Impact of Early Lenvatinib Administration on Survival in Patients with Intermediate-Stage Hepatocellular Carcinoma: A Multicenter, Inverse Probability Weighting Analysis.

AIM/BACKGROUND: Transarterial chemoembolization (TACE) is recommended for patients with intermediate-stage hepatocellular carcinoma (HCC). In this study, we investigated the impact of early lenvatinib administration in patients with intermediate-stage HCC, especially those with tumors beyond the up-to-7 criteria. MATERIALS/METHODS: A total of 208 patients with intermediate-stage HCC whose initial treatment was early lenvatinib administration or TACE were enrolled. Multivariate overall survival analysis was performed in this cohort. In addition, the impact of early lenvatinib administration on survival in patients with HCC beyond the up-to-7 criteria was clarified using inverse probability weighting (IPW) analysis. RESULTS: The overall cumulative survival rates at 6, 12, 18, and 24 months were 94.4, 79.9, 65.8, and 50.1%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that HCC treatment with lenvatinib (hazard ratio [HR], 0.199; 95% confidence interval [CI], 0.077-0.517; p < 0.001), α-fetoprotein ≥100 ng/mL (HR, 1.687), Child-Pugh class B disease (HR, 1.825), and beyond the up-to-7 criteria (HR, 2.016) were independently associated with overall survival. The 6-, 12-, 18-, and 24-month cumulative survival rates were 96.0, 90.4, 65.7, and 65.7%, respectively, in patients treated with lenvatinib, and 94.1, 78.5, 65.3, and 48.4%, respectively, in patients who received TACE (p < 0.001). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that lenvatinib therapy was significantly associated with overall survival in patients with HCC beyond the up-to-7 criteria (HR, 0.230; 95% CI, 0.059-0.904; p = 0.035). CONCLUSIONS: Lenvatinib may be a suitable first-line treatment for patients with intermediate-stage HCC beyond the up-to-7 criteria.

AFP and eGFR are related to early and late recurrence of HCC following antiviral therapy.

BACKGROUND: An unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment. METHODS: Of 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as 'early recurrence', and recurrence more than 1 year after as 'late recurrence'. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated. RESULTS: Ninety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026-1.087, p < 0.001) and post-treatment estimated glomerular filtration rate (eGFR) (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99, p = 0.032) as a predictor of HCC recurrence in the late phase. CONCLUSION: Patients with higher post-treatment AFP in the early phase and those with lower post-treatment eGFR in the late phase had a high risk of HCC recurrence. The risk factors associated with HCC recurrence after DAA treatment were different between the early and late phases.

Switching from entecavir to tenofovir disoproxil fumarate for HBeAg-positive chronic hepatitis B patients: a phase 4, prospective study.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is widely used and recommended as first-line treatment for patients infected with the hepatitis B virus (HBV). However, current data are limited regarding the efficacy and safety of switching to TDF for the treatment of chronic hepatitis B in hepatitis B e-antigen (HBeAg)-positive patients who are virologically suppressed with another nucleos(t)ide analogue. The primary objective of this study was to evaluate the hepatitis B surface antigen (HBsAg) reduction potential of switching from entecavir (ETV) to TDF at week 48 in HBeAg-positive chronic hepatitis B patients with undetectable serum HBV-DNA. METHODS: In this multicenter, single-arm, open-label, phase 4 clinical study, 75 participants currently treated with ETV 0.5 mg once daily were switched to TDF 300 mg once daily for 96 weeks. RESULTS: At week 48, 3/74 participants (4%) achieved 0.25 log10 reduction of HBsAg levels from baseline (the primary endpoint). Mean HBsAg reduction was -0.14 log10 IU/mL and 12% (9/74) achieved 0.25 log10 reduction by 96 weeks. No participants achieved HBsAg seroclearance. HBsAg reduction at weeks 48 and 96 was numerically greater in participants with higher alanine aminotransferase levels (≥ 60 U/L). Seventeen participants (25%) achieved HBeAg seroclearance up to week 96. No participants experienced viral breakthrough. All drug-related adverse events (18 participants [24%]) were mild in intensity, including an increase in urine beta-2-microglobulin (15 participants [20%]). CONCLUSIONS: In conclusion, HBsAg reduction was limited after switching from ETV to TDF in this study population. Further investigation is warranted to better understand the clinical impact of switching from ETV to TDF. ClinicalTrials.gov: NCT03258710 registered August 21, 2017. https://clinicaltrials.gov/ct2/show/NCT03258710?term=NCT03258710&draw=2&rank=1.

