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.

HBcrAg-based risk score performs better than the HBV DNA-based scores for HCC prediction in grey zone patients who are HBeAg-negative.

Background & Aims: Risk scores have been designed to predict the development of hepatocellular carcinoma (HCC) in treatment-naive patients with chronic hepatitis B (CHB). However, little is known about their predictive accuracy in HBeAg-negative patients in the grey zone (GZ). We aimed to develop a HBcrAg-based HCC risk score and explore whether it outperforms other risk scores in GZ patients. Methods: Two retrospective cohorts of HBeAg-negative patients with American Association for the Study of Liver Diseases-defined GZ were established for derivation and validation (Taiwanese, N = 911; Japanese, N = 806). All of them were non-cirrhotic at baseline and remained treatment-naive during the follow-up. The primary endpoint was HCC development. Results: In a median follow-up period of 15.5 years, 85 patients developed HCC in the derivation cohort. We found that age, sex, alanine aminotransferase, platelet count, and HBcrAg, but not HBV DNA levels, were independent predictors and a 20-point GZ-HCC score was developed accordingly. The 10-year and 15-year area under the ROC curve (AUROC) ranged from 0.83 to 0.86, which outperformed the HBV DNA-based HCC risk scores, including REACH-B and GAG-HCC scores (AUROC ranging from 0.66 to 0.74). The better performance was also validated in EASL- and Asian Pacific Association for the Study of the Liver-defined GZ patients. These findings remained consistent in the validation cohort. Finally, the low-risk and high-risk GZ patients (stratified by a score of 8) had an HCC risk close to inactive CHB and immune-active CHB patients, respectively, in both cohorts. Conclusions: The HBcrAg-based GZ-HCC score predicts HCC better than other HBV DNA-based risk scores in GZ patients who are HBeAg-negative patients, which may help optimise their clinical management. Impact and implications: We have developed a risk score based on HBcrAg, which has shown better predictive ability for HCC compared with other risk scores based on HBV DNA. Using a score of 8, GZ patients can be classified into low- and high-risk groups, which can guide follow up and early treatment, respectively. This validated risk score is a valuable tool for optimising the management of GZ patients who are HBeAg-negative.

A new imaging classification for safer radial access visceral intervention of the liver and optimal case selection: A preliminary report.

AIM: The aim of this study was to evaluate the use of a new classification for safer transradial access hepatic interventional radiology, based on preoperative evaluation of the location of the left subclavian artery bifurcation in the aortic arch. METHODS: A total of 38 consecutive patients with hepatocellular carcinoma and 74 sessions of radial access for visceral intervention (R.A.V.I.) were reviewed. We classified the location of the left subclavian artery bifurcation in the aortic arch in three areas using an oblique view computed tomography image matched with the curve of the aortic arches according to a new criteria Three Areas Criteria For R.A.V.I. (named "TAC-F-R"), and measured the required time from initial left radial artery arteriography to celiac artery or superior mesenteric artery arteriography. RESULTS: The median time required for left radial artery arteriography to the celiac artery or superior mesenteric artery arteriography in each of the three areas were: area A, 0:11:10 (h, min, s); area B, 0:14:44; and area C, 0:31:51. There were significant differences between each area after Bonferroni correction (p < 0.01; A vs. B, p = 0.086; A vs. C, p = 0.001; and B vs. C, p = 0.045), with areas A and B requiring a significantly shorter time. Finally, no patients showed neurogenic disfunction within 1 week after the R.A.V.I. CONCLUSIONS: The new classification, "TAC-F-R," for safer transradial access hepatic interventional radiology is effective for avoiding difficult cases, and selects more suitable patients with hepatocellular carcinoma for the R.A.V.I.

Favorable Impact of Serum TERT C228T for Prognosis after Surgical Resection for Liver Cancer.

INTRODUCTION: Personalized medicine and molecular therapies with the diagnosis of somatic genetic alterations are expected to be developed for liver cancer. Nevertheless, it is unknown whether a mutation in the telomere reverse transcriptase promoter (TERT C228T) in serum cfDNA might be useful for making prognostic predictions after surgical resection for primary liver cancer. METHODS: This cohort study retrospectively investigated 111 patients who had undergone surgical resection of liver cancer for the first time. We investigated the differences between clinicopathological features and prognosis according to classification of three tumor markers, including AFP, PIVKAII, and TERT C228T. RESULTS: Multivariate analysis identified etiology (fatty liver disease vs. HBV odds ratio [OR] 6.853) and fibrosis stage (2-4, OR: 0.137) as determinants of TERT C228T-positive liver cancer with normal levels of AFP and PIVKAII (TERT single positive liver cancer). TERT single positive (Yes, OR: 0.301), fibrosis (FIB)-4 index (≥3.25, OR: 2.038), Child-Pugh classification (B, OR: 4.975), and number of tumors (≥2, OR: 4.098) were identified as determinants of the recurrence of liver cancer. TERT single positive (Yes, OR: 3.311), FIB-4 index (≥3.25, OR: 0.433), and number of tumors (≥2, OR: 0.262) were identified as determinants of disease-free survival. CONCLUSIONS: Our results highlight the impact of classification of prognostic tumor markers. TERT single positive is one predictor of favorable prognosis after surgical resection for liver cancer.

Efficacy of the Combination of Systemic Sequential Therapy and Locoregional Therapy in the Long-Term Survival of Patients with BCLC Stage C Hepatocellular Carcinoma.

BACKGROUND: The aim of this study was to evaluate the clinical impact of a combination of systemic sequential therapy and locoregional therapy on the long-term survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). METHODS: Sixty-four consecutive patients with intrahepatic target nodules who had initially received systemic therapy (lenvatinib and atezolizumab plus bevacizumab) were reviewed. The clinical impact of the combined use of systemic sequential therapy and locoregional therapy was evaluated by determining overall survival (OS). The combined use of systemic sequential therapy with more than two agents and locoregional treatment was defined as multidisciplinary combination therapy (MCT), while only systemic sequential therapy and repeated locoregional-treatment was defined as a single treatment procedure (STP). RESULTS: R0 resection, MCT, and STP resulted in significantly better OS compared with no additional treatment (median OS, not reached vs. 18.2 months and 12.6 vs. 8.1 months, respectively; p = 0.002). Multivariate analysis confirmed that the use of R0 resection and MCT were associated with better OS (hazard ratio [HR]; 0.053, p = 0.006 and 0.189, p < 0.001, respectively) compared with that for STP (HR; 0.279, p = 0.003). CONCLUSIONS: MCT is may effective in patients with BCLC stage C HCC and intrahepatic target nodules who have previously received systemic therapy-based treatment.

Simple Predictive Markers and Clinicopathological Features of Primary Liver Cancer following HCV Clearance with Direct-Acting Antivirals.

INTRODUCTION: Simple predictive markers enabling even nonspecialized medical doctors and clinicopathological features of primary liver cancer (PLC) following HCV clearance with direct-acting antivirals (DAAs) are unclear. METHODS: The subjects of this retrospective study were 2,476 patients following HCV clearance with DAAs. All patients were confirmed to be PLC-free before and during DAAs. RESULTS: PLC was diagnosed in 73 patients during the follow-up, with an incidence rate per 1 000 person-years of 5.9. The annual rate of PLC during the first 6 years was 0.6%. Multivariate analysis identified gender, GGT, and FIB-4 index as the significant determinants of PLC. According to a combination of these risk factors, the cumulative PLC incidence rates were significantly different among the five subgroups based on the number of PLC risk scores. In 73 patients with PLC, the rates of abnormal AFP, PIVKAII, and serum TERT C228T positive were 37.0, 32.4, and 22.2%. PIVKAII levels in BCLC stage A and B were significantly higher than those in stage 0. In 41 patients, who underwent surgical resection for PLC, maximum tumor diameters of abnormal PIVKAII were significantly larger than those of normal PIVKAII. PLC of abnormal PIVKAII significantly indicated presence of vp more than that of normal PIVKAII, and did not contain well-differentiated HCC. CONCLUSIONS: Combination of simple markers, enabling even nonspecialized medical doctors, is useful for the evaluation of PLC risk following HCV clearance with DAAs. However, imaging studies are regularly recommended for the early detection of PLC.

Well-preserved liver function enhances the clinical impact of curative-intent subsequent treatment during lenvatinib treatment for unresectable hepatocellular carcinoma.

BACKGROUND: The aims of this study were to evaluate the clinical impact of curative-intent subsequent treatment on overall prognosis in lenvatinib-treated hepatocellular carcinoma (HCC) patients. METHODS: Eighty-three consecutive patients with intrahepatic target nodules who received lenvatinib were reviewed. The clinical impact of curative-intent subsequent treatments was investigated through analysis of overall survival (OS) according to pathological deterioration stratified by mALBI grade. RESULTS: In patients with mALBI grade 1 and 2a liver function, R0 resection and lenvatinib-transarterial chemoembolization (lenvatinib-TACE) sequential therapy resulted in significantly better OS compared with other, non-curative-intent subsequent therapy and lack of additional treatment (median OS, 37.6 vs 29.0 months and 17.1 vs 8.9 months, respectively; P < 0.001). Multivariate analysis confirmed that use of R0 resection and lenvatinib-TACE sequential therapy were associated with better OS (hazard ratio [HR], 0.021; P < 0.001 and 0.108; P < 0.001) compared with other, non-curative-intent subsequent treatment (HR 0.256; P = 0.010). In contrast, in patients with mALBI grade 2b liver function, multivariate analysis confirmed higher treatment efficacy for non-curative-intent subsequent treatment with respect to OS (HR 0.041; P < 0.001) compared with R0 resection and lenvatinib-TACE sequential therapy (HR 0.057; P = 0.027 and 0.063; P = 0.001). CONCLUSION: Curative-intent subsequent treatment is more useful for HCC patients with better liver function (mALBI grade 1 and 2a) and intrahepatic target nodules who have received lenvatini b-based treatment.

The Impact of Lenvatinib on Tumor Blood Vessel Shrinkage of Hepatocellular Carcinoma during Treatment: An Imaging-Based Analysis.

INTRODUCTION: When lenvatinib is administered to people with hepatocellular carcinoma (HCC), tumor blood flow is reduced due to the inhibition of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR). Few studies have examined the decrease in tumor blood flow with respect to changes in tumor blood vessels (TBVs) in clinical practice. We investigated the mechanism of tumor blood flow control by investigating changes in the diameter of relatively large TBVs in large-sized lesions with high blood flow. METHODS: From January 2011 to October 2021, patients receiving lenvatinib for unresectable intrahepatic HCC at Toranomon Hospital, Tokyo, Japan, were considered for inclusion. We investigated the TBV diameter in the arterial phase of dynamic computed tomography before treatment and its change over time (2-12 weeks after lenvatinib initiation). The relationship between changes in TBV diameter and prognosis was also examined. RESULTS: Of 114 patients treated with lenvatinib for HCC, 26 patients who had intrahepatic lesions with a tumor diameter of 30 mm or more enrolled in the study. The median tumor and TBV diameters before treatment were 58 mm and 2.55 mm, respectively. Twenty-five patients (96%) had a shrinkage in TBV diameter 2-12 weeks after lenvatinib administration. The maximum TBV diameter shrinkage of 20% or more was observed in 19 patients (73%), and progression-free survival was prolonged in these patients compared to the group with less than 20% TBV diameter shrinkage (p = 0.039). DISCUSSION/CONCLUSION: Due to the antiangiogenic effect of lenvatinib, a shrinkage in the TBV diameter of HCC was observed. The shrinkage of TBV may be regarded as a process of normalization of TBVs. The shrinkage of TBVs in imaging analysis may be associated with improved prognosis; however, additional studies are still required.

A case of drug-induced acute liver failure caused by corticosteroids.

We report a 61-year-old man treated with betamethasone for sudden-onset deafness. Several days later, he had a temperature > 38 °C. He sought care at another hospital and was admitted based on abnormal liver function tests (aspartate aminotransferase [AST], 866 IU/L [normal < 31 IU/L] and alanine aminotransferase [ALT] 1524 IU/L [normal < 31 IU/L]). Liver function improved daily and the patient was discharged from the hospital after 5 days. Two days after discharge, he had a recurrent fever and liver dysfunction. After admission to our hospital, liver function improved spontaneously. A liver biopsy was performed, but a diagnosis was not established; however, a tentative diagnosis of antinuclear antibody-negative autoimmune hepatitis was made and the patient was started on prednisolone (30 mg). Two days later, he developed a fever and persistent liver dysfunction, thus the prednisolone was discontinued. The next day, the AST and ALT increased significantly (18,000 and 12,000 U/L, respectively). Because the level of consciousness was altered, plasma exchange was started for acute liver failure. After discontinuing the prednisolone, the hospital course was uneventful. Drug-induced liver injury due to corticosteroids is rare. Herein, we report a patient with acute liver failure who survived with timely treatment.

Pretreatment Positron Emission Tomography with 18F-Fluorodeoxyglucose May Be a Useful New Predictor of Early Progressive Disease following Atezolizumab plus Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND AND AIMS: The aim of this study was to identify the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a predictor of early progressive disease (e-PD) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). METHODS: Twenty consecutive patients with measurable intrahepatic target nodules who received Atezo/Bev treatment were reviewed. The oncological aggressiveness of tumors estimated by 18F-FDG-PET/CT was analyzed using the rate of e-PD within 12 weeks and early progression-free survival (e-PFS) and overall survival (OS). Multivariate analysis was used to identify potential confounders for PD during Atezo/Bev therapy. RESULTS: Using the Response Evaluation Criteria in Solid Tumors version 1.1, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with lower objective response rates compared with TLR values <2 (18% vs. 33%, respectively). Moreover, TLR values ≥2 were significantly associated with higher e-PD rates compared with TLR values <2 (64% vs. 11%, respectively) and worse e-PFS (p = 0.021). In multivariate analysis, TLR ≥2 showed marginal significance as a predictor of e-PD (p = 0.053), and utility as a predictor for worse e-PFS (hazard ratio, 7.153; 95% confidence interval, 1.258-40.689; p = 0.027). In contrast, no significant differences in OS with/without e-PD were observed during the treatment course. In this study, 8 patients experienced e-PD and almost 40% of patients experienced acceptable disease control following subsequent lenvatinib treatment. CONCLUSION: Pretreatment 18F-FDG-PET/CT may be a useful new predictor of e-PD and may enable early decision-making based on early treatment changes following Atezo/Bev treatment of HCC.

Serum TERT C228T is an important predictor of non-viral liver cancer with fatty liver disease.

BACKGROUND: Molecular therapies and precision medicine are expected to be developed for liver cancer based on the diagnosis of DNA somatic alterations. However, it remains unclear whether TERT promoter mutation (TERT C228T) in serum cfDNA is useful for the diagnosis of liver cancer with non-viral fatty liver disease (FLD). METHODS: This retrospective cohort study examined 258 Japanese patients who had a confirmed diagnosis of primary liver cancer. We investigated the factors associated with TERT C228T and abnormal levels of liver cancer-specific tumor markers (AFP and PIVKAII) in serum samples. RESULTS: Multivariate analysis identified the etiology of FLD, vascular invasion, and non-cirrhosis as determinants of TERT C228T-positive liver cancer. Rates of positive TERT C228T in FLD were significantly higher than those of HBV and HCV. Conversely, rates of abnormal AFP in FLD were significantly lower than those of HBV and HCV. Viral suppression of HBV/HCV and alcohol intake did not affect TERT C228T, but AFP was significantly reduced by viral suppression. The rates of positive TERT C228T were significantly lower in HCV patients with viral clearance than those of FLD patients. CONCLUSION: Our results highlight the importance of serum TERT C228T for the detection of non-viral FLD-related liver cancer. TERT C228T is a tumor marker that might not be influenced by inflammation.

Hepatitis B Core-Related Antigen Stratifies the Risk of Liver Cancer in HBeAg-Negative Patients With Indeterminate Phase.

INTRODUCTION: Many patients with chronic hepatitis B (CHB) are classified as indeterminate patients because they fall outside the defined CHB phases. We aimed to explore hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-negative patients with indeterminate phase and investigated whether the risk could be stratified by serum levels of hepatitis B core-related antigen (HBcrAg). METHODS: Two retrospective cohorts enrolling HBeAg-negative, treatment-naïve CHB patients without cirrhosis were constructed (N = 2,150 in Taiwanese discovery cohort and N = 1,312 in Japanese validation cohort with a mean follow-up period of 15.88 and 12.07 years, respectively). The primary end point was HCC development. RESULTS: According to the American Association for the Study of Liver Disease guidelines, 990 (46%) HBeAg-negative patients had indeterminate CHB phase at baseline in the Taiwanese cohort. Compared with the patients with inactive CHB and those with immune-active CHB, the indeterminate patients exhibited intermediate but diverse risk of HCC. When HCC risk was stratified by a HBcrAg level of 10,000 U/mL, 10-year HCC cumulative incidence was 0.51% and 5.33% for low HBcrAg and high HBcrAg groups, respectively, with a hazard ratio of 4.47 (95% confidence interval: 2.62-7.63). This cutoff was validated to stratify HCC risk not only in different subgroup analyses but also in an independent Japanese cohort. Finally, the overall HBeAg-negative CHB patients could be simply reclassified into high-risk and low-risk groups by combining ALT, hepatitis B virus DNA, and HBcrAg levels in both cohorts. DISCUSSION: Serum HBcrAg level of 10,000 U/mL stratifies HCC risk in HBeAg-negative patients with indeterminate phase, which is useful for optimizing their clinical management.

Renal safety and biochemical changes for 2 years after switching to tenofovir alafenamide from long-term other nucleotide analog treatment in patients with chronic hepatitis B.

BACKGROUND: Long-term use of nucleotide analogs such as adefovir (ADV) or tenofovir disoproxil fumarate (TDF) may cause renal impairment. Tenofovir alafenamide (TAF) has less systemic exposure than TDF did. The aims were to examine longitudinal changes in renal function and biochemical parameters for 2 years after switching from long-term ADV and TDF to TAF, and to explore factors associated with improved renal function after TAF in patients with chronic hepatitis B. METHODS: The prospective observational cohort study included 306 patients with chronic hepatitis B who underwent switching from long-term TDF or ADV to TAF. The primary outcome was the changes in estimated glomerular filtration rate (eGFR) after TAF. RESULTS: Among 306 patients, 190 (65.3%) and 106 (34.7%) had chronic kidney disease (CKD) stages 1-2 and 3a-4 at baseline. In patients with CKD stages 3a-4, the mean eGFR significantly increased until week 12 and plateaued from week 12 to year 2 (adjusted slope using linear mixed effect models: +9.01 ml/min/1.73 m2 /year until week 12; p < 0.001). In contrast, the mean eGFR plateaued from baseline to year 2 in the CKD stages 1-2 subgroup. Multivariate logistic regression showed that baseline CKD stage ≥3a, steeper decline in eGFR 1 year before TAF, and shorter duration of any nucleotide analog use was significantly associated with ≥10% improvement in eGFR in year 1. CONCLUSIONS: Switching from TDF or ADV to TAF resulted in favorable renal safety for 2 years. In CKD stage 3a-4 subgroup, eGFR after TAF was recovered in the first 12 weeks and subsequently stabilized.

Ultrasensitive Assay for Hepatitis B Core-Related Antigen Predicts Hepatocellular Carcinoma Incidences During Entecavir.

Serum hepatitis B core-related antigen (HBcrAg) and surface antigen (HBsAg) are surrogate markers of intrahepatic covalently closed circular DNA. The measurement range of the current HBcrAg assay is relatively narrow. Thus, we examined the potential of HBcrAg and HBsAg measured by ultrasensitive assays for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B treated with entecavir (ETV). We conducted a retrospective cohort study of 180 patients who received ETV for >1 year. All patients had hepatitis B e-antigen negativity at baseline. Serum HBcrAg and HBsAg levels at baseline and year 1 were measured in all patients by ultrasensitive assays using immunoassay for total antigen including complex by pretreatment (iTACT) technology. During the median follow-up of 11.0 years, 22 patients developed HCC (11.8/1,000 person-years). Baseline HBsAg levels were not associated with HCC development during ETV treatment. However, high HBcrAg levels at baseline and at year 1 were significantly associated with HCC development (log-rank test; P < 0.001). In 110 patients (61.1%) with ≥4.0 log U/mL at baseline (high HBcrAg cohort), HBcrAg declined to ≤2.9 log U/mL at year 1 in 25 patients (22.7%). The adjusted hazard ratio for HCC incidence was significantly lower in patients with HBcrAg ≤2.9 log U/mL at year 1 than in those in the high HBcrAg cohort. Conclusion: Measurement of HBcrAg by ultrasensitive assay has better potential for predicting HCC during antiviral treatment than the current HBcrAg assay.

Changes in the Mean Intrahepatic Target Computed Tomography Attenuation Value During Treatment May Be a Useful New Predictor of the Post-progression Survival Associated with Lenvatinib Treatment.

Objective The relationship between the prognosis and magnitude of a decrease in tumor blood flow according to estimated tumor differentiation remains unclear. This study investigated the relationship between reductions in the rate of mean computed tomography (CT) attenuation values and the clinical prognosis. Methods We evaluated 63 consecutive patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC). The oncological aggressiveness of the tumors was estimated using classification by dynamic CT enhancement patterns. The utility of changes in mean CT attenuation values of intra-hepatic targets during treatment to estimate the prognosis was investigated by calculating the progression-free survival (PFS) and post-progression survival (PPS). A multivariate analysis was used to identify potential confounders for the survival after progression during lenvatinib therapy. Results The rate of decrease in the mean CT attenuation value gradually increased according to the degree of deterioration in estimated tumor differentiation, and the rate of a decrease in attenuation ≥40% showed a tendency to increase (p=0.064). This trend was reflected by a better objective response in oncological aggressiveness heterogeneous enhancement patterns (Type-3 and Type-4) than a homogeneous enhancement pattern (Type-2) (83% vs. 56% of modified Response Evaluation Criteria in Solid Tumors). This resulted in a similar PFS between the groups (p=0.773), whereas the PPS was significantly worse when the rate of decrease in the attenuation value was ≥40% (p=0.012). A multivariate analysis confirmed that a rate of decease in attenuation value ≥40% was a poor prognostic factor for the PPS (hazard ratio, 2.993; 95% confidence interval, 1.196-7.490; p=0.019). Conclusion A rate of decrease in attenuation ≥40% may reflect a good response of a highly malignant tumor to lenvatinib. Therefore, this value may have utility as a surrogate marker for estimating the oncological aggressiveness of tumors and their associated prognosis.

Clinicopathological assessment of steatohepatitic hepatocellular carcinoma.

AIM: To compare the clinicopathological features of typical steatohepatitic HCC (SH-HCC) with other HCCs. METHODS: Subjects were 486 patients with untreated HCC who underwent hepatectomy at our hospital from January 2015 to December 2020. We compared patient backgrounds, preoperative laboratory data, imaging findings (ultrasonography, computed tomography [CT], and magnetic resonance imaging [MRI]), and postoperative pathological findings (tumor and background of liver). The Liver Imaging Reporting And Data System (LI-RADS) was used to examine CT and MRI findings. RESULTS: Typical SH-HCCs were significantly different from other HCCs with respect to age, hepatitis B virus (HBV) infection, and nonalcoholic steatohepatitis (NASH). Diabetes and hyperlipidemia were also significantly more common. Regarding histopathology, tumor size and background steatosis were significantly different between groups. Although ultrasonography, CT, and MRI could each alone diagnose SH-HCCs with a diameter < 20 mm in ≥ 50% of patients, the combined use of these tests improved diagnostic accuracy. By LI-RADS, 87% of SH-HCC cases were classified as LR-5, which are considered to be malignant tumors. CONCLUSIONS: It seems possible to diagnose SH-HCC by combining ultrasonography, CT, and MRI.

Dynamics of Circulating miR-122 Predict Liver Cancer and Mortality in Japanese Patients with Histopathologically Confirmed NAFLD and Severe Fibrosis Stage.

INTRODUCTION: It is unclear whether the relationships between changes in fibrosis and circulating microRNA-122 (miR-122) dynamics might influence the prognosis of nonalcoholic fatty liver disease (NAFLD). METHODS: This study investigates the impact of serum miR-122 dynamics and histological changes on the incidence of liver cancer and mortality in 81 Japanese NAFLD patients who underwent serial liver biopsies. The median interval between the first and second liver biopsies was 2.9 years. RESULTS: The fibrosis stage scores indicated progression, no change, and improvement (a decrease of one point or more) in 21.0%, 56.8%, and 22.2% of the patients, respectively. There were 64 patients in the high-risk group who had no improvement in stage scores. Among these, the miR-122 levels were significantly lower in 7 patients with liver cancer than those of the 54 patients who had no liver cancer at the second liver biopsy. The cumulative rates of liver cancer were significantly higher in cases with miR-122 ratios <0.5 (serum miR-122 level at second biopsy to that at first biopsy) than those with ratios ≥0.5. The cumulative survival rates in cases with miR-122 ratios <0.5 tended to be lower than those with ratios ≥0.5. Of the 64 high-risk patients, 39 indicated stage 2 or greater (severe fibrosis stage) at the first liver biopsy and also showed similar results of cumulative liver cancer and survival rates. CONCLUSIONS: Longitudinal examination of serial liver biopsies indicated that the circulating miR-122 dynamics might be useful in predicting the prognosis for NAFLD patients with severe fibrosis stage and no improvement of the stage scores.

PNPLA3 genotype and fibrosis-4 index predict cardiovascular diseases of Japanese patients with histopathologically-confirmed NAFLD.

BACKGROUND: Reliable noninvasive predictors of the top three causes of death [cardiovascular diseases (CVDs), malignancies, and liver-related events in patients with non-alcoholic fatty liver disease (NAFLD)] have not yet been determined. METHODS: We retrospectively investigated the incidence of three complications [CVDs, malignancy (except for liver cancer), and liver-related events] in 477 Japanese patients with histo-pathologically confirmed NAFLD for a median follow-up of 5.9 years. In addition to histological findings, we also investigated noninvasive predictors. RESULTS: A score of ≥ 2.67 for the noninvasive diagnosis of stage 4 fibrosis based on the Fibrosis-4 (FIB-4) index indicated a high level area under the receiver operating characteristic (AUROC) curve (0.90), sensitivity (82.9%), specificity (86.4%), and negative predictive value [(NPV) of 98.5%]. The yearly incidence rates of CVDs, malignancies, and liver-related events were found to be 1.04%, 0.83%, and 0.30%, respectively. Multivariate analysis identified a FIB-4 index ≥ 2.67 score as a significant and independent, noninvasive predictor of these three complications. Furthermore, the cumulative incidence rates of CVDs were significantly different among the three genotypes of PNPLA3. PNPLA3 genotype CC, chronic kidney disease (CKD), and FIB-4 index ≥ 2.67 was could be attributed to these three significant CVD risk factors. The rates of CVDs were significantly different among the three subgroups based on the combination of risk factors. In malignancy (except for liver cancer), the incidence rate of colon cancer was 25.0%; in particular, the rate in females was 53.8%. CONCLUSIONS: Our results highlighted the importance of the PNPLA3 genotype and FIB-4 index ≥ 2.67 on the incidence of complications in Japanese patients with NAFLD, especially the incidence of CVDs. Early diagnosis, based on the presence of one or more risk factors, and early treatment might improve the prognosis for NAFLD patients.