Predictive factors for transition to conversion therapy in hepatocellular carcinoma using atezolizumab plus bevacizumab.

BACKGROUND: To identify predictive factors associated with successful transition to conversion therapy following combination therapy with atezolizumab and bevacizumab in the treatment of unresectable hepatocellular carcinoma (HCC). METHODS: In total, 188 patients with HCC, who received atezolizumab plus bevacizumab combination therapy as the first-line chemotherapy, were studied. Patients who achieved complete response (CR) with systemic chemotherapy alone were excluded. Clinical factors possibly linked to successful transition to conversion therapy and the achievement of cancer-free status were identified. RESULTS: Fifteen (8.0%) patients underwent conversion therapy. In the conversion group, there was a significantly higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage A or B (73.3% versus [vs.] 45.1%; p = .03) and tended to have lower Child-Pugh scores and alpha-fetoprotein levels. Multivariate analysis revealed that BCLC stage was a predictive factor for the implementation of conversion therapy (A or B; odds ratio 3.7 [95% CI: 1.1-13]; p = .04). Furthermore, 10 (66.7%) patients achieved cancer-free status and exhibited a smaller number of intrahepatic lesions at the start of treatment (3.5 vs. 7; p < .01), and a shorter interval between systemic chemotherapy induction and conversion therapy (131 vs. 404 days; p < .01). In addition, the rate of achieving cancer-free status by undergoing surgical resection or ablation therapy was significantly higher (p = .03). CONCLUSION: BCLC stage was the sole predictive factor for successful transition to conversion therapy when using combination therapy with atezolizumab and bevacizumab to treat HCC. Furthermore, a small number of intrahepatic lesions and early transition to conversion therapy were associated with the achievement of cancer-free status.

Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA.

BACKGROUND: Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepatitis, there should be a rationale for the choice of therapeutic options based on these etiologies. Although cabozantinib, an oral multikinase inhibitor, has demonstrated clinical effectiveness in advanced HCC, subgroup analyses showed a lower HR for death in HBV-related HCC. This study aimed to determine the therapeutic effects of cabozantinib in HBV-related HCC. METHODS: Using HBV infection models and gene knockout cells, we determined the crucial signaling axis responsible for the effects of cabozantinib on HBV. A chromatin immunoprecipitation assay was performed to determine the interaction between the signaling molecules and HBV DNA. Agonists and inhibitors were used for confirmation. RESULTS: Cabozantinib inhibited HBV replication through the HGF-mesenchymal-epithelial transition factor-signal transducer and activator of transcription 3 (MET-STAT3) signaling axis. The importance of STAT3 in viral replication has been confirmed using gene-edited STAT3 knockout cells. The chromatin immunoprecipitation assay revealed that the binding levels of phosphorylated STAT3 to enhancer region 1 of HBV covalently closed circular DNA were significantly increased by HGF stimulation. CONCLUSIONS: Cabozantinib has favorable therapeutic effects on HBV-related HCC because it inhibits HCC not only directly but also indirectly by means of inhibitory effects on HBV.

Predictive Factors for Recovery from Alcoholic Liver Failure.

Alcoholic liver disease is a risk factor for non-virus-related hepatocellular carcinoma (HCC), which is increasing in prevalence. This study aimed to identify the factors for recovery from alcoholic liver failure. Sixty-two consecutive patients hospitalized for alcoholic liver failure at Okayama City Hospital were enrolled. The characteristics of patients who survived to the 1-month follow-up and whose liver function improved to Child-Pugh A at 3 months (CPA3) and 12 months (CPA12) were compared with the rest of the patients. The survivors at 1 month (50 patients) were significantly younger than the deceased patients and had better liver and renal function with higher levels of γ-glutamyl transferase (GGT). The same factors, except renal function, were correlated with achieving CPA3. High AST, ALT, and GGT levels as well as short spleen length, total abstinence, and good Child-Pugh scores at admission were identified as factors for achieving CPA12. The extent of alcohol intake before admission was not identified as a risk factor in any analysis. In conclusion, baseline liver function is crucial for survival and achieving CPA3, whereas high transaminase and γ-GTP levels, the absence of splenomegaly, and total abstinence are significant factors for achieving CPA12.

Chronological change in serum albumin as a prognostic factor in patients with hepatocellular carcinoma treated with lenvatinib: proposal of albumin simplified grading based on the modified albumin-bilirubin score (ALBS grade).

BACKGROUND: The albumin-bilirubin (ALBI) score and the modified ALBI (mALBI) grade are known useful prognostic factors for patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN-HCC). However, the ALBI score requires complicated logarithmic calculations. Therefore, we attempted to create a simplified score. METHODS: We developed the albumin simplified (ALBS) grade that corresponded to mALBI using the data of 5985 newly developed HCC and examined the usefulness of this grading system for the prediction of the prognosis of 678 patients with LEN-HCC. RESULTS: The analysis using Cox proportional hazard models revealed that the overall survival of patients with LEN-HCC was not correlated with the total bilirubin but albumin (Alb), which means that the prediction with Alb alone was logical. The ALBS grade cutoffs that corresponded to mALBI grade 1, 2a, 2b, and 3 were Alb ≧ 4.0 g/dL, 4.0 g/dL > Alb ≧3.5 g/dL, 3.5 g/dL > Alb≧2.8 g/dL, and Alb < 2.8 g/dL, respectively. The stratification ability of the ALBS grade for LEN-HCC was good. The Akaike information criterion (AIC) and c-index were comparable with those of mALBI (AIC 4096.3 vs. 4090.7, c-index 0.765 vs. 0.778). The prognosis of LEN-HCC was stratified by the ALBS grade at 1 month after starting LEN, and patients with ALBS grade 1/2a demonstrated better survival than patients with ALBS grade 2b/3 regardless of the ALBS grade before treatment. CONCLUSION: The ALBS grade is easy to calculate and is useful for the prediction of the prognosis of LEN-HCC.

Global and regional long-term survival following resection for HCC in the recent decade: A meta-analysis of 110 studies.

Surgical resection for HCC remains a major curative treatment option, but it is unclear whether there are differences in outcomes by region and whether outcomes have improved over time. We aimed to estimate pooled overall survival (OS), recurrence-free survival (RFS), and complication rates in patients with hepatocellular carcinoma (HCC) following curative surgical resection and to compare outcomes by region and by time period. In this systematic review and meta-analysis, we searched Pubmed, Embase, and Cochrane databases from inception to May 15, 2020. We selected studies reporting OS, RFS, and complications in adult patients with HCC undergoing curative surgical resection. Two authors independently searched the literature and extracted the data. We screened 6983 articles and included 110 eligible studies with 82,392 patients, with study periods spanning from 1980-2017. The global pooled 1-year and 5-year survival rates were 88.9% (95% confidence interval [CI] 87.1-90.4) and 56.2% (95% CI 52.8-59.6) for OS and 71.1% (95% CI 67.6-74.3) and 35.2% (95% CI 32.5-38.0) for RFS, respectively. Five-year OS was higher in Asia (57.03%) than in other regions (Europe 48.3%; North America 48.0%; and South America 49.5%); p = 0.002. Five-year RFS was higher in patients with hepatitis B virus versus patients with hepatitis C virus (34.8% vs. 24.1%; p = 0.02). There was no significant improvement in 5-year OS and RFS over time. The pooled rate for complications was 27.6% (95% CI 23.4-32.3), with 9.7% (95% CI 6.3-14.7) classified as major. One-year OS after surgical resection for HCC is excellent (~90%). However, 5-year OS (~55%) and RFS (~35%) are still poor, suggesting that long-term care is suboptimal. Greater efforts are required to improve survival through enhanced surveillance and preventing recurrence through antiviral therapy.

Abnormal fucosylation of alpha-fetoprotein in patients with nonalcoholic steatohepatitis.

AIM: Nonalcoholic steatohepatitis (NASH) is a risk factor for nonvirus-related hepatocellular carcinoma, which is increasing in prevalence. The aim of this study was to clarify the clinical application of fucosylated alpha-fetoprotein (AFP-L3) in the process of nonalcoholic fatty liver (NAFL) disease development. METHODS: Serum samples from 115 diabetes mellitus (DM), 36 NAFL, and 119 NASH patients were analyzed for AFP-L3 expression using raw data of a micro total analysis system. These data were then compared with the clinical characteristics of the patients. A validation study was also undertaken with 55 samples (17 NAFL and 38 NASH). RESULTS: Trace amounts of AFP-L3 were detected in 3.5%, 16.7%, and 58.0% of patients with DM, NAFL, and NASH, respectively. The odds ratio of AFP-L3 positivity for the diagnosis of NASH in multivariate analysis was 9.81 (95% confidence interval, 3.77-25.5). The rates in patients without fibrosis or with stage 1, stage 2, stage 3, and stage 4 fibrosis were 14.7%, 31.3%, 63.0%, 86.2%, and 100%, respectively. The rates were significantly increased according to the advancement of liver fibrosis (p < 0.001); however, no difference in the positive rate of AFP-L3 was observed between patients with and without fatty livers and between patients with normal and abnormal transaminase. The same relationship was also observed in the validation cohort. CONCLUSION: Abnormal fucosylation of AFP occurred in patients with NASH, so it could be useful for the screening of NASH in patients with DM, as well as for the differential diagnosis of NASH and the evaluation of fibrosis.

Comparison of the impact of tenofovir alafenamide and entecavir on declines of hepatitis B surface antigen levels.

OBJECTIVE: Tenofovir alafenamide is a new prodrug of tenofovir that allows for the treatment of patients with hepatitis B virus (HBV) at a lower dose than with tenofovir disoproxil fumarate, due to the more efficient delivery of tenofovir to hepatocytes. In this study, we compared entecavir and tenofovir alafenamide in terms of their ability to reduce hepatitis B surface antigen (HBsAg) in the same group of patients with HBV infection. METHODS: During March and June 2018, 129 patients who received entecavir were switched to tenofovir alafenamide. Every 3- 6 months for 1 year before and after switching to tenofovir alafenamide, all patients underwent measurements of HBsAg, hepatitis core-related antigen (HBcrAg), calcium (Ca), inorganic phosphorus, and estimated glomerular filtration rate (eGFR). RESULTS: The percent decline rate during the entecavir and tenofovir alafenamide phases at 6 months were 2.38% (-3.57 to 0.00) and -3.57% (-7.14 to 0.00), respectively, and those at 12 months were 3.03% (-6.57 to 0.00) and -5.56% (-7.41 to -2.50), respectively. HBsAg levels were reduced significantly more during the tenofovir alafenamide phase than during the entecavir phase (P < 0.0001). There were no significant differences in the percent declines of HBcrAg, Ca, inorganic phosphorus, or eGFR during the entecavir and tenofovir alafenamide phases after 1 year. CONCLUSION: tenofovir alafenamide significantly decreased HBsAg levels compared to entecavir.

Long-term prognosis with or without nucleot(s)ide analogue therapy in hepatitis B virus-related decompensated cirrhosis.

The development of nuleos(t)ide analogues (NAs) has dramatically changed the natural history of chronic hepatitis B virus (HBV) infection. In this study, we compared patients with HBV-related decompensated cirrhosis with and without NA therapy in terms of hepatocarcinogenesis and all-cause, liver-related, and non-liver-related mortality. This study enrolled 160 patients with decompensated cirrhosis, 78 of whom were treated with NA therapy (NA group) and 82 of whom were not (non-NA group). Propensity score matching and inverse probability weighting were performed to adjust the baseline characteristics in the NA and non-NA groups. Liver-related and non-liver-related mortality were analysed using the competing risks IPW cumulative incidence functions estimator. The Cox proportional hazards model and the Fine and Gray proportional hazards model were used to analyse factors associated with hepatocarcinogenesis and all-cause, liver-related, and non-liver-related mortality. HBV DNA ≥20,000 IU/ml (adjusted hazard ratio [aHR], 8.440) and dyslipidemia (aHR, 0.178) were independently associated with hepatocarcinogenesis. HBV DNA ≥20,000 IU/ml (aHR, 4.360) and non-NA group (aHR, 4.802) were independently associated with all-cause mortality. Diabetes mellitus (aHR, 4.925), FIB-4 score >3.6 (aHR, 4.151), non-NA group (aHR, 9.180), presence of dyslipidemia (aHR, 0.182) and male gender (aHR, 3.045) were independently associated with liver-related mortality. HBV DNA ≥20,000 IU/ml (aHR, 3.216) and high age (aHR, 2.692) were independently associated with non-liver-related mortality. Although the cumulative incidence rate of hepatocarcinogenesis and non-liver-related mortality was not reduced by NA therapy, viral suppression reduced liver-related mortality in patients with DC.

Early detection of hepatocellular carcinoma in patients with diabetes mellitus.

OBJECTIVES: Diabetes mellitus is a risk factor for non-B, non-C hepatocellular carcinoma (NBNC-HCC); however, the number of diabetes mellitus patients is too large to examine tumor occurrence with periodic imaging modalities. Thus, the aim of this study was to develop a novel strategy for early detection of NBNC-HCC in diabetes mellitus patients. PATIENTS AND METHODS: Ninety-three diabetes mellitus patients who had a single NBNC-HCC tumor less than 2 cm in diameter were selected from 6789 HCC patients. As controls, 172 tumor-free diabetes mellitus patients were enrolled. Characteristics were compared between groups. Furthermore, the efficacy of FIB4A, a new integrated score with FIB4 and alpha-fetoprotein, was analyzed as a marker for the early diagnosis of NBNC-HCC. RESULTS: Age, percentage of males, alcohol consumption, total bilirubin, transaminases, γ-glutamyl transpeptidase, FIB4 index, alpha-fetoprotein, and des-gamma-carboxy-prothrombin were higher in NBNC-HCC patients, whereas albumin and platelet counts were higher in the diabetes mellitus control group. Among these factors, the FIB4 index showed the highest odds ratio [OR: 20.0, 95% confidence interval (CI): 9.60-41.7] followed by alpha-fetoprotein (OR: 12.8, 95% CI: 6.53-25.4). A newly developed score, FIB4A, showed the highest area under the receiver operating characteristic curve (0.959) among the factors examined. The sensitivity was 86.2% at a Youden index cutoff (3.5) and it increased to 95.4%, while keeping high specificity (70.9%) when a cutoff of 2.5 was used. CONCLUSION: FIB4A is a potential marker for early detection of NBNC-HCC in patients with diabetes mellitus. However, further studies are needed to confirm these findings.

Natural history of liver-related disease in patients with chronic hepatitis C virus infection: An analysis using a Markov chain model.

BACKGROUND: Long-term prognosis of patients with chronic hepatitis C infection (HCV) remains incompletely characterized. We investigated the long-term prognosis of liver disease in patients with chronic HCV infection who have not received antiviral therapy. METHODS: A total of 2304 patients with chronic HCV who were not received interferon-based therapy were included. RESULTS: In the assessment of 1-year disease state of liver transition probabilities, progression to chronic hepatitis occurred in 12% to 14% of patients across all age groups in male asymptomatic carriers. In male patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (7.6%) and ≥70 age groups (9.6%). In addition, in male patients with cirrhosis, HCC development occurred in approximately 5% of patients over the age of 40. In female asymptomatic carriers, progression to chronic hepatitis was observed in 6% to 14% of patients across all age groups. In female patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (8.7%) and ≥70 (7.4%) age groups. In addition, in female patients with cirrhosis, HCC development occurred in 0.9% to 3.3% of patients over the age of 50. Under assumptions of either chronic hepatitis or asymptomatic carrier state at age 40 as the starting condition for simulation over the following 40 years, the probability of HCC gradually increased with age and was higher in male patients. CONCLUSIONS: There is a risk of cirrhosis or HCC development in HCV patients with not only chronic hepatitis but the asymptomatic carrier state as well.

Long-term prognosis of liver disease in patients with chronic hepatitis B virus infection receiving nucleos(t)ide analogue therapy: an analysis using a Markov chain model.

AIM: Even during nucleos(t)ide analogue therapy, development of hepatocellular carcinoma (HCC) has been observed in patients with chronic hepatitis B virus (HBV) infection. We simulated the long-term prognosis of liver disease in patients with chronic HBV who received nucleos(t)ide analogue therapy. PATIENTS AND METHODS: A total of 254 patients with chronic HBV receiving nucleos(t)ide analogue therapy were enrolled. Yearly transition probabilities between liver disease states [chronic hepatitis, cirrhosis, HCC, and hepatitis B surface antigen (HBsAg)-negative status] were calculated using a Markov chain model. RESULTS: In the analysis of 1-year liver disease state transition probabilities, the development of HCC occurred in men with chronic hepatitis in their 50s (1.8%) and at least 70 years (2.8%) and in patients with cirrhosis in all age groups (40-49, 50-59, 60-69, and ≥ 70 years). HBsAg-negative status was present in patients with chronic hepatitis in their 50s (1.8%) and 60s (2.6%), and in patients with cirrhosis in their 60s (0.6%). In female patients, the development of HCC occurred in patients with cirrhosis during their 50s (0.8%), 60s (0.8%), and older (4.5%). HBsAg-negative status was simulated in patients with cirrhosis in their 50s (0.8%) and 60s (0.8%). Assuming a chronic hepatitis state at age 40 as the starting condition for simulation over the next 40 years, the probability of developing HCC increased gradually with age in male patients and in female patients after the age of 70 years. CONCLUSION: There is a risk of development of HCC in middle-aged men with chronic hepatitis or cirrhosis and older women with cirrhosis even while receiving nucleos(t)ide analogue therapy.

Type 2 diabetes mellitus: A risk factor for progression of liver fibrosis in middle-aged patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIM: The severity of liver fibrosis is strongly associated with prognosis in patients with non-alcoholic fatty liver disease (NAFLD). We evaluated clinical risk factors for progression of liver fibrosis in patients with NAFLD. METHODS: This study included 1562 middle-aged (36-64 years) patients with NAFLD and less severe liver fibrosis (fibrosis-4 index < 1.3). RESULTS: During follow-up, 186 patients progressed to advanced fibrosis (fibrosis-4 index > 2.67). The 3-, 5-, 7-, and 10-year cumulative incidence of progression to advanced fibrosis was 4.4%, 6.7%, 11.0%, and 16.7%, respectively. In the univariate analysis, age, albumin concentration, and type 2 diabetes mellitus (T2DM) were significantly associated with progression to advanced fibrosis. Multivariate analysis with adjustment for age, smoking, body mass index, albumin, estimated glomerular filtration rate, dyslipidemia, T2DM, and steatosis showed that age ≥ 50 years (hazard ratio [HR], 2.121; 95% confidence interval [CI], 1.462-3.076; P < 0.001), albumin concentration < 4.2 g/dL (HR, 1.802; 95% CI, 1.285-2.528; P < 0.001), and the presence of T2DM (HR, 1.879; 95% CI, 1.401-2.520; P < 0.001) were independently associated with progression to advanced fibrosis. Conversely, degree of steatosis was not associated with progression to advanced fibrosis. The respective 3-, 5-, 7-, and 10-year cumulative incidence of progression to advanced fibrosis was 3.6%, 5.0%, 8.2%, and 12.9% in patients without T2DM (n = 1077) and 6.1%, 10.4%, 16.7%, and 24.0% in patients with T2DM (n = 485) (P < 0.001). CONCLUSIONS: Type 2 diabetes mellitus is associated with progression to advanced liver fibrosis in middle-aged NAFLD patients, even those with less severe liver fibrosis.

Efficacy of multidetector computed tomography for diagnosis of unroofed coronary sinus.

The patient was a 62-year-old woman with a chest X-ray abnormality. Transthoracic echocardiography (TTE) showed a dilated right ventricle and right atrium and an enlarged coronary sinus (CS), but definite diagnosis was not possible. Using contrast-enhanced 64-slice multidetector computed tomography (MDCT), curved planar reconstruction along the CS showed a direct connection of the left atrium and CS, in addition to the CS to right atrium connection. Unroofed CS is a rare congenital cardiac anomaly that is difficult to diagnose with TTE alone. Our case indicates that MDCT is useful for determining structural information that cannot be obtained from TTE. .