Varying Impact of Lenvatinib or Sorafenib Therapy on Skeletal Muscle Loss in Patients with Hepatocellular Carcinoma.

INTRODUCTION: Lenvatinib and sorafenib are key therapeutic agents for hepatocellular carcinoma (HCC). However, there are no useful biomarkers for selecting molecular-targeted agents (MTAs). Skeletal muscle volume is associated with the clinical outcomes in these patients. We investigated the effects of lenvatinib and sorafenib on the skeletal muscles of patients with HCC. METHODS: We evaluated the impact of skeletal muscle changes over a 3-month period for each MTA (n = 117; lenvatinib/sorafenib, 45/72). The skeletal muscle mass index (SMI) was measured at the third lumbar vertebra. Furthermore, we evaluated the direct effect of each MTA on primary human skeletal muscle cells by estimating muscle protein synthesis using western blot analysis. RESULTS: The median change in SMI was -0.7% (p = 0.959) and -5.9% (p < 0.001) for the lenvatinib and sorafenib groups, respectively. Sorafenib had a greater effect on skeletal muscle loss than lenvatinib (p < 0.001). Additionally, SMI significantly decreased in the sorafenib group regardless of initial skeletal muscle volume (p < 0.001), whereas no significant differences were observed in the lenvatinib group. Sorafenib therapy (odds ratio [OR], 2.98; p = 0.023) and non-muscle depletion (OR, 3.31; p = 0.009) were associated with a decreased SMI. In vitro analysis showed that sorafenib negatively affected muscle synthesis compared to lenvatinib. CONCLUSIONS: Sorafenib may have a more negative effect on skeletal muscle than lenvatinib.

Double cancer of primary hepatic angiosarcoma and hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

AIM: Primary hepatic angiosarcoma (PHA) is extremely rare, and its imaging findings are similar to those of other liver tumors including hepatocellular carcinoma (HCC). Here, we report a case of hepatitis C virus (HCV)-related HCC followed by PHA that showed remarkable clinical response to atezolizumab plus bevacizumab (Atezo/Bev) therapy. CASE PRESENTATION: A 78-year-old man with recurrent HCC had a liver tumor with lymphadenopathy. Although considered as HCC recurrence, microscopic examination of the resected liver and lymph node showed PHA. Three months later, a solitary lung nodule was newly detected and subsequently resected. The pathological diagnosis was poorly differentiated HCC. Therefore, the patient was finally diagnosed with double cancer of PHA and HCC. Thereafter, he developed a new liver tumor with lymphadenopathy and received Atezo/Bev therapy. Liver tumor biopsy was carried out before the treatment. The pathological diagnosis was angiosarcoma. The patient showed a partial response after two courses of Atezo/Bev therapy. CONCLUSION: To our best knowledge, this report is the first case to present HCV-related HCC followed by PHA and to show that Atezo/Bev therapy is beneficial for PHA.

Screening for portopulmonary hypertension using computed tomography-based measurements of the main pulmonary artery and ascending aorta diameters in patients with portal hypertension.

AIM: This study aimed to demonstrate the feasibility of identifying candidates of portopulmonary hypertension (PoPH) from general portal hypertension patients based on chest computed tomography (CT) results. METHODS: One hundred and thirty patients with portal hypertension who had undergone interventional radiology therapies at our hospital between August 2011 and July 2021 were included, and preoperative clinical data were collected. Suspicious PoPH was defined as main pulmonary artery diameter (mPA-D) ≥ 29 mm or the ratio of mPA-D to ascending aorta diameter (mPA-D/aAo-D) ≥ 1.0, and probable PoPH as mPA-D ≥ 33 mm based on the chest CT. Prevalence of suspicious and probable PoPH was evaluated, and the differences in clinical characteristics of each population were compared. RESULTS: Overall, 29 (22.3%) and 5 (3.8%) patients were categorized as suspicious and probable PoPH, respectively. Univariate analyses revealed that female sex, higher shortest diameter of inferior vena cava, presence of portosystemic shunts ≥ 5 mm, and lower blood urea nitrogen levels were significantly associated with suspicious PoPH (p < 0.05). Multivariate analyses identified all four factors as significantly independent determinants of suspicious PoPH (p < 0.05). In addition, among the population of suspicious PoPH, there were significant differences in seven parameters, including total bilirubin levels and spleen volume between patients with and without probable PoPH (p < 0.05). However, no significant independent indicators of probable PoPH were found. CONCLUSIONS: CT-based measurements of mPA-D and mPA-D/aAo-D have the potential to screen patients with suspicious PoPH in clinical practice focused on portal hypertension.

Liver stiffness measured by transient elastography as predictor of prognoses following portosystemic shunt occlusion.

BACKGROUND AND AIM: This study aimed to identify predictors of model for end-stage liver disease sodium score reductions and improvements in vital prognoses following portosystemic shunt occlusion in portal hypertension patients. METHODS: Seventy cirrhotic patients with major portosystemic shunts and a mean model for end-stage liver disease sodium score of 10.5 underwent balloon-occluded retrograde transvenous obliteration between February 2008 and March 2017. We calculated the scores before and 1 month after shunt occlusion. The long-term outcomes were monitored, and vital prognoses were analyzed. RESULTS: The model for end-stage liver disease sodium score did not change significantly 1 month post-balloon-occluded retrograde transvenous obliteration, and the score decreased postoperatively in 31 (44.3%) patients. Univariate analyses showed that decline in the score after portosystemic shunt occlusion was strongly associated with hepatic encephalopathy as a procedural indication, lower liver volumes, and lower liver stiffness levels measured by transient elastography before treatment (P < 0.05). Multivariate logistic regression analysis identified preoperative liver stiffness level as an independent predictor of model for end-stage liver disease sodium score amelioration following balloon-occluded retrograde transvenous obliteration (P < 0.05), and receiver operating characteristic curve analysis determined a liver stiffness cutoff value of 21.6 kPa, with a sensitivity of 76.0% and specificity of 69.6%. The Kaplan-Meier method determined that overall survival rates after treatment in patients with liver stiffness < 21.6 kPa were significantly higher than in patients with liver stiffness ≥ 21.6 kPa (P < 0.05). CONCLUSIONS: Liver stiffness measured by transient elastography may predict improvements in model for end-stage liver disease sodium scores and in survival rates after portosystemic shunt occlusion in portal hypertension patients.

Analysis of tolvaptan non-responders and outcomes of tolvaptan treatment of ascites.

BACKGROUND AND AIM: The goals of the study were to identify an effective treatment for ascites and to examine the influence of tolvaptan on outcomes by investigating non-responders to tolvaptan and comparing outcomes of hepatic cirrhosis in patients treated with and without tolvaptan. METHODS: In Study 1, of 145 patients with hepatic cirrhosis who were treated with tolvaptan between September 2013 and March 2018, 45 who did not achieve weight loss of ≥1.5 kg within one week were investigated. In Study 2, 83 patients who received tolvaptan for ascites between September 2013 and March 2017 were compared with 131 patients who were treated for ascites without use of tolvaptan between January 2006 and January 2012. RESULTS: In Study 1, the 45 patients were divided into three groups based on changes in dosing of diuretics. Renal function was retained in the dose reduction group compared with that in the other groups, and the rate of discharge with remission and the outcomes were also favorable in patients with dose reduction. In Study 2, survival was significantly more favorable in patients treated with tolvaptan. CONCLUSIONS: Dose reduction of diuretics may be effective for patients with reduced renal function for whom tolvaptan is ineffective or the effect is insufficient and may also improve outcomes of patients with hepatic cirrhosis by preventing a decline in renal function caused by an increased dose of diuretics.

Comparison of patients with hepatic encephalopathy and those with gastric varices before and after balloon-occluded retrograde transvenous obliteration.

AIM: To compare the clinical characteristics of patients with hepatic encephalopathy (HE) and those with gastric varices (GV) before and after balloon-occluded retrograde transvenous obliteration (BRTO). METHODS: Eighty cirrhotic patients who underwent BRTO, including 42 men and 38 women, and whose mean age was 68 years, comprised the HE (n = 18) and GV (n = 62) groups. The patients' data before and 1 month after BRTO were analyzed. RESULTS: Before BRTO, the groups did not differ in their portal flow volume (PFV) or hepatic venous pressure gradient (HVPG). The portal vein (PV) was narrower and the splenic vein (SpV) was wider in the HE group than in the GV group. The SpV flow was hepatofugal in 75.0% of HE patients and hepatopetal in 92.6% of GV patients. The Child-Pugh (CP) score of the HE group was significantly higher than that of the GV group pre-BRTO. After BRTO, the PFV and HVPG increases in the HE group equaled those in the GV group, and the PV dilation was similar in both groups. Conversely, the SpV was significantly contracted for HE patients, but significantly dilated for GV patients. Postoperatively, the SpV flow was hepatopetal in all patients. Compared to that in the GV group, the CP score decreased markedly in the HE group, and no significant increases in complications occurred post-BRTO for HE patients. CONCLUSIONS: The HE patients showed distinct portal-splenic hemodynamics before and after BRTO. Balloon-occluded retrograde transvenous obliteration markedly improved hepatic function in the HE group compared with the GV group.

Evaluation of the "assessment for continuous treatment with hepatic arterial infusion chemotherapy" scoring system in patients with advanced hepatocellular carcinoma.

AIM: Sorafenib is the recommended standard of care for advanced hepatocellular carcinoma (HCC) patients. However, hepatic arterial infusion chemotherapy (HAIC) is a treatment option in Asia. We recently developed the assessment for continuous treatment with HAIC (ACTH) score to guide decision-making for continuous HAIC treatment. The purpose of this study was to validate the utility of the ACTH score in a dedicated cohort. METHODS: One hundred and thirty-one patients with advanced HCC were enrolled in this study (90 in the training group and 41 in the validation group). The point score (range, 0-3) was calculated as follows: Child-Pugh score before HAIC (A = 0, B = 1), α-fetoprotein (AFP) response (yes = 0, no = 1), and des-γ-carboxy prothrombin (DCP) response (yes = 0, no = 1). The AFP and DCP responses were assessed 2 weeks after HAIC induction; a positive response was defined as a reduction of ≥20% from the baseline. RESULTS: The DCP response in the validation group was significantly associated with treatment response, and the median survival time (MST) was longer in patients with an ACTH score ≤1 (15.9 months) than in those with a score ≥2 (7.0 months; P = 0.002). Survival in all patients showed significant stratification according to the ACTH score; the MSTs associated with scores of 0, 1, 2, and 3 points were 21.7, 14.4, 9.5, and 3.8 months, respectively. CONCLUSION: The ACTH score can aid in the therapeutic assessment and continued treatment planning of HCC patients receiving HAIC.

Hemobilia immediately after transcatheter arterial chemoembolization using drug-eluting beads for hepatocellular carcinoma with intrahepatic bile duct invasion.

Transcatheter arterial chemoembolization (TACE) is used as a palliative treatment for unresectable hepatocellular carcinoma (HCC) worldwide. Recently, a novel drug delivery-embolic agent, the drug-eluting bead (DEB), was introduced for TACE. There are a few reports of tumor hemorrhage after TACE using DEB (DEB-TACE) for HCC. However, there have not been any reports of hemobilia immediately after DEB-TACE for HCC with intrahepatic bile duct invasion. Here, the first such case is reported. A 71-year-old woman was admitted to our hospital to undergo DEB-TACE for multiple HCCs with worsening left intrahepatic bile duct dilatation. She was diagnosed with HCC that extensively invaded the left hepatic duct. After DEB-TACE through the left hepatic artery, a hepatic arteriogram showed extra flow of the contrast agent to the left hepatic and common bile ducts. Therefore, transcatheter arterial embolization (TAE) of the responsible vessel was carried out using coils, and no extra flow of the contrast agent was identified. The patient was discharged 14 days after TAE without deterioration of liver function. Although hemobilia immediately after DEB-TACE is rare, there may be increased potential for hemobilia when DEB-TACE is carried out for HCC with extensive bile duct invasion. We suggest that DEB-TACE may be contraindicated for such cases.

Clinical characteristics and prognosis of non-B non-C hepatocellular carcinoma patients with modest alcohol consumption.

AIM: Alcoholic hepatocellular carcinoma (ALD-HCC) accounts for the majority of non-B non-C HCC (NBNC-HCC) cases. Although alcohol is a potent carcinogen, there have been few reports on the influence of modest alcohol consumption in NBNC-HCC. This study aimed to investigate the clinical characteristics and prognosis of NBNC-HCC patients with modest alcohol consumption. METHODS: From 2007 to 2010, 2283 HCC patients were evaluated at 10 hospitals. We collected detailed etiology data of 588 NBNC-HCC patients and compared the clinical characteristics and prognosis between ALD-HCC and modest alcohol-HCC patients. RESULTS: There were 69 HCC patients with modest alcohol consumption, accounting for 3% of all HCC patients evaluated. This patient group had significantly more women and higher prevalence of Child-Pugh class A, hypertension and advanced disease stage, and were diagnosed with HCC at an older age than the ALD-HCC group (266 patients). Additionally, among the modest alcohol-HCC patients, diabetes was significantly more common in the anti-hepatitis B core (HBc) negative subgroup than in the anti-HBc positive subgroup. However, no significant difference in survival was observed between the two patient groups regardless of significant differences in tumor staging. Alcohol consumption and metabolic factors were not significant independent predictors of survival. CONCLUSION: The clinical characteristics of modest alcohol-HCC included advanced staging, favorable liver reserve capacity and older age at diagnosis. HCC development in patients with modest alcohol consumption may relate to metabolic factors. Although approximately 30% of the evaluated HCC cases were in advanced stages, the prognosis of NBNC-HCC patients with modest alcohol consumption was relatively favorable.

Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib.

Although sorafenib is expected to have a chemopreventive effect on hepatocellular carcinoma (HCC) recurrence, there are limitations to its use because of adverse effects, including effects on liver function. We have reported that the iron chelator, deferoxamine can prevent liver fibrosis and preneoplastic lesions. We investigated the influence of administering a new oral iron chelator, deferasirox (DFX), on the effects of sorafenib. We used the choline-deficient l-amino acid-defined (CDAA) diet-induced rat liver fibrosis and HCC model. We divided rats into four groups: CDAA diet only (control group), CDAA diet with sorafenib (sorafenib group), CDAA diet with DFX (DFX group), and CDAA diet with DFX and sorafenib (DFX + sorafenib group). Liver fibrosis and development of preneoplastic lesions were assessed. In addition, we assessed adverse effects such as changes in body and liver weight, skin damage (eruption, dryness, and hair loss), which is defined as hand-foot skin syndrome, in the sorafenib and DFX + sorafenib groups. The combination of DFX + sorafenib markedly prevented liver fibrosis and preneoplastic lesions better than the other treatments. Furthermore, the combination therapy significantly decreased adverse effects compared with the sorafenib group. In conclusion, the combination therapy with DFX and sorafenib may be a useful adjuvant therapy to prevent recurrence after curative treatment of HCC.

Serum transferrin as a predictor of prognosis for hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma.

AIM: We recently reported that the iron chelator deferoxamine (DFO) is efficacious in advanced hepatocellular carcinoma (HCC) patients. Iron regulation may thus have an important impact in HCC therapy. Because transferrin is a native chelator that regulates iron homeostasis, it may act as an anticancer agent in a similar manner as DFO. The objective of this study was to evaluate serum transferrin as a prognostic predictor in advanced HCC patients undergoing hepatic arterial infusion chemotherapy (HAIC). METHODS: We retrospectively studied 44 patients receiving HAIC and analyzed various parameters for their possible use as prognostic predictors. RESULTS: The 1-, 2- and 3-year cumulative survival rates were 36.4%, 18.2% and 8.5%, respectively, and the median survival time (MST) was 7.0 months. The survival rates of patients who had serum transferrin of 190 mg/dL or more (MST, 12.0 months) were significantly better than those of patients who had serum transferrin of less than 190 mg/dL (MST, 4.9 months). Multivariate analysis identified serum transferrin of 190 mg/dL or more (hazard ratio [HR], 0.282; 95% confidence interval [CI], 0.132-0.603; P = 0.001) and Child-Pugh score B (HR, 1.956; 95% CI, 1.034-3.700; P = 0.039) as independent prognostic predictors. There was a significant correlation between serum transferrin level and therapeutic effect (P < 0.001). CONCLUSION: Serum transferrin could be useful as a prognostic predictor in advanced HCC patients before HAIC treatment.

Association of tyrosine with insulin resistance in hepatitis C virus-related chronic liver disease.

AIM: Insulin resistance (IR) increases during the early stages of hepatitis C virus (HCV)-related chronic liver disease and is a sign of poor prognosis as well as a risk factor for hepatic fibrosis and hepatocellular carcinoma. We aimed to determine the factors affecting IR in HCV-related chronic liver disease. METHODS: We retrospectively examined 71 patients with HCV-related chronic liver disease and analyzed various parameters, including amino acids, as possible predictors of IR. IR was assessed using the Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR). Amino acids were assayed by examining branched-chain amino acids (BCAA), tyrosine level, and the ratio of BCAA to tyrosine level (BTR). RESULTS: HOMA-IR was significantly correlated with body mass index, platelet count, prothrombin time, hemoglobin, total bilirubin, total protein, albumin, total cholesterol, fasting glucose, BTR (r = -0.46, P = 0.0001) and tyrosine (r = 0.55, P < 0.0001). However, BCAA were not significantly correlated with HOMA-IR (r = -0.21, P = 0.082). In multivariate analysis, only two factors were identified as independent parameters contributing to a HOMA-IR of 2.5 or more: total cholesterol (odds ratio [OR], 6.511; 95% confidence interval [95% CI], 1.554-27.284; P = 0.010) and tyrosine (OR, 4.839; 95% CI, 1.087-21.549; P = 0.039). CONCLUSION: Serum tyrosine levels may be associated with IR in patients with HCV-related chronic liver disease.

Systemic gemcitabine combined with hepatic arterial infusion chemotherapy with cisplatin, 5-fluorouracil, and isovorin for the treatment of advanced intrahepatic cholangiocarcinoma: a pilot study.

BACKGROUND/AIMS: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis and usually presents as advanced disease. Hepatic arterial infusion chemotherapy (HAIC) is a promising option for advanced hepatocellular carcinoma; however, there have been few reports on the use of HAIC in patients with ICC. In the present study, we investigated the efficacy of treatment with systemic gemcitabine (GEM) combined with HAIC with cisplatin (CDDP), 5-fluorouracil (5-FU), and isovorin in patients with advanced ICC. METHODOLOGY: Seven patients with advanced ICC, who received systemic GEM combined with HAIC with CDDP, 5-FU, and isovorin were studied. RESULTS: The response rate after the first chemotherapy cycle was 57.1% (partial response, 4; stable disease, 2; progressive disease, 1). The cumulative survival rates at 1 and 2 years were 85.7% and 28.6%, respectively, and the median survival time was 22.3 months. With regard to grade 3 or 4 adverse reactions, the percentages of patients developing leukopenia, neutropenia, thrombocytopenia, anemia, and anorexia were 28.6%, 28.6%, 42.9%, 14.3%, and 14.3%, respectively. Na treatment-related deaths were encountered. CONCLUSIONS: Although this is a pilot study, we suggest that systemic GEM combined with HAIC with CDDP, 5-FU, and isovorin, may be a useful therapy for patients with advanced ICC.

Initial clinical experience with durvalumab plus tremelimumab in patients with unresectable hepatocellular carcinoma in real­world practice.

Although durvalumab plus tremelimumab (Dur/Tre) has been approved as first-line therapy for patients with unresectable hepatocellular carcinoma (u-HCC), its outcomes in real-world clinical practice are unclear. The present study aimed to evaluate the efficacy and safety of Dur/Tre treatment. This multicenter study was conducted between March 2023 and January 2024, and included 120 patients with u-HCC treated with Dur/Tre. Among the patients, 44 had no history of systemic treatment. Progression-free survival (PFS), therapeutic response and adverse events (AEs) were assessed. The objective response rate (ORR) and disease control rates (DCR) were 15.8 and 53.3%, respectively. The median PFS was 3.9 months. The incidence rates of AEs of any grade and those grade 3 or higher were 83.3 and 36.7%, respectively. Liver injury was the most frequent AE of any grade and grade 3 or higher. Although there was no significant difference in ORR and PFS between the first and later line groups (ORR 15.8 vs. 15.7%, P=0.986; PFS 4.5 vs. 3.6 months, P=0.213), there was a significant difference in DCR between the two groups (65.8 vs. 45.9%, P=0.034). No significant differences were noted between the first- and later-line treatment groups regarding the incidence rate of AEs. Decision tree analysis revealed that poor liver function and advanced age were significant variables for discontinuation owing to AEs. In conclusion, Dur/Tre as first-line therapy had better disease control responses compared with later-line therapy; however, this regimen should be carefully administered to patients with deteriorating hepatic function or advanced age.

A Phase 2, Prospective, Multicenter, Single-Arm Trial of Transarterial Chemoembolization Therapy in Combination Strategy with Lenvatinib in Patients with Unresectable Intermediate-Stage Hepatocellular Carcinoma: TACTICS-L Trial.

Introduction: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase 2, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better objective response rate (ORR) than sorafenib (jRCTs031180074). Methods: Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14-21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child-Pugh A liver function, 0-2 prior TACE sessions, tumor size ≤10 cm, number of tumors ≤10, and ECOG performance status 0-1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was progression-free survival (PFS) by RECICL, and secondary endpoints were time to untreatable progression, ORR, overall survival (OS), and safety. Results: A total of 62 HCC patients were enrolled in this trial. The median age was 72 years, 77.4% of patients were men, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (90% confidence interval [CI] 25.1-31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (90% CI 35.5 months-NR). LEN-TACE achieved a high response rate and high complete response (CR) rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR rate) were similar and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the non-simple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR rate/ORR by LEN-TACE. No new safety concerns were observed. Conclusion: The results of this trial provide encouraging evidence, supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.

A combination of liver stiffness and international normalized ratio is an ideal prognostic predictor of portosystemic shunt occlusion in patients with portal hypertension.

BACKGROUND: We previously reported liver stiffness (LS) as a prognostic predictor of portosystemic shunt (PSS) occlusion. This study aims to reinvestigate the predictive factors of the model for end-stage liver disease-sodium (MELD-Na) score amelioration following balloon-occluded retrograde transvenous obliteration (BRTO) and to evaluate the postoperative prognoses of patients with portal hypertension by using newly identified factors. METHODS: Seventy-five patients who underwent BRTO between 2008 and 2021 were retrospectively enrolled. The MELD-Na scores were calculated preoperatively and one month postoperatively. We monitored long-term outcomes and analyzed postoperative survival. RESULTS: At one month postoperatively, the MELD-Na score decreased in 46 (61.3%) patients. Univariate analyses revealed a significant association of the score amelioration with nine factors, including lower LS levels and a higher international normalized ratio (INR). A multivariate logistic regression analysis with receiver operating characteristic curve analyses identified preoperative LS levels and INR as significant independent predictors of the postoperative MELD-Na score amelioration, with optimal cutoffs of 28.1 kPa and 1.06, respectively. The combination of LS < 28.1 kPa and INR ≥ 1.06 showed a sensitivity and specificity of 84.8% and 75.9% for the prediction of the score amelioration, respectively. For the propensity score model, we matched 24 patients with similar age, sex, MELD-Na score, and concomitant hepatocellular carcinoma. Kaplan-Meier analysis determined significantly higher cumulative survival rates in patients with LS < 28.1 kPa and INR ≥ 1.06 than in other populations. CONCLUSIONS: A combination of LS and INR can predict the MELD-Na score amelioration and prognosis improvement following PSS occlusion.

Impact of skeletal muscle volume on patients with BCLC stage-B hepatocellular carcinoma undergoing sorafenib therapy.

AIM: Skeletal muscle volume has been reported to be an important factor that determines overall survival (OS) and post-progression survival (PPS) in patients with hepatocellular carcinoma (HCC). However, the impact of skeletal muscle volume on HCC with Barcelona Clinic Liver Cancer (BCLC) stage B (BCLC-B) remains unclear. We conducted sub-analyses of a previous study on BCLC-B and compared our findings with data on HCC with BCLC stage C (BCLC-C). METHODS: We retrospectively enrolled 356 patients with HCC (BCLC-B, n = 78; and BCLC-C, n = 278) undergoing sorafenib therapy. Prognostic factors were analyzed using various parameters, including skeletal muscle volume. Muscle volume (MV) depletion was designated as less than the median value of the skeletal muscle index for each gender (cutoff value: 45.0 cm2 /m2 for male and 38.0 cm2 /m2 for female participants). RESULTS: Both OS and PPS showed no significant differences in patients with non-MV depletion and those with MV depletion in the BCLC-B group (Median OS [MST] 19.3 vs. 13.5 months [p = 0.348]; median PPS 9.7 vs. 10.8 months [p = 0.578]). In the BCLC-C group, patients with non-MV depletion had a significantly longer OS and PPS compared to patients with MV depletion (MST 12.4 vs. 9.0 months [p = 0.001] and median PPS 7.9 vs. 5.4 months [p = 0.002]). Multivariate analysis revealed that MV depletion was an independent prognostic factor of OS and PPS in the BCLC-C group but not in the BCLC-B group. CONCLUSIONS: Skeletal muscle volume showed little impact on the clinical outcomes of patients with BCLC-B undergoing sorafenib therapy.

Early Prediction of Response Focused on Tumor Markers in Atezolizumab plus Bevacizumab Therapy for Hepatocellular Carcinoma.

Despite the promising efficacy of atezolizumab plus bevacizumab (atezo/bev), some patients with unresectable hepatocellular carcinoma (HCC) experience disease progression. This retrospective study, which included 154 patients, aimed to evaluate predictors of treatment efficacy of atezo/bev for unresectable HCC. Factors associated with treatment response were examined, focusing on tumor markers. In the high-alpha-fetoprotein (AFP) group (baseline AFP ≥ 20 ng/mL), a decrease in AFP level > 30% was an independent predictor of objective response (odds ratio, 5.517; p = 0.0032). In the low-AFP group (baseline AFP < 20 ng/mL), baseline des-gamma-carboxy prothrombin (DCP) level < 40 mAU/mL was an independent predictor of objective response (odds ratio, 3.978; p = 0.0206). The independent predictors of early progressive disease were an increase in AFP level ≥ 30% at 3 weeks (odds ratio, 4.077; p = 0.0264) and the presence of extrahepatic spread (odds ratio, 3.682; p = 0.0337) in the high-AFP group and up-to-seven criteria, OUT (odds ratio, 15.756; p = 0.0257) in the low-AFP group. In atezo/bev therapy, focusing on early AFP changes, baseline DCP, and tumor burden of up-to-seven criteria are useful in predicting response to treatment.

Methylated SEPT9 assay-based liquid biopsy as a biomarker in molecular targeted agent-treated hepatocellular carcinoma.

BACKGROUND: The development of molecular targeted agents (MTAs) has changed the treatment strategy for hepatocellular carcinoma (HCC). However, currently, there are no established predictive biomarkers for the treatment efficacy of MTAs. Previously, we developed a novel liquid biopsy test for HCC screening using sensitive methylated DNA testing of septin 9 gene (SEPT9). Here, we hypothesized that SEPT9 could be used as a biomarker for MTA treatment efficacy. METHODS: We enrolled 157 patients receiving sorafenib or lenvatinib as a first-line therapy and allocated 85 and 72 patients to the training and validation cohorts, respectively. For the methylation assay, DNA was treated with methylation-sensitive restriction enzymes, followed by multiplex droplet digital PCR. Various clinical parameters were compared with clinical outcomes. RESULTS: The multivariate analysis revealed Eastern Cooperative Oncology Group performance status (≥ 1; p = 0.048), alpha-fetoprotein (AFP) (≥ 400 ng/mL; p < 0.001), and methylated-septin-9 (m-SEPT9) (≥ 205 copies/mL; p = 0.018) as significant predictors of poor overall survival (OS) in the training cohort. m-SEPT9 was identified as a predictor of poor OS in the validation cohort. We developed a predictive score, called the MTA score, consisting of these three significant OS parameters (two points were added for AFP and one point for each of the other predictors). Patients with MTA scores ≥ 2 showed a significantly poor prognosis compared to those with MTA scores ≤ 1 in both the training and validation cohorts. CONCLUSIONS: m-SEPT9 could be a potential predictive biomarker for survival in patients with HCC treated with MTAs.