gene Bcl-xl indicated activated HSC apoptosis following TDF treatment. TDF simultaneously increased autophagy, which also regulated apoptosis through crosstalk. TDF inactivated the PI3K/Akt/mTOR signalling pathway, which was associated with the activation of both apoptosis and autophagy. In the liver fibrosis mouse model, the fibrotic area and activated HSC markers were decreased by TDF but not ETV treatment. Additionally, apoptotic cells were concentrated in the periportal fibrotic area after TDF treatment, which indicated the specific antifibrotic effect of TDF. CONCLUSIONS: TDF directly ameliorates liver fibrosis by downregulating the PI3K/Akt/mTOR signalling pathway, which results in the apoptosis of activated HSCs. The antifibrotic effects of TDF indicate that it may be a therapeutic agent for the treatment of liver fibrosis.

The Role of Urinary N-Acetyl-ß-d-glucosaminidase in Cirrhotic Patients with Acute Kidney Injury: Multicenter, Prospective Cohort Study.

BACKGROUND AND AIMS: Currently, it is difficult to predict the reversibility of renal function and to discriminate renal parenchymal injury in cirrhotic patients with acute kidney injury (AKI). The aim of this study is to evaluate whether urine N-acetyl-ß-d-Glucosaminidase (NAG) can predict the survival and response to terlipressin in cirrhotic patients with AKI. METHODS: Two hundred sixty-two cirrhotic consecutive patients who developed AKI were prospectively enrolled from 11 tertiary medical centers in Korea between 2016 to 2019. AKI was defined as an increase in serum Cr (SCr) of 0.3 mg/dL or a 50% increase in baseline SCr. Patients diagnosed with hepatorenal syndrome (HRS-AKI) were treated with terlipressin plus albumin. RESULTS: The patients were 58.8 ± 12.9 years old on average and were predominantly male (72.5%). The mean MELD score was 25.3 ± 9.1. When classified according to the AKI phenotype, there were 119 pre-renal, 52 acute tubular necrosis, 18 miscellaneous, and 73 HRS-AKI patients. However, the urine NAG was not effective at discriminating AKI phenotypes, except for HRS-AKI. The baseline urine NAG increased as the baseline AKI stage increased (p < 0.001). In addition, within the same AKI stage, the urine NAG values were significantly lower in the AKI-resolved group than in the unresolved group. The urine NAG level was significantly lower in living patients compared with those who died or who underwent a liver transplant within 3 months (p = 0.005). In the multivariate analysis, the increased urine NAG was a significant risk factor for the 3-month transplant-free survival (TFS) rate, especially in patients with Child-Pugh class ≤ B or MELD < 24. The urine NAG did not predict the response to terlipressin treatment in patients with HRS. CONCLUSIONS: Urine NAG is strongly associated with the severity of AKI in patients with liver cirrhosis and is useful for predicting the 3-month TFS.

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.

Comparative Analysis of Lenvatinib and Hepatic Arterial Infusion Chemotherapy in Unresectable Hepatocellular Carcinoma: A Multi-Center, Propensity Score Study.

The comparative efficacy and safety between lenvatinib and hepatic artery infusion chemotherapy (HAIC) in patients with unresectable hepatocellular carcinoma (HCC) is still unclear. This multicenter historical cohort study enrolled 244 patients who were treated with HAIC (n = 173) or lenvatinib (n = 71) between 2012 and 2020. Propensity score matching (PSM) was performed, and 52 patients were selected per group. Clinical outcomes and safety were compared. Objective response rate (ORR) was not different between the two groups (26.0% vs. 23.1%, p = 0.736). Before PSM, the HAIC group had a higher proportion of Child-Pugh B and portal vein tumor, whereas the lenvatinib group had more patients with extrahepatic metastases, which was adjusted after PSM. There were no differences in progression-free survival (PFS) and overall survival (OS) after PSM (HAIC vs. lenvatinib, median PFS, 3.6 vs. 4.0 months, p = 0.706; median OS 10.8 vs. 7.9 months, p = 0.106). Multivariate Cox-regression showed that alpha-fetoprotein ≤1000 ng/mL was only an associated factor for OS after PSM in all patients (hazard ratio = 0.421, p = 0.011). Subgroup analysis for patients with a high tumor burden beyond the REFLECT eligibility criteria revealed that the HAIC group (n = 29) had a significantly longer OS than did the lenvatinib group (n = 30) (10.0 vs. 5.4 months, p = 0.004). More patients in the HAIC group achieved better liver function than those in the lenvatinib group at the time of best responses. There was no difference in the incidence of grade 3 and 4 adverse events between the two groups. Therefore, lenvatinib is comparable to HAIC in terms of ORR and OS in unresectable HCC meeting REFLECT eligibility criteria.

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.

A Real-World Comparative Analysis of Lenvatinib and Sorafenib as a Salvage Therapy for Transarterial Treatments in Unresectable HCC.

BACKGROUND/AIMS: Lenvatinib was recently approved as a first-line oral multikinase inhibitor for unresectable hepatocellular carcinoma (HCC). In this study, we aimed to compare the efficacy and safety of lenvatinib and sorafenib for the treatment of unresectable HCC in patients with prior failure of transarterial treatment. METHODS: Between January 2019 and September 2020, 98 unresectable HCC patients treated with lenvatinib or sorafenib as salvage therapy were enrolled from five Korean university-affiliated hospitals. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate were calculated to assess the antitumor response. RESULTS: A total of 43 and 55 patients were treated with lenvatinib and sorafenib, respectively, as salvage therapy after the failure of transarterial treatments. The median PFS was 4.97 months in the lenvatinib group and 2.47 months in the sorafenib group (p = 0.001, log-rank test). The ORR was significantly higher in the lenvatinib group (25.6%) than in the sorafenib group (3.6%, p = 0.002). Use of lenvatinib over sorafenib (hazard ratio: 0.359, 95% confidence interval: 0.203-0.635, p < 0.001) was the most significant factor for a favorable PFS after the failure of transarterial treatments in all enrolled patients. For favorable OS, achieving objective response was the significant factor (hazard ratio 0.356, 95% confidence interval: 0.132-0.957, p = 0.041). There were no significant differences in the safety profile between the two groups. CONCLUSIONS: In this real-world study, lenvatinib was demonstrated to be more efficacious than sorafenib as a salvage therapy for transarterial treatments in unresectable HCC.

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.