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.

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.

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.

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.

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.

Comparison of medication adherence and satisfaction between entecavir and tenofovir alafenamide therapy in chronic hepatitis B.

Adherence to nucleotide/nucleoside analog therapy is important in improving prognosis in chronic hepatitis B. We aimed to compare medical adherence and satisfaction with entecavir (ETV) and tenofovir alafenamide (TAF) and to assess the effect of switching from ETV to TAF. Patients taking ETV (n = 114) and TAF (n = 35), and who switched from ETV to TAF (n = 15) were included. Medication adherence and satisfaction were assessed using a questionnaire. There was no significant difference in adherence between the ETV and TAF groups, but the medication satisfaction rates (0-10, prefer-dislike) were 1.72 ± 2.2 and 0.69 ± 1.5, respectively (P = .01; significantly higher in the TAF group). In patients who switched from ETV to TAF, medication adherence significantly improved (P = .04) as follows: never forgetting, from 40% to 87%; forgetting once every 2 to 3 months, from 33% to 7%; forgetting once every 2 months, from 20% to 7%, and forgetting once every 4 weeks, from 7% to 0%. Similarly, the medication satisfaction rate significantly improved from 4.53 ± 3.2 to 1.27 ± 2.4 after switching (P = .008). In conclusion, switching from ETV to TAF can be a useful approach to improve medication adherence and satisfaction.

Validation of albumin, bilirubin, and platelet criteria for avoiding screening endoscopy in patients with advanced fibrosis.

AIM: The albumin, bilirubin, and platelet (ABP) criteria was proposed to avoid screening endoscopy for detecting high-risk varices (HRV) and it has high diagnostic accuracy. We carried out a retrospective cross-sectional study to verify the diagnostic accuracy. METHODS: A total of 610 patients with advanced fibrosis were enrolled in the study. ABP criteria are defined as follows: albumin >4.0 g/dL, bilirubin <22 µmol/L, and platelets >114 000/µL. RESULTS: Background liver disease were hepatitis C/hepatitis B/non-alcoholic fatty liver disease/others:405 (66.4%)/67 (10.5%)/78 (12.8%)/60 (10.3%). A total of 105 patients (17.2%) had HRV. In multivariate analysis, serum bilirubin <22 µmol/L (HR 2.00, 95% CI 1.2-3.4), albumin >4.0 g/dL (HR 2.56, 95% CI 1.7-3.8), and platelets >114 000/µL (HR 3.52, 95% CI 2.1-5.8) levels were independently associated with no presence of HRV. When the ABP criteria were examined, 200 patients (32.8%) fulfilled the criteria, and 194 patients had no HRV (positive predictive value 97.0%) When classified by etiologies (hepatitis C/hepatitis B/non-alcoholic fatty liver disease), positive predictive value were 97.7/100/92.0%, respectively. CONCLUSIONS: The ABP criteria are easy to examine, because they use only standard laboratory tests, and they are available for screening patients who might avoid endoscopy regardless of etiologies.

Strategy for advanced hepatocellular carcinoma based on liver function and portal vein tumor thrombosis.

AIM: Tyrosine kinase inhibitor (TKI) therapy resulted in better prognosis for patients with hepatocellular carcinoma (HCC). However, some cases with Barcelona Clinic Liver Cancer (BCLC) stage C disease still had poor prognosis. This study aimed to investigate prognosis and characteristics of patients with HCC treated with TKI based on liver function and the extent of portal vein tumor thrombosis (PVTT). METHODS: Patients receiving TKI therapy (n = 345) were recruited retrospectively. Child-Pugh score and albumin-bilirubin (ALBI) score were used for assessment of liver function. The extent of PVTT was classified from Vp0 to Vp4. Radiotherapy or hepatic arterial infusion chemotherapy were carried out as additional therapy to TKI. The end-point for this analysis was overall survival (OS). RESULTS: A total of 291 and 54 patients received sorafenib and lenvatinib as first-line TKI therapy, respectively. The median OS of patients treated with TKI were significantly stratified by ALBI grade (grade 1, 20.1 months; grade 2a, 16.3 months; grades 2b and 3, 9.8 months; P = 0.0003). The classification of PVTT significantly stratified the prognosis of patients treated with TKI (median OS: Vp0, 18.5 months; Vp1/2, 14.4 months; Vp3/4, 5.5 months; P < 0.0001). In the ALBI 2b/3 and Vp3/4 groups, the median OS of patients treated with TKI and additional therapies was significantly longer than those treated with TKI only (9.2 months vs.. 3.6 months; P = 0.0129). CONCLUSION: Liver function and PVTT are useful for stratifying prognosis of HCC patients treated with TKI. The applicative classification could lead to appropriate therapy and better prognosis.

Three criteria for radiological response on survival in patients with hepatocellular carcinoma treated with lenvatinib.

AIM: Lenvatinib (LEN) is a newly approved, multikinase inhibitor for treating unresectable hepatocellular carcinoma. In the present study, we investigated the impact of three different criteria for evaluating radiological objective response (OR) on overall survival in real-world data. METHODS: Consent for LEN therapy was obtained from 51 patients from April 2018 to March 2019. A total of 40 patients who received a minimal cumulative duration of 4 weeks of LEN were included in the analysis. Enhanced computed tomography scan was performed at baseline and every 4-8 weeks after LEN administration. Overall survival and OR were assessed with three different evaluations, as follows: Response Evaluation Criteria in Solid Tumors 1.1, modified Response Evaluation Criteria in Solid Tumors, and Choi criteria. RESULTS: The average observation period for all participants after LEN introduction was 209.4 ± 77.5 days. The Response Evaluation Criteria in Solid Tumors 1.1, modified Response Evaluation Criteria in Solid Tumors, and Choi criteria identified 10 of 40 (25.0%), 15 of 40 (37.5%), and 18of 40 (45.0%) patients with OR, respectively. The median overall survival in progressive disease evaluated by each criterion was 227 days. This result was significantly shorter than OR. Furthermore, the cumulative duration of LEN administration (>150 days) represented a significant prognostic factor (HR 0.160. 95% CI 0.039-0.646, P = 0.001). CONCLUSION: The Response Evaluation Criteria in Solid Tumors 1.1, modified Response Evaluation Criteria in Solid Tumors, and Choi criteria were useful therapeutic evaluation methods in LEN therapy for unresectable hepatocellular carcinoma. LEN's appropriate effect evaluation and management might lead to a better prognosis.

Validation of hepatocellular carcinoma risk scores in Japanese chronic hepatitis B cohort receiving nucleot(s)ide analog.

BACKGROUND AND AIM: The prediction of hepatocellular carcinoma (HCC) development during nucleotide/nucleoside analog (NA) therapy is clinically important in patients with chronic hepatitis B. Although several useful models for HCC prediction have been previously reported, their usefulness in the Japanese population is unclear. Therefore, this study examines the applicability of these models in Japanese patients. METHODS: Four hundred forty-three patients with no history of HCC who were treated with entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate were enrolled. PAGE-B, modified-PAGE-B, and REACH-B scores were calculated, and subsequent HCC development was investigated. RESULTS: The mean follow-up duration was 5.1 years, and a total of 33 patients (7.4%) developed HCC during the follow-up period. Multivariate analysis revealed that old age (hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.01-1.09, P = 0.011), male gender (HR 2.62, 95% CI 1.06-6.49, P = 0.037), and low platelet count (HR 0.83, 95% CI 0.77-0.91, P < 0.001) were independent predictors of HCC development. These factors are the same as the factors identified in the PAGE-B model. Time-dependent area under the receiver operating characteristic (AUROC) curve revealed that the AUROCs for 3 and 7 years of PAGE-B (AUROC: 0.786 and 0.744 at 3 and 7 years, respectively) were continuously higher than those of REACH-B (0.658 and 0.543) and modified PAGE-B AUROC (0.772 and 0.731). CONCLUSIONS: PAGE-B, which can easily identify high-risk cases, can be useful for predicting HCC development in Japanese patients treated with NA therapy.

Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein as a Screening Tool for Significant Liver Fibrosis in Health Checkup.

Chronic liver disease is generally widespread, and a test for screening fibrotic subjects in a large population is needed. The ability of Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA+-M2BP) to detect significant fibrosis was investigated in health checkup subjects in this research. Of 2021 health checkup subjects enrolled in this prospective cross-sectional study, those with WFA+-M2BP ≥ 1.0 were defined as high risk. Liver fibrosis was evaluated using magnetic resonance elastography (MRE) in subjects with high risk. The primary outcome was the positive predictive value (PPV) of WFA+-M2BP for significant fibrosis (liver stiffness ≥ 2.97 kPa by MRE). This trial was registered with the UMIN clinical trial registry, UMIN000036175. WFA+-M2BP ≥ 1.0 was observed in 5.3% of the 2021 subjects. The PPV for significant fibrosis with the threshold of WFA+-M2BP at ≥1.0, ≥1.1, ≥1.2, ≥1.3, ≥1.4, and ≥1.5 was 29.2%, 36.4%, 43.5%, 42.9%, 62.5%, and 71.4%, respectively. A WFA+-M2BP of 1.2 was selected as the optimal threshold for significant fibrosis among high-risk subjects, and the PPV, negative predictive value, sensitivity, and specificity for significant fibrosis were 43.5%, 84.0%, 71.4%, and 61.8%, respectively. WFA+-M2BP ≥ 1.2 was significantly associated with significant fibrosis, with an odds ratio (OR) of 4.04 (95% confidence interval (CI): 1.1-16, p = 0.04), but not FIB-4 ≥ 2.67 (OR: 2.40, 95%CI: 0.7-8.6, p-value = 0.2). In conclusion, WFA+-M2BP is associated with significant fibrosis and could narrow down potential subjects with liver fibrosis. The strategy of narrowing down fibrosis subjects using WFA+-M2BP may be used to screen for fibrotic subjects in a large population.

Elevation of Neutrophil-to-Lymphocyte Ratio before First-Line Chemotherapy Predicts a Poor Prognosis for Second-Line Chemotherapy in Gastric Cancer.

OBJECTIVES: The neutrophil-to-lymphocyte ratio (NLR) has been proposed as an indicator of cancer-related inflammation. The aim of our study was to examine the prognostic value of the NLR for patients with advanced gastric cancer receiving second-line chemotherapy. METHODS: The association of overall survival (OS) in second-line chemotherapy and the clinicopathological findings including NLR were analyzed retrospectively. The selection criteria were patients who received second-line chemotherapy between January 2010 and June 2015, had histologically confirmed gastric adenocarcinoma, and were followed up until death or for 180 days or longer. RESULTS: Eighty-six patients met the selection criteria. Multivariate analysis revealed that performance status 2, hemoglobin < 10 g/dL, and NLR before first-line chemotherapy ≥3 were adverse predictive markers. NLR before second-line chemotherapy was not associated with OS. A prognostic model was constructed dividing patients into three groups according to the number of adverse predictive factors: good (no factor), intermediate (one factor), and poor (more than two factors). The median OS for the good, intermediate, and poor groups was 14.3, 7.2, and 4.4 months, respectively (p < 0.001). CONCLUSIONS: Patients with advanced gastric cancer with performance status 2, hemoglobin < 10 g/dL, and NLR before first-line chemotherapy ≥3 are not likely to benefit from second-line chemotherapy.

The source of "fairy rings": 2-azahypoxanthine and its metabolite found in a novel purine metabolic pathway in plants.

Rings or arcs of fungus-stimulated plant growth occur worldwide; these are commonly referred to as "fairy rings". In 2010, we discovered 2-azahypoxanthine (AHX), a compound responsible for the fairy-ring phenomenon caused by fungus; AHX stimulated the growth of all the plants tested. Herein, we reveal the isolation and structure determination of a common metabolite of AHX in plants, 2-aza-8-oxohypoxanthine (AOH). AHX is chemically synthesized from 5-aminoimidazole-4-carboxamide (AICA), and AHX can be converted into AOH by xanthine oxidase. AICA is one of the members of the purine metabolic pathway in animals, plants, and microorganisms. However, further metabolism of AICA remains elusive. Based on these results and facts, we hypothesized that plants themselves produce AHX and AOH through a pathway similar to the chemical synthesis. Herein, we demonstrate the existence of endogenous AHX and AOH and a novel purine pathway to produce them in plants.

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.

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.

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.

Early radiological response evaluation with response evaluation criteria in solid tumors 1.1 stratifies survival in hepatocellular carcinoma patients treated with lenvatinib.

BACKGROUND AND AIM: Lenvatinib (LEN) has an antitumor effect with an early reduction in contrast enhancement for unresectable hepatocellular carcinoma (HCC). The aim of this study was to reveal the most useful radiological response evaluation for overall survival (OS) in patients treated with LEN. METHODS: Patients receiving LEN therapy (n = 80) were retrospectively recruited from April 2018 to January 2020. Enhanced computed tomography scans were performed at baseline and every 4-8 weeks. OS and radiological response were evaluated using response evaluation criteria in solid tumors (RECIST 1.1), modified RECIST (mRECIST), and Choi criteria. To be eligible for study, a minimal cumulative duration of LEN was 4 weeks. A total of 62 patients were included in the analysis. RESULTS: The median OS was 469 days. The RECIST 1.1, mRECIST, and Choi criteria identified 14 (22.5%), 30 (48.3%), and 33 (53.2%) patients with an objective response, respectively. In the univariate analysis, Child-Pugh class B, major vascular invasion, and high alpha-fetoprotein (>200) were statistically significant poor prognostic factors. Radiological response was a significantly better prognostic factor in each criterion (RECIST, mRECIST, and Choi). In the multivariate analysis, radiological response evaluated by RECIST (hazard ratio, 0.259; 95% confidence interval, 0.0723-0.928; P = 0.038) was an independent factor. Furthermore, only RECIST significantly stratified prognosis (P = 0.041) when limited to the first evaluation. CONCLUSION: RECIST 1.1 was useful even as early therapeutic evaluation for HCC patients treated with LEN. Understanding the characteristics of radiological response over time may contribute to improving the prognosis of patients with HCC.

Relative dose intensity over the first four weeks of lenvatinib therapy is a factor of favorable response and overall survival in patients with unresectable hepatocellular carcinoma.

Lenvatinib is an approved first-line therapy for unresectable hepatocellular carcinoma (HCC), but the effect of dose modification on its efficacy is unclear. We analyzed the relationship between the relative dose intensity during the initial 4 weeks of therapy [4W-relative dose intensity (RDI)] and the efficacy of lenvatinib therapy in the real-world setting. A total of 48 consecutive patients with unresectable HCC who received lenvatinib therapy for more than 4 weeks were included. The 4W-RDI was calculated as the cumulative dose in the initial 4 weeks divided by the weight-based standard dose, and we evaluated its association with overall survival (OS) and best response by modified Response Evaluation Criteria in Solid Tumor (mRECIST). The baseline factors predicting high 4W-RDI were analyzed further. The median durations of follow-up and of therapy among the 48 participants were 7.6 and 6.6 months, respectively. The median OS was not reached. Drug interruption and/or dose reduction were necessary in 30 patients (62.5%) and the median 4W-RDI was 70% (range 22%-100%). Patients with 4W-RDI ≥70% had longer OS [hazard ratio (HR) 0.28, 95% confidential interval (CI):0.09-0.90, p = 0.03], and longer duration of lenvatinib therapy (HR 0.39, 95%CI:0.16-0.92, p = 0.03). Patients with 4W-RDI ≥70% showed higher disease control rate compared to those with 4W-RDI <70% (91.7% vs. 54.2%, p = 0.008). A baseline albumin level >3.4g/dL or ALBI score less than -2.171 were significantly associated with achieving 4W-RDI ≥70%. In conclusion, 4W-RDI of lenvatinib therapy is associated with favorable radiological response and longer OS.

Hepatitis B surface antigen reduction as a result of switching from long-term entecavir administration to tenofovir.

BACKGROUND AND AIM: Loss of hepatitis B surface antigen (HBsAg) is an important goal in the treatment of chronic hepatitis B. We investigated whether switching from long-term entecavir (ETV) administration to tenofovir (TFV) (tenofovir alafenamide [TAF] or tenofovir disoproxil fumarate [TDF]) could contribute to the reduction of HBsAg levels. METHODS: The degree of HBsAg reduction by 48 weeks in 30 patients following switching from ETV to TFV was compared with results from 147 patients who continued ETV as a control. RESULTS: TFV group switched to TFV after mean 6.79 years of ETV administration. HBV-DNA levels remained below 1.0 log IU/mL in all cases in both groups during 48 weeks. Median HBsAg reduction at 48 weeks was 0.075 (-0.05 to 0.38) log/IU/mL in the TFV switch group, and 0.070 (-0.28 to 0.50) in the ETV continuation group, which was not statistically significant (p = 0.5). In a subgroup of hepatitis B e antigen negative patients whose HBsAg had not been reduced (HBsAg reduction ≤0 log IU/mL) in the 48 weeks prior to entry into the study, HBsAg reduction was significantly higher in the TFV switch group than in the ETV continuation group (0.15 [0.07-0.135] in TFV, 0.09 [-0.14 to 0.25] log IU/mL in ETV, p = 0.04). CONCLUSION: Although HBsAg reduction is equivalent with ETV continuation and switching to TFV in all patients at 48 weeks, switching from ETV to TFV could provide an alternative therapeutic strategy toward HBsAg elimination in a specific subpopulation of patients.