Therapeutic efficacy of lenvatinib as third-line treatment after regorafenib for unresectable hepatocellular carcinoma progression.

AIM: Multiple molecular agents have been developed for treating unresectable hepatocellular carcinoma. This study aimed to elucidate the clinical efficacy of sequential treatment with lenvatinib after regorafenib failure. METHODS: From June 2017 to October 2020, 63 patients with Child-Pugh A and treated with regorafenib followed by sorafenib were enrolled (median age 71 years, 52 men, Barcelona Clinic Liver Cancer B:C = 23:40). They were divided into two groups, those treated with lenvatinib after regorafenib treatment (R-L group, n = 47) and those who did not receive lenvatinib after regorafenib (non-R-L group, n = 16). Prognostic factors were retrospectively analyzed after adjustment with inverse probability weighting. RESULTS: Serum albumin level at the start of regorafenib and reasons for discontinuation of regorafenib were significantly different between the R-L and non-R-L groups, whereas the albumin-bilirubin score, Child-Pugh class, and tumor burden were not. Progression-free survival was also not significantly different (median 4.1 vs. 3.8 months, p = 0.586). As for overall survival, the R-L group showed better prognosis after introducing regorafenib and after introducing sorafenib, following inverse probability weighting adjustment (MST 19.7 vs. 10.3 months, 33.8 vs. 15.3 months, p < 0.001 and p = 0.022, respectively). Modified albumin-bilirubin grade 2b (score >-2.27) at the start of regorafenib (HR 2.074, p = 0.041) and the presence of lenvatinib treatment after regorafenib failure (HR 0.355, p = 0.004) were found to be significant prognostic factors in Cox proportional hazards multivariate analysis, after inverse probability weighting adjustment. CONCLUSION: These results show that lenvatinib is a good sequential treatment option after progression under regorafenib therapy in unresectable hepatocellular carcinoma patients with better hepatic reserve function.

Clinical importance of muscle volume in lenvatinib treatment for hepatocellular carcinoma: Analysis adjusted with inverse probability weighting.

BACKGROUND AND AIM: This study aimed to elucidate the clinical importance of muscle volume loss (pre-sarcopenia) in patients receiving lenvatinib as treatment for unresectable hepatocellular carcinoma (u-HCC). METHODS: Of 437 u-HCC patients treated with lenvatinib at specific institutions in Japan between March 2018 and May 2020, 151 with available computed tomography imaging data from the time of lenvatinib introduction were enrolled. Pre-sarcopenia was diagnosed based on a previously reported cut-off value calculation formula [psoas muscle area at level of middle of third lumbar vertebra (cm2 )/height (m)2 ]. Clinical features and prognostic factors for overall survival (OS) with inverse probability weighting were investigated retrospectively for their relationship with pre-sarcopenia. RESULTS: Cox hazard multivariate analysis showed alpha-fetoprotein (≥400 ng/mL) (hazard ratio [HR] 2.271, P < 0.001), Barcelona Clinic Liver Cancer stage (C and D) (HR 1.625, P = 0.018), and positive for pre-sarcopenia (HR 1.652, P = 0.042) to be significant prognostic factors. OS rates for the pre-sarcopenia group (n = 41) were worse than those for the non-pre-sarcopenia group (n = 110) (0.5-, 1-, and 1.5-year OS: 72.5%, 27.9%, and 7.0% vs 80.7%, 56.7%, and 46.1%, respectively; P < 0.001), as was progression-free survival (P = 0.025). Time to stopping lenvatinib or disease progression was better in the non-pre-sarcopenia group (0.5-, 1-, and 1.5-year OS: 48.0%, 24.5%, and 8.4% vs 20.0%, 10.3%, and 4.2%, respectively; P < 0.001). Also, the frequency of the adverse event appetite loss (any grade) was greater in the pre-sarcopenia group (43.9% vs 18.2%, P = 0.003). CONCLUSION: Pre-sarcopenia was shown to be a significant prognostic factor in patients treated with lenvatinib for u-HCC.

