Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines.

In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.

Detecting advanced liver fibrosis using ultrasound shear wave velocity measurement in the general population.

Background: Advanced fibrosis detection in the general population is an unmet need. Additionally, screening method for advanced fibrosis in the general population is not established. Thus, this study aimed to examine the use of shear wave measurement (SWM), which measures liver stiffness by ultrasound elastography as a screening tool for advanced fibrosis in health checkups that represents the general population. Methods: SWM was performed in all subjects. Magnetic resonance elastography (MRE) was performed in those with SWM shear wave velocity (Vs) ≥1.3 m/s to determinate advanced fibrosis. The diagnostic accuracy of SWM Vs for advanced fibrosis (determined by MRE of ≥3.62 kPa) was examined. This prospective study was registered with the University Hospital Medical Information Network clinical trial registry (UMIN000041609). Results: A total of 2,233 subjects were included. SWM Vs of 1.64 m/s was selected as the best threshold for advanced fibrosis. Using the threshold of SWM Vs at ≥1.64 m/s, subjects were narrowed down to 1.7%, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for advanced fibrosis were 53.3%, 92.4%, 47.1%, and 94.0%, respectively, among these subjects. The multivariable analysis, after adjusting the age, sex, body mass index (BMI), hypertension, diabetes mellitus (DM), dyslipidemia, and alcohol use, revealed an SWM Vs of ≥1.64 m/s as the significant factor for advanced fibrosis with an odds ratio (95% confidence interval) of 14.5 (3.4-62; P<0.001). Conclusions: SWM has high diagnostic accuracy for advanced fibrosis (PPV 47.1%) and may be used as a screening tool for liver fibrosis in the general population.

Effect of fatty liver and fibrosis on hepatocellular carcinoma development in patients with chronic hepatitis B who received nucleic acid analog therapy.

The number of patients with fatty liver has been increasing worldwide; however, the significance of fatty liver in patients with chronic hepatitis B who are receiving nucleic acid analog (NA) therapy remains unclear. Thus, we aimed to determine whether fatty liver affects the development of hepatocellular carcinoma (HCC) in patients receiving NA therapy. This study included 445 patients who received NA therapy, and the development of HCC was investigated. The primary outcome was the association between fatty liver and HCC development. During a mean follow-up period of 7.4 years, 46 patients (10.3%) developed HCC. No significant difference in the cumulative incidence of HCC was observed between patients with fatty liver and those without (p = 0.17). Multivariable analysis for age, gender, platelet count, alanine aminotransferase level at 1 year following NA therapy, and fatty liver revealed that the presence of fatty liver was not a significant factor for HCC development (hazard ratio [HR]: 0.96, 95% confidence interval [CI]: 0.5-1.9). In another multivariable analysis for advanced fibrosis, gender, and fatty liver, advanced fibrosis was found to be a significant factor for HCC development (HR: 9.50, 95% CI: 5.1-18) but not fatty liver (HR: 0.90, 95% CI: 0.5-1.7). In conclusion, in patients with chronic hepatitis B who received NA therapy, advanced fibrosis was found to be an important risk factor for HCC development but not fatty liver, suggesting the importance of providing treatment before the progression of liver fibrosis regardless of the presence of fatty liver.

Alanine aminotransferase levels as therapeutic targets after nucleotide/nucleoside analog therapy in patient with chronic hepatitis B.

AIM: Alanine aminotransferase (ALT) is a criterion for the introduction of nucleotide/nucleoside analog (NA), and ALT levels are decreased by NA treatment. However, the association between post-treatment ALT levels and hepatocellular carcinoma (HCC) risk remains unclear. To fill this gap, we aimed to establish a target value of ALT level during NA treatment. METHODS: In total, 413 patients with chronic hepatitis B who received entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate were enrolled. The subsequent development of HCC was examined and a target value of ALT level during NA treatment as a risk marker for HCC was evaluated. RESULTS: The median follow-up duration was 5.1 years, during which time 27 patients (8.6%) developed HCC. ALT level at the start of treatment was not associated with HCC development (p = 0.08). When stratified by ALT at 1 year after NA initiation, the cumulative 3- and 5-year rates of HCC for patients with ALT ≥21 IU/L were 11.5% and 18.1%, and those with ALT <21 IU/L was 2.3% and 6.5%, respectively. Patients with ALT <21 IU/L had a significantly lower risk of HCC development compared with patients with ALT ≥21 IU/L (p = 0.002). In multivariable analysis adjusting age, sex, and platelet counts, ALT ≥21 IU/L was an independent risk factor of HCC development with hazard ratio of 4.5 (95% confidence interval: 1.01-20.4). CONCLUSIONS: ALT <21 IU/L at 1 year after NA initiation has a lower risk of HCC and could be used as a target value for NA treatment.

Conversion surgery for hepatocellular carcinoma after tyrosine kinase inhibitor treatment.

Background and Aim: Conversion surgery (CS), which aims to cure after systematic therapy, is only scarcely reported in the field of hepatocellular carcinoma (HCC). However, advancements in systemic therapy for HCC are expected to increase the candidates eligible for CS because of the higher response rate. The aim of this study was to clarify the characteristics of patients who underwent CS after tyrosine kinase inhibitor (TKI) therapy. Methods: In all, 364 patients who were treated with first-line sorafenib (SOR; n = 292) and lenvatinib (LEN; n = 72) from July 2009 to October 2020 were retrospectively enrolled. The endpoint of this analysis was overall survival (OS), and factors associated with CS are revealed. Results: Six patients underwent CS after TKI therapy, and of these four (1.4%) and two (2.7%) patients received SOR and LEN, respectively. At baseline, patients who underwent CS were significantly younger (median 52 [range, 46-83] years of age, P = 0.019), and their etiology included viral hepatitis, especially hepatitis B virus (HBV) (P = 0.049). Improvements or maintenance of preoperative modified albumin-bilirubin grade from baseline were observed in five (83.3%) patients, and partial radiologic response was observed in four (66.7%) patients. The median OS and 3-year survival rate of patients treated with CS were "not reached" and 80.0%, respectively. Conclusion: The patients who underwent CS after TKI therapy for HCC experienced long survival, were relatively young, and exhibited radiologic response to TKIs, and their liver function was either maintained or improved. Therefore, CS may lead to a better prognosis in patients with advanced HCC.

Validation of magnetic resonance elastography plus fibrosis-4 for significant fibrosis in nonalcoholic fatty liver disease.

BACKGROUND AND AIM: MEFIB (the combination of magnetic resonance elastography [MRE] ≥ 3.3 kPa and fibrosis-4 (FIB-4) ≥ 1.6) is useful for detecting patients with significant fibrosis (fibrosis stage ≥ 2) having nonalcoholic fatty liver disease (NAFLD). However, age-dependent thresholds of FIB-4 have been proposed, and it remains unclear whether MEFIB could be applied with the same FIB-4 threshold in a different cohort. Therefore, in this study, we examined the best threshold of FIB-4 and validated the utility of MEFIB. METHODS: This study included 105 biopsy-proven NAFLD patients with contemporaneous MRE assessment. The primary outcome was a diagnostic accuracy for significant fibrosis. RESULTS: The median (interquartile range) age was 65 (58-72) years, and significant fibrosis was 76.2% (80/105). FIB-4 of 2.1 was defined as the best threshold for significant fibrosis in the cohort. The area under the receiver operating characteristics curves (AUROCs) of the combination of MRE and FIB-4 (MRE ≥ 3.3 kPa + FIB-4 ≥ 1.6: 0.80, MRE ≥ 3.3 kPa + FIB-4 ≥ 2.1: 0.84) were higher than those of each index alone (MRE ≥ 3.3 kPa: 0.76, FIB-4 ≥ 1.6: 0.72, and FIB-4 ≥ 2.1: 0.77), but AUROCs of MRE ≥ 3.3 kPa + FIB-4 ≥ 1.6 and MRE ≥ 3.3 kPa + FIB-4 ≥ 2.1 were equivalent (P = 0.3). CONCLUSIONS: MEFIB is useful for detecting patients with significant fibrosis and could be utilized in a different cohort without changing the threshold of FIB-4, and it may then be used as a two-step screening strategy.

Clinical usefulness of geriatric assessment in elderly patients with unresectable hepatocellular carcinoma receiving sorafenib or lenvatinib therapy.

BACKGROUND: Therapeutic strategies for unresectable hepatocellular carcinoma (u-HCC) in geriatric patients are important for real-world practice. However, there remain no established biomarkers or therapeutic strategies regarding the best second-line agent after atezolizumab plus bevacizumab therapy. AIM: In this study, we investigated the usefulness of modified Geriatric 8 (mG8) score in examining elderly patients (≥75 years old) with unresectable hepatocellular carcinoma (u-HCC) using sorafenib or lenvatinib as first-line therapy. METHODS AND RESULTS: This study assessed 101 elderly patients with u-HCC for their mG8 score (excluding elements of age from 8 items) and classified them into 2 groups according to their mG8 score: ≥11 as the high-score group and ≤ 10 as the low-score group. Among those taking sorafenib, no significant differences were noted in overall survival (OS) and progression free survival (PFS) between low and high mG8 score groups. Only modified albumin-bilirubin (ALBI) grade (2b/3 vs. 1/2a: HR 0.34; 95% CI, 0.17-0.69; p = .0029) was significantly associated with OS. Among those taking lenvatinib, patients with a high mG8 score (n = 26) had longer survival than those with a low mG8 score (n = 10) (20.0 months vs. 7.7 months: HR 0.31, 95% CI 0.11-0.89; p = .029). Intrahepatic tumor volume (<50% vs. ≥50%: HR 16.7; 95% CI, 1.71-163; p = .016) and α-fetoprotein (AFP) (<400 vs. ≥400: HR 3.38; 95% CI 0.84-19.7; p = .031) remained significant factors independently associated with OS. CONCLUSIONS: The mG8 score may contribute to making a decision when considering either sorafenib or lenvatinib as a treatment option for u-HCC in elderly patients.

Clinical evaluation of Elecsys PIVKA-II for patients with advanced hepatocellular carcinoma.

BACKGROUND: Prothrombin induced by vitamin K absence-II (PIVKA-II) was reported as a diagnosis and prognosis marker for hepatocellular carcinoma (HCC). Although the development of systemic therapies for advanced HCC has been remarkable, the role of PIVKA-II is unclear. This prospective study aimed to verify Elecsys PIVKA-II compared with Lumipulse PIVKA-II in a cohort with advanced HCC undergoing systemic therapy. METHODS: A total of 62 HCC patients who were treated with atezolizumab and bevacizumab (ATZ+BEV) and molecular targeted agents (MTAs) were prospectively enrolled at Musashino Red Cross Hospital from January 2020 to December 2020. A total of 208 serum samples from 52 patients were tested using Elecsys PIVKA-II and Lumipulse PIVKA-II assays. Furthermore, the relationship of Elecsys PIVKA-II and progression-free survival (PFS) was investigated with 48 patients (24 ATZ+BEV and 24 MTAs) whose Lumipulse PIVKA-II levels were >40 mAU/mL. RESULTS: In the test accuracy analysis, the Elecsys assay has a correlation coefficient (R) of 0.92 compared with that of the Lumipulse assay (ATZ+BEV, 0.95; MTAs, 0.91). In the PFS analysis, the number of patients who received ATZ+BEV and MTAs as first- and late-line therapy were 9 and 13, and 15 and 11, respectively. The PIVKA-II response was defined for patients who had a reduction in the Elecsys PIVKA-II level on the first month of treatment evaluation. The PFS of patients with Elecsys PIVKA-II response was significantly longer than that of nonresponse patients (5.8 months vs 3.8 months, p = 0.0205). CONCLUSION: The Elecsys PIVKA-II was not only as useful as the Lumipulse PIVKA-II but also for stratifying the PFS of patients with advanced HCC.

The impact of background liver disease on the long-term prognosis of very-early-stage HCC after ablation therapy.

BACKGROUND AND AIM: The long-term prognosis of hepatocellular carcinoma (HCC) treated at a very-early-stage (the Barcelona Clinical Liver Cancer (BCLC) classification stage 0) was unclear, especially in terms of background liver disease. METHODS: This single-center, retrospective study included 302 patients with BCLC stage 0 HCC treated with radiofrequency ablation (RFA) and followed for at least six months. We examined the impact of background liver disease on overall survival and recurrence. RESULTS: The median age was 72 (range; 36-91) years; the median tumor diameter was 15 (range; 8-20) mm. The etiologies of background liver disease were hepatitis B virus infection (HBV) in 24 cases, hepatitis C virus infection (HCV) in 195 cases, and non-viral (NBNC) in 83 cases. Among the patients with HCV, 63 had achieved sustained virological response (SVR) by antiviral therapy (HCV SVR) before developing HCC (n = 37) or after HCC treatment (n = 26), and 132 had active HCV infection (HCV non-SVR). The median overall survival was 85 (95% CI; 72-98) months, and the median recurrence-free survival was 26 (95% CI; 20-30) months. Active infection with hepatitis C virus negatively contributed to overall survival (HR 2.91, 95% CI 1.31-3.60, p = 0.003) and recurrence-free survival (HR 1.47, 95% CI 1.06-2.05, p = 0.011). CONCLUSIONS: The prognosis of RFA treatment for very early-stage HCC was favorable. Achieving SVR in hepatitis C was important for further prognosis improvement.

Early experience of atezolizumab plus bevacizumab therapy in Japanese patients with unresectable hepatocellular carcinoma in real-world practice.

BACKGROUND: We aimed to investigate the efficacy and safety of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (u-HCC) based on whether they had previously received systemic therapy, as well as the association of atezolizumab plus bevacizumab with early alpha-fetoprotein (AFP) response in real-world practice. METHODS: A total of 52 patients with u-HCC were treated with atezolizumab plus bevacizumab between October 2020 and April 2021. The Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST were used to evaluate radiological responses. RESULTS: The patients received atezolizumab plus bevacizumab as 1st-line (n = 23), 2nd-line (n = 16), 3rd-line (n = 6), 4th-line (n = 3), 5th-line (n = 3), or 6th-line (n = 1) therapy. According to RECIST, the objective response rate (ORR) and disease control rate (DCR) in all patients were 15.4% and 57.7%. In the 1st-line patients, ORR and DCR based on RECIST 1.1 were 27.3% and 81.8%. The median time to progression (TTP) assessed by RECIST was significantly longer among patients receiving atezolizumab plus bevacizumab as 1st-line therapy than in patients receiving atezolizumab plus bevacizumab as later-line therapy (P < 0.001). Patients with an AFP response (reduction ≥ 20% from baseline) at 6 weeks had a significantly longer TTP assessed by RECIST than those without an AFP response (P = 0.02). CONCLUSION: Patients who received atezolizumab plus bevacizumab as 1st-line therapy had better clinical outcome than those who received atezolizumab plus bevacizumab in later lines. The AFP response at 6 weeks could be a predictor of disease progression.

Plasma Renin Activity Predicts Prognosis and Liver Disease-Related Events in Liver Cirrhosis Patients with Ascites Treated by Tolvaptan.

BACKGROUND AND AIMS: A retrospective study was to analyze the association of plasma renin activity (PRA) with overall survival and liver disease-related events in decompensated liver cirrhosis with ascites treated by tolvaptan. METHODS: We included 196 patients with decompensated cirrhosis treated with tolvaptan and for whom hepatic ascites had remained uncontrolled by conventional diuretics. Factors associated with prognosis and appearance of liver disease-related events were investigated, including vasopressin, sympathetic nervous system hormones (adrenaline, noradrenaline, and dopamine), and the renin-angiotensin system (PRA and aldosterone) at the beginning of tolvaptan treatment. RESULTS: Age, history of hepatocellular carcinoma (HCC), and PRA were identified as independent factors for prognosis after tolvaptan treatment. The median survival time in patients with PRA ≥9.5 ng/mL/h at the beginning of tolvaptan treatment was significantly shorter than in patients with PRA <9.5 ng/mL/h (193 vs. 893 days, p < 0.001). PRA and a history of HCC were independent factors for the occurrence of liver disease-related events. The median event-free period in patients with PRA ≥3.2 ng/mL/h was significantly shorter than that of patients with PRA <3.2 ng/mL/h (89 vs. 222 days, p < 0.001). CONCLUSIONS: PRA is an independent predictor of prognosis and appearance of liver disease-related events in patients with decompensated cirrhosis who have started tolvaptan treatment.

Longitudinal association of magnetic resonance elastography-associated liver stiffness with complications and mortality.

BACKGROUND: Magnetic resonance elastography (MRE) has the highest diagnostic accuracy for liver fibrosis; however, the association between MRE-associated liver stiffness and the development of hepatic and extrahepatic complications as well as mortality remains unclear. AIM: In this study, we investigated the longitudinal association between MRE-associated liver stiffness and complications and mortality. METHODS: This retrospective study included 2373 consecutive patients with chronic liver disease. All patients received standard of care and the development of complications was assessed every 1-6 months. RESULTS: Newly diagnosed hepatocellular carcinoma (HCC), decompensation, major adverse cardiovascular events (MACE), extrahepatic cancer and death were observed in 99, 117, 73, 77 and 170 patients respectively. In multivariable analysis, the adjusted hazard ratios (aHR) (95% confidence interval [CI]) for HCC, decompensation, MACE, extrahepatic cancer and mortality were 1.28 (1.2-1.4), 1.34 (1.3-1.4), 0.96 (0.9-1.1), 1.00 (0.9-1.1) and 1.17 (1.1-1.2), respectively, with each 1-kPa increase in liver stiffness. Similarly, the aHR (95% CI) for HCC, decompensation, MACE, extrahepatic cancer and mortality were 4.20 (2.2-8.2), 67.5 (9.2-492), 0.83 (0.4-1.7), 0.90 (0.5-1.7) and 2.90 (1.6-5.4), respectively, in patients with cirrhosis (>4.7 kPa) compared to those with minimal fibrosis (<3 kPa). CONCLUSIONS: Increased MRE-associated liver stiffness was associated with increased risk for HCC, decompensation and mortality in a dose-dependent fashion but not with MACE or extrahepatic cancer, implicating a significant role for MRE in liver-related events and mortality; however, further studies are warranted to explore its role in MACE and extrahepatic cancer.

Tenofovir alafenamide for prevention and treatment of hepatitis B virus reactivation and de novo hepatitis.

BACKGROUND AND AIM: Administration of tenofovir alafenamide (TAF) as prevention or treatment of hepatitis B virus (HBV) reactivation is not well known. The aim of this study is to reveal the efficacy and safety of TAF against HBV reactivation. METHODS: Entecavir (ETV) and TAF were given to 66 and 11 patients, respectively, as prophylaxis against or treatment of HBV reactivation during chemotherapy or immune suppression therapy from January 2010 to June 2020. The antiviral effects and safety were assessed. RESULTS: At week 24, the antiviral effects on patients receiving ETV and TAF were similar in terms of reduction of HBV DNA (-2.83 ± 1.45log IU/mL vs -3.05 ± 2.47log IU/mL; P = 0.857) and achieving undetectable levels of HBV DNA (78.8 vs 90.9%; P = 0.681). There was no significant difference in the decrease in the estimated glomerular filtration rate (eGFR) between the two groups (-0.62 ± 11.2 mL/min/1.73 m2 vs -3.67 ± 13.2 mL/min/1.73 m2; P = 0.291). CONCLUSION: TAF is safe and effective against HBV reactivation.

Liver fibrosis and fatty liver as independent risk factors for cardiovascular disease.

BACKGROUND AND AIM: The association between liver fibrosis, fatty liver, and cardiovascular disease (CVD) risk is unknown. Hence, this study aimed to investigate the association of liver fibrosis and fatty liver with CVD risk independent of already known CVD risk comorbidities. METHODS: This is a prospective study registered with the University Hospital Medical Information Network clinical trial registry (UMIN000036175). Liver fibrosis was assessed by serum fibrosis markers including FIB-4, nonalcoholic fatty liver disease fibrosis score (NFS), and Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP), whereas fatty liver was diagnosed by ultrasonography. CVD risk was evaluated using the Framingham risk score (FRS), and a high CVD risk was defined as an FRS ≥ 20%. RESULTS: A total of 3512 subjects were enrolled, and high CVD risk (FRS ≥ 20%) was observed in 17.5%. Advanced fibrosis (FIB-4 ≥ 2.67, NFS ≥ 0.675, and WFA+ -M2BP ≥ 1.0) and the presence of fatty liver were significantly associated with high CVD risk independent of diabetes mellitus, dyslipidemia, and hypertension. When subjects were stratified by liver fibrosis and fatty liver, subjects with advanced fibrosis and fatty liver have the highest odds for high CVD risk (odds ratio [OR]: 5.90-35.6), followed by subjects with advanced fibrosis and without fatty liver (OR: 2.53-9.62) using subjects without advanced fibrosis and fatty liver as a reference. CONCLUSIONS: Liver fibrosis and fatty liver were associated with CVD risk independent of already known CVD risk comorbidities. The assessment of liver fibrosis and fatty liver may be useful to identify high CVD risk subjects.

Hepatitis B core-related antigen predicts disease progression and hepatocellular carcinoma in hepatitis B e antigen-negative chronic hepatitis B patients.

BACKGROUND AND AIM: The serum hepatitis B core-related antigen (HBcrAg) is considered a surrogate marker of the amount and activity of intrahepatic covalently closed circular DNA. This study aims to investigate the virological characteristics of HBcrAg in chronic hepatitis B (CHB) patients and to reveal the hepatocellular carcinoma (HCC) risk factors of hepatitis B e antigen (HBeAg)-negative patients. METHODS: Hepatitis B core-related antigen was measured in 245 naive CHB patients before receiving nucleoside/nucleotide analog (NA) therapy. All patients were receiving NA (entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide) continuously for more than 1 year until the end of follow-up, and they did not have a history of HCC. Hepatitis B viral status was compared between 106 HBeAg-positive and 139 HBeAg-negative patients. RESULTS: Median HBcrAg levels were significantly higher in HBeAg-positive patients than in HBeAg-negative patients (> 6.8 vs 3.7 log U/mL, P < 0.01). In HBeAg-negative patients, higher HBcrAg levels were associated with cirrhosis (119 chronic hepatitis/20 cirrhosis = 3.5/4.7 log U/mL, P = 0.03) and higher serum hepatitis B virus DNA. During a median follow-up of 5.28 (1.03-12.0) years, the 5-year cumulative HCC incidence rate was 5.4% in the HBeAg-negative cohort. In the multivariate Cox regression analysis, higher HBcrAg levels at 1 year were independent predictive factors for HCC development in HBeAg-negative patients who received NA therapy (cutoff value, 4.1 log U/mL; hazard ratio, 6.749; 95% confidence interval, 1.334-34.15, P < 0.01) and even in non-cirrhosis patients. CONCLUSION: Hepatitis B core-related antigen was useful for understanding disease progression in CHB patients and for stratifying the risk for carcinogenesis in HBeAg-negative patients receiving NA therapy.

Prognosis of intrahepatic cholangiocarcinoma stratified by albumin-bilirubin grade.

AIM: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy. However, the characteristics and prognosis of ICC is not well known. This study aims to reveal the relationship between liver function and prognosis of ICC. METHODS: A total of 83 ICC patients were recruited retrospectively from March 2009 to August 2020. Child-Pugh (CP) and albumin-bilirubin (ALBI) scores were used to assess liver function. The extent of portal vein tumor thrombosis (PVTT) was classified from Vp0 to Vp4. The end-point for this analysis was overall survival (OS). RESULTS: The median age was 72 (44-88) years, 48 patients were male (57.8%), and 70 patients were classified as CP grade A (84.3%). At baseline, chronic liver disease (hepatitis B, 9.6%; hepatitis C, 15.7%; alcoholic liver disease, 9.6%; and nonalcoholic fatty liver disease, 4.8%) were diagnosed. The median OS of all ICC patients was 21.2 months. A total of 27 patients underwent surgical resection; these patients showed a longer median OS compared to those who did not undergo surgery (50.8 months vs. 5.5 months, p < 0.001). The prognosis of patients with ICC can be stratified by ALBI grade (grade 1, 54.3 months; grade 2a, 8.4 months; grade 2b, 3.9 months; and grade 3, 1.4 months; p < 0.001) and the extent of PVTT (Vp0, 54.3 months; Vp1/2, 8.4 months; and Vp3/4, 3.9 months; p = 0.0039). CONCLUSION: In this study, viral hepatitis (25.3%) was identified as the most prevalent background liver disease of ICC. Assessing liver function using ALBI grade is useful for stratifying the prognosis of patients with ICC.

Dynamic evaluation of hepatocellular carcinoma prediction models in patients with chronic hepatitis B receiving nucleotide/nucleoside analogue treatment.

Carcinogenesis risk scores for chronic hepatitis B have been proposed, but it remains unclear whether these scores during nucleoside/nucleotide analogue (NA) therapy are useful for risk assessment. In this study, we examined changes of these scores and the predictability during NA treatment. 432 patients with no history of hepatocellular carcinoma (HCC) treated with NA were enrolled. PAGE-B, modified PAGE-B (mPAGE-B), and REACH-B scores were calculated at NA administration, 1 and 2 years after administration. The median follow-up duration was 5.1 years, during which 37 patients (8.6%) developed HCC. Cumulative incidence HCC development in patients with high risk of PAGE at NA administration, and 1 and 2 years after NA administration was significantly higher than those with intermediate and low-risk groups (p < .05 for all time points), whereas HCC incidence in patients with high risk of mPAGE-B and REACH-B at 2 years after NA administration were equivalent to those with intermediate and low-risk groups (p = .2 for mPAGE-B, and p = .1 for REACH-B). The area under the receiver operating characteristic (AUROC) for HCC development of PAGE-B at NA administration, and 1 and 2 years after administration were 0.773, 0.803 and 0.737, respectively. The AUROCs of PAGE-B at each point were continuously higher than those of REACH-B (0.646, 0.725, and 0.653, respectively) and mPAGE-B (0.754, 0.734, and 0.678, respectively).PAGE-B score has a high diagnostic accuracy for HCC development at any time point during NA treatment, indicating its potential use as a real-time monitor of HCC development.

Changes of liver stiffness measured by magnetic resonance elastography during direct-acting antivirals treatment in patients with chronic hepatitis C.

Almost all patients achieved sustained virological response (SVR) by direct-acting antivirals (DAA) therapy, but it is not clear as to what extent DAA therapy affects changes in liver fibrosis after achieving SVR. In this study, we investigated the changes of liver stiffness by magnetic resonance elastogaraphy (MRE) during DAA therapy. A total of 308 patients were enrolled in the study. Liver stiffness was measured twice before and after DAA treatment using MRE and time-course change of liver stiffness was investigated. The median (interquartile range) values for liver stiffness were 4.2 (3.2-6.1) kPa at baseline and 3.3 (2.6-4.8) kPa at SVR, demonstrating a significant improvement (p < .01). A total of 44% of patients had no improvement in liver stiffness despite achieving SVR. In patients with advanced fibrosis (lower level of albumin [Alb] or histological fibrosis stage F4), it was difficult to improve liver stiffness. Except for Alb, there were no blood tests associated with nonimprovement in liver stiffness, making these cases difficult to predict. In conclusion, despite obtaining SVR, improvement in liver stiffness could not be obtained in some cases, especially in patients with advanced fibrosis. In these patients, liver stiffness must be followed even if SVR is obtained.