Sex difference in the development of hepatocellular carcinoma after direct-acting antiviral therapy in patients with HCV infection.

Sex differences in the predictors for hepatocellular carcinoma (HCC) development after direct-acting antiviral (DAA) therapy was investigated. DAA therapy was given to 1438 (663 male, 775 female) patients. Sex differences in the HCC development rate and the factors contributing to HCC development after DAA therapy were investigated. Male patients had a significantly higher cumulative HCC incidence (log-rank test, P = .007). On multivariate analysis, the fibrosis-4 index (HR = 1.11; 95%CI, 1.042-1.202, P = .002) and posttreatment α-fetoprotein (AFP) (HR = 1.11; 95%CI, 1.046-1.197, P = .001) were found to be independent factors that contributed to HCC development following DAA therapy in female patients, whereas only posttreatment AFP (HR = 1.090; 95%CI, 1.024-1.160, P = .007) was an independent factor in male patients. The optimal posttreatment AFP cut-off values were set based on receiver operating characteristic curve analyses. The optimal posttreatment AFP cut-off value was much higher in females (6.0 ng/mL) than in male (3.5 ng/mL) patients. In conclusion both in male and female patients, posttreatment AFP was an independent predictor of HCC development after DAA therapy. However, the cut-off values differed between the sexes. In male patients, HCC could be seen in patients with relatively low posttreatment AFP levels; more careful observation might be needed in such patients.

Nutritional Index as Prognostic Indicator in Patients Receiving Lenvatinib Treatment for Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIM: Few studies have examined the details of nutritional status in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing systemic chemotherapy with lenvatinib. We evaluated the prognostic/predictive value of nutritional status using Onodera's prognostic nutritional index (O-PNI) for overall survival among patients with u-HCC treated with lenvatinib. METHODS: Three-hundred and seventy-five u-HCC patients treated with lenvatinib were enrolled (median age 72 years; Child-Pugh class A/B/C: n = 312/60/3; BCLC stage A/B/C/D: n = 2/159/212/2). We examined median survival time (MST) and time to progression (TTP) in all patients (n = 375), prognosis according to the O-PNI (high/low: >40/≤40) in 298 patients with lymphocyte findings, and the prognostic/predictive values of Child-Pugh stage, albumin-bilirubin (ALBI)/modified ALBI (mALBI) grade, and O-PNI for Chemotherapy grade (OPNIC grade 1/2/3: O-PNI >40/≤40 to >36/≤36). RESULTS: The MST and TTP were 16.6 and 8.0 months, respectively. The MST and TTP according to the O-PNI (>40/≤40) were "not reached" (NR)/12.4 months (p < 0.001) and 10.0/6.1 months (p = 0.012), respectively. There was a good correlation noted between ALBI score and O-PNI (r = -0.939, p < 0.001). The predictive value of the O-PNI for mALBI grade 2a was 36.0 (specificity/sensitivity = 0.894/0.942; area under the curve [AUC] = 0.978), while that for mALBI grade 1 was 39 (specificity/sensitivity = 0.920/0.929; AUC = 0.972), which was very similar to a high O-PNI. The MST analyzed with the OPNIC in the 298 patients was NR/16.2/10.4 months for OPNIC grade 1/2/3 (p < 0.001), respectively, and the c-index was 0.632, the same as that for mALBI grade (0.632), while that for Child-Pugh class was 0.571. CONCLUSIONS: OPNIC grading might have a potential for easy substitution of mALBI grading. A good nutritional status (OPNIC grade 1) or mALBI grade 1 is the best indication for lenvatinib use, while with an OPNIC grade 3, lenvatinib might be not suitable.

Neutrophil-to-lymphocyte ratio is associated with survival in patients with unresectable hepatocellular carcinoma treated with lenvatinib.

BACKGROUND AND AIMS: Lenvatinib, a newly developed molecularly targeted agent, has become available for patients with unresectable hepatocellular carcinoma (HCC). Neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with poor outcomes in numerous malignancies. In this study, we investigated the impact of NLR on associating outcomes in patients with HCC treated with lenvatinib. METHODS: A total of 237 patients with HCC treated with lenvatinib were included. We performed univariate and multivariate analyses in this cohort. In addition, we clarified appropriate cut-off NLR levels for associating overall survival using hazard ratio (HR) spline curves. RESULTS: Cumulative overall survival at 100, 200 and 300 days was 95.2%, 83.4% and 66.6% respectively. Multivariate analysis showed that NLR ≥ 4 (HR, 1.874; 95% confidence interval [CI], 1.097-3.119), α-foetoprotein ≥ 400 ng/mL (HR, 1.969; 95% CI, 1.188-3.265) and modified albumin-bilirubin grade 2b or 3 (HR, 2.123; 95% CI, 1.267-3.555) were independently associated with overall survival. Cumulative progression-free survival at 100, 200 and 300 days was 72.4%, 49.8% and 38.7% respectively. Multivariate analysis showed that NLR ≥ 4 (HR, 1.897; 95% CI, 1.268-2.837) and BCLC stage ≥ C (HR, 1.516; 95% CI, 1.028-2.236) were independently associated with progression-free survival. Disease control rate was significantly different between the patients with low NLR (<4) (85.5%) and high NLR (≥4) (67.3%) (P = .007). Spline curve analysis revealed that NLR of approximately 3.0-4.5 is an appropriate cut-off for associating overall survival. CONCLUSIONS: NLR can be associated with outcomes in patients with HCC treated with lenvatinib.

SARC-F combined with a simple tool for assessment of muscle abnormalities in outpatients with chronic liver disease.

AIM: An easily performed method for examination of muscle abnormalities is anticipated. We aimed to elucidate the clinical usefulness of simple assessments for muscle abnormality including a simple five-item questionnaire (SARC-F) in chronic liver disease patients. METHODS: From February to July 2019, 383 outpatients (median age 71 years, 259 men; chronic hepatitis (CH) : liver cirrhosis Child-Pugh A : liver cirrhosis Child-Pugh B : liver cirrhosis Child-Pugh C = 157:176:39:11) who underwent a computed tomography examination were enrolled. SARC-F, previously reported cut-off values for muscle strength decline (MSD; handgrip), pre-muscle volume loss (pre-MVL), calf circumference and finger-circle test results were used, and these results were analyzed retrospectively. RESULTS: A high SARC-F score (≥4) was observed in 25 patients, and a low score (<4) in 358 patients. The frequency of high SARC-F increased significantly with progression of chronic liver disease (chronic hepatitis : liver cirrhosis Child-Pugh A : liver cirrhosis Child-Pugh B/C = 2.5%:8.0%:14.0%, P=0.010). MSD frequency was 22.4% in men and 41.1% in women. Muscle volume loss and pre-MVL were noted in 22% and 30.5%, respectively, of the male patients, and 9.7% and 32.3%, respectively, of the female patients. In cases with high SARC-F and MSD, calf circumference and finger-circle abnormalities were found in 56% and 40.0% of patients, respectively, whereas those values for patients with low SARC-F and MSD were 14.5% and 10.6%, respectively (P < 0.001, for each; positive/negative predictive values: 0.560/0.855 and 0.400/0.894, respectively). Each SARC-F item showed a good area under the curve for MSD, but not pre-MVL. CONCLUSION: SARC-F score in combination with MSD and calf circumference or finger-circle test results may be an easy and simple method for surveillance of chronic liver disease patients with a high risk of sarcopenia and decline of quality of life.

Zinc deficiency as an independent prognostic factor for patients with early hepatocellular carcinoma due to hepatitis virus.

AIM: Although a reduced serum zinc level is often observed in patients with chronic liver disease due to hepatitis virus, its prognostic importance has not been adequately investigated. This study aimed to elucidate the association of zinc deficiency with prognosis, especially in early hepatocellular carcinoma (HCC) patients. METHODS: From 2005 to 2018, 466 patients with naïve HCC due to hepatitis virus were enrolled (327 men, 139 women; median age 70 years; hepatitis C virus [HCV] n = 389, hepatitis B virus [HBV] n = 69, hepatitis C virus and hepatitis B virus n = 8; Child-Pugh A n = 367, Child-Pugh B n = 82; Child-Pugh C n = 17; TNM-LCSGJ stage I n = 150, stage II n = 181, stage III n = 91, stage IVa n = 26, state IVb n = 18). Of the 466 patients, 287 were within the Milan criteria (early HCC) and treated curatively. Zinc deficiency was defined as <60 µg/dL. Clinical records and prognostic factors were retrospectively evaluated. RESULTS: The levels of serum zinc became lower with chronic liver disease progression (Child-Pugh A, B, C: 64.3 ± 14.3, 52.3 ± 15.7, 48.4 ± 13.5 µg/dL, respectively; P < 0.001). In early HCC patients treated curatively, overall survival and recurrence rates were better in patients treated curatively and without zinc deficiency as compared with patients with zinc deficiency (3-year overall survival 86.5% vs. 77.2%, 5-year overall survival 73.5% vs. 43.8%, P < 0.001; 3-year recurrence 44.8% vs. 58.3%, 5-year recurrence 56.8% vs. 77.5%, P = 0.002). Not only infection control of hepatitis virus (sustained virological response in HCV or nucleos(t)ide analogs in HBV; HR 0.078, P < 0.001), but also zinc deficiency (HR 1.773, P = 0.041) were significant prognostic factors for death. CONCLUSION: Serum levels of zinc were reduced in association with chronic liver disease grade progression. In addition to infection control of hepatitis virus, zinc deficiency might be a significant prognostic factor for survival in patients with early HCC due to viral hepatitis treated curatively.

Safety and efficacy of lenvatinib in elderly patients with unresectable hepatocellular carcinoma: A multicenter analysis with propensity score matching.

AIM: Lenvatinib has become available as first-line therapy for patients with unresectable hepatocellular carcinoma (HCC). However, the safety and efficacy of lenvatinib in elderly patients with HCC has not been sufficiently investigated. We compared the frequency of adverse events and prognosis between elderly and non-elderly patients with HCC who received lenvatinib. METHODS: A total of 100 patients with HCC who received lenvatinib were selected using propensity score matching: 50 patients were elderly (age ≥75 years) and 50 patients were non-elderly. RESULTS: In the elderly group, >20% of patients experienced fatigue (36.0%), decreased appetite (26.0%), hypothyroidism (24.0%), proteinuria (22.0%), palmar-plantar erythrodysesthesia (22.0%), and hypertension (20.0%) of any grade as treatment-related adverse events. In addition, >10% of patients experienced grade ≥3 treatment-related fatigue (12.0%). In the non-elderly group, >20% of patients experienced palmar-plantar erythrodysesthesia (42.0%), fatigue (28.0%), decreased appetite (22.0%), and diarrhea (20.0%) of any grade as treatment-related adverse events. In addition, >10% of patients experienced grade ≥3 treatment-related proteinuria (10.0%). There were no significant differences between the elderly and non-elderly groups in the frequency of adverse events. Regarding overall and progression-free survival, there were no significant differences between the elderly and non-elderly groups (hazard ratio 0.972, 95% confidence interval 0.374-2.529; and hazard ratio 1.362, 95% confidence interval 0.687-2.700, respectively). Palmar-plantar erythrodysesthesia (hazard ratio 0.117, 95% confidence interval 0.015-0.916) was independently associated with overall survival in a multivariate analysis. CONCLUSIONS: Lenvatinib can be used safely and efficaciously regardless of age in patients with HCC.

Role of severe thrombocytopenia in preventing platelet count recovery in thrombocytopenic patients with chronic liver disease.

BACKGROUND AND AIM: Certain thrombocytopenic patients with chronic liver disease have inadequate platelet count recovery after platelet transfusion or lusutrombopag administration. We aimed to identify the reasons for this phenomenon. METHODS: We investigated 58 and 86 thrombocytopenic patients with chronic liver disease who received lusutrombopag (3 mg orally for up to 7 days) or underwent blood transfusions, respectively. Thirty patients underwent simultaneous hepatic surgery and splenectomy. Factors preventing platelet count recovery above 50 × 103 /µL were identified. RESULTS: The median patient age was 64 years. Eleven, 78, and 55 patients had hepatitis B, hepatitis C, or another etiology, respectively; 59, 69, and 16 had Child-Pugh classes A, B, and C, respectively. The median spleen volume was 432 mL, and a median of 10 blood units were transfused per patient. The median platelet count rose significantly (from 41.5 × 103 /µL to 81.0 × 103 /µL) after lusutrombopag administration but not after blood transfusion before invasive procedures. However, maximum platelet counts in patients who underwent splenectomy before platelet transfusion were markedly improved over those who did not. Increasing platelet counts above 50 × 103 /µL required baseline platelets > 30 × 103 /µL and lusutrombopag administration for all patients. Platelet count recovery was dependent on a spleen volume of < 300 mL and baseline platelets of > 40 × 103 /µL in patients who underwent platelet transfusions, while a baseline platelet count of > 30 × 103 /µL was required for patients administered with lusutrombopag. CONCLUSION: Neither blood transfusion nor lusutrombopag improves thrombocytopenia in patients with severe conditions; however, the degree of platelet count elevation following lusutrombopag administration is higher than that following blood transfusion.

Marked heterogeneity in the diagnosis of compensated cirrhosis of patients with chronic hepatitis C virus infection in a real-world setting: A large, multicenter study from Japan.

BACKGROUND AND AIM: The presence of cirrhosis is an important factor for the management of patients with hepatitis C virus (HCV) infection and it determines the duration of treatment for HCV with the direct-acting antiviral (DAA) regimen of glecaprevir (GLE) and pibrentasvir (PIB), that is, 8 or 12 weeks, if patients do not have a history of DAA failure. However, in real-world settings, determination of cirrhosis depends on the discretion of the attending hepatologists, and it is unclear whether compensated cirrhosis was homogenously diagnosed or not. In this study, we investigated the real-world diagnosis of cirrhosis by characterizing DAA-naïve patients who underwent a 12-week GLE/PIB regimen in whom cirrhosis was diagnosed, comparing their characteristics with those of patients who underwent an 8-week regimen in whom cirrhosis was absent. METHODS: In a large, multicenter cohort study, we compared background characteristics and treatment outcomes among DAA-naïve patients who underwent an 8-week versus a 12-week GLE/PIB regimen. RESULTS: Among 977 patients enrolled, 296 (30.3%) were determined to have cirrhosis and underwent a 12-week regimen. Some patient characteristics largely overlapped between the two groups, including liver fibrosis indices. Sustained viral response rates were similar between groups after adjusting liver fibrosis index with propensity score matching. CONCLUSION: Although adequately diagnosed, the determination of cirrhosis varied widely among institutions or by hepatologists in real-world settings, and the severity of liver fibrosis overlapped significantly between patients in whom compensated cirrhosis was determined to be present and patients in whom cirrhosis was absent. Virologic efficacy was similar after adjusting for the degree of liver fibrosis.

Analysis of factors associated with the prognosis of cirrhotic patients who were treated with tolvaptan for hepatic edema.

BACKGROUND AND AIM: The prognosis of cirrhotic patients with hepatic edema is poor. Although several short-term predictors of tolvaptan (novel diuretic agent) treatment for such patients have been reported, the factors related to long-term survival are still unclear. METHODS: Among 459 patients with hepatic edema enrolled in a retrospective, multicenter collaborative study, we analyzed 407 patients who received tolvaptan. RESULTS: Patients consisted of 266 men and 141 women, with the median age of 68 years (range, 28-93 years). The frequency of short-term responders to tolvaptan was 59.7% (243/407). In the Cox regression analysis, short-term response to tolvaptan, low average dosages of furosemide and spironolactone during tolvaptan treatment, Child-Pugh classification A and B, and absence of hepatocellular carcinoma were independent factors contributed to 1-year survival. The 1-year and long-term cumulative survival rates in short-term responders were significantly higher than those in non-responders (P = 0.011 and 0.010, respectively). Using a receiver operating characteristic curve analysis, the optimal cut-off values of average daily dosages of furosemide and spironolactone for predicting 1-year survival were 19 and 23 mg/day, respectively. The long-term cumulative survival rates in patients who received a mean dosage of spironolactone < 23 mg/day during tolvaptan treatment were significantly higher than those receiving a mean dosage of ≥ 23 mg/day (P = 0.001). CONCLUSIONS: The present study suggests that the short-term response to tolvaptan and low dosages of conventional diuretics during tolvaptan treatment might improve the 1-year and long-term survival rates in cirrhotic patients with hepatic edema.

Real-world experience of 12-week direct-acting antiviral regimen of glecaprevir and pibrentasvir in patients with chronic hepatitis C virus infection.

BACKGROUND: In clinical trials, a pangenotype direct-acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real-world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12-week regimen in a large multicenter study from Japan. METHODS: In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12-week GLE/PIB regimen. RESULTS: Of 1190 patients, 509 (42.8%) underwent the 12-week regimen, and the remaining patients underwent an 8-week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12-week regimen was 99.0%, comparable with that of patients treated with the 8-week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period. CONCLUSION: The 12-week GLE/PIB regimen was well-tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA-naïve, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen.

[A case of mass-forming chronic pancreatitis with amputation neuroma-like neurogenesis of the bile duct].

A man in his 40s visited a facility with the chief complaint of abdominal pain;liver dysfunction was detected, and consequently, he was referred to our hospital for further examinations. His medical history was unremarkable. He used to drink alcohol (beer, 1500mL) every day. Magnetic resonance imaging and computed tomography showed stenosis of the distal bile duct and slight dilation of the upstream bile duct. Common bile duct stones and gallbladder stones were not detected. Malignant tumors in the bile duct biopsy were not discovered. The patient underwent subtotal stomach preserving pancreatoduodenectomy. The pathological diagnosis was chronic pancreatitis with amputation neuroma-like neurogenesis of the bile duct.

Early Relative Change in Hepatic Function with Lenvatinib for Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIM: Lenvatinib (LEN) has been developed for the treatment of unresectable hepatocellular carcinoma (u-HCC). We aimed to elucidate the relative change in hepatic reserve function early following LEN treatment in affected patients. MATERIALS/METHODS: From March 2018 to April 2019, 123 u-HCC patients (median age 71 years; male:female ratio 95:28; Child-Pugh score 5:6:7 = 65:50:8; modified albumin-bilirubin [mALBI] grade 1:2a:2b:3 = 44:28:50:1, Barcelona Clinic Liver Cancer stage A:B:C = 1:49:73) were enrolled. Relative changes in hepatic reserve function at 2 and 4 weeks after starting LEN were retrospectively evaluated. RESULTS: The median survival was 11.3 months. The Child-Pugh score declined from the start to 4 weeks after commencing LEN (score 5:6:7:8:9:≥10 = 65:50:8:0:0:0 vs. 50:39:22:8:0:4, p < 0.001). A comparison among ALBI scores at the start of LEN and those at 2 and 4 weeks revealed significant relative changes (-2.36 ± 0.45 to -2.20 ± 0.49 at 2 weeks, -2.15 ± 0.50 at 4 weeks, p < 0.001, Bonferroni method), while there was no significant difference between those at 2 and 4 weeks (p= 0.210, Bonferroni method). Assessments of relative changes of ALBI score in patients divided by mALBI grade 1, 2a, and 2b or more showed a significant decline in score regardless of grade (-2.82 ± 0.17 to -2.53 ± 0.34, p < 0.001; -2.46 ± 0.10 to -2.31 ± 0.33, p = 0.017; and -1.90 ± 0.26 to -1.75 ± 0.42, p= 0.009, respectively). CONCLUSION: Decline in hepatic function is common in the early stage (≤4 weeks, especially within 2 weeks) after introducing LEN. It is important to introduce molecular targeting agent drugs for u-HCC in patients with better hepatic function, who show transarterial catheter chemoembolization failure, as much as possible, along with consideration of the negative influence of LEN on the early response of hepatic function.

Important Clinical Factors in Sequential Therapy Including Lenvatinib against Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIM: We evaluated clinical factors related to improved prognosis of unresectable hepatocellular carcinoma patients (u-HCC), who were treated with tyrosine kinase inhibitor (TKI) sequential therapy, including lenvatinib (LEN). MATERIALS/METHODS: We enrolled 84 u-HCC cases treated with TKIs including LEN from March 2018 to January 2019 (median age 71 years, 63 males, Child-Pugh score (CPS) 5/6/7 = 62/21/1, tumor-node-metastasis stage of Liver Cancer Study Group of Japan 6th (TNM-LCSGJ) II/III/IVa/IVb = 12/30/5/37, Barcelona Clinic Liver Cancer stage B/C = 33:51). Clinical findings at introduction of the initial TKI were retrospectively evaluated. RESULTS: The median albumin-bilirubin (ALBI) score at introduction of the initial TKI (sorafenib [SOR]/LEN = 80/4) was -2.56, and the past number of transarterial catheter chemoembolization was 3 (IQR: 2-5) (second-line: regorafenib [REG]/LEN/SOR = 31/49/4, third-line: LEN/REG = 31:1). The total period of administration with TKIs showed a good relationship with overall survival (OS) (r = 0.946, 95% confidence interval [CI]: 0.918-0.965, p < 0.001). The prognosis of the entire cohort was good (estimated median survival time: 46.4 months, 1-/2-/3-year OS rate [OSR] = 87.7/63.0/57.2%). A modified-ALBI grade (mALBI) of 2b (ALBI score >-2.27) was the only significant factor at the start of the initial TKI for poor prognosis (hazard ratio 2.319, 95% CI: 1.064-5.052, p = 0.034), while CPS (≥6) was not. Although there was no significant difference in TNM-LCSGJ (p = 0.213), the prognosis of patients with mALBI 1/2a (n = 66) showed better prognosis as compared to those with mALBI 2b (n = 18) (1-year/2-year/3-year OSR = 89.1/69.8/66% vs. 82.4/47.1/23.5%, p = 0.029). CONCLUSION: Good hepatic function (mALBI 1/2a) at introduction of the initial TKI is a requirement for improved prognosis of u-HCC undergoing TKI sequential therapy.

Combination of Resection and Ablative Treatment for Hepatocellular Carcinoma: Usefulness of Complementary Radiofrequency Ablation.

AIM/BACKGROUND: In HCC patients with multiple tumors in separate segments, monotherapy with surgical resection is often difficult when the estimated residual liver volume after surgery is thought to be inadequate. We evaluated the usefulness of resection combined with low invasive radiofrequency ablation (RFA) for treatment of such cases. MATERIALS/METHODS: We analyzed 115 HCC patients with countable multiple tumors (≤5) without vascular invasion and/or extrahepatic metastasis, and treated solely with resection (SR group: n = 82), or with both resection and RFA (Comb group: n = 33) from January 2000 to December 2017. Clinical characteristics, overall survival rate (OSR), and disease-free survival rate (DFSR) were analyzed in a retrospective manner. RESULTS: There were 88 males (76.5%) and the average age of all patients was 67.8 ± 8.9 years. The average number of tumors and average maximum tumor size were 2.4 ± 0.7 and 4.1 ± 2.1 cm, respectively. Forty-two (36.5%) patients were classified as beyond up-to-7 criteria. The 3- and 5-year OSRs in the SR group were 82.0 and 67.0%, respectively, and in the Comb group were 75.2 and 65.6%, respectively (p = 0.244), while the 3- and 5-year DFSRs in the SR group were 45.2 and 28.0%, respectively, and those in the Comb group were 37.3 and 23.3%, respectively (p = 0.257). CONCLUSION: The combination of surgical resection and complementary RFA may be an effective strategy for treating HCC patients with countable multiple tumors, who are otherwise difficult to treat with surgical resection or RFA alone.

Predictors of hepatocellular carcinoma occurrence after direct-acting antiviral therapy in patients with hepatitis C virus infection.

AIM: The predictors for the development of hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment were investigated. METHODS: A total of 1174 patients with chronic hepatitis C virus infection were treated with DAA therapy (sofosbuvir and ledipasvir [n = 615], sofosbuvir and ribavirin [n = 380], and daclatasvir and asunaprevir [n = 179]) and achieved sustained virologic response (SVR). The HCC development rate and the factors that might contribute to the development of HCC after the end of DAA treatment were analyzed. RESULTS: During the median observation period of 537 days, HCC developed in 33 cases. The incidence of HCC was 1.9%, 3.2%, and 4.1% at 1, 1.5, and 2 years after the end of DAA therapy, respectively. Multivariate analysis with pre- and post-treatment factors identified the Fibrosis-4 (FIB-4) index (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 1.021-1.178; P = 0.011) and post-treatment α-fetoprotein (AFP) (HR = 1.11; 95% CI, 1.054-1.172; P < 0.001) as independent factors that contributed to the development of HCC after DAA therapy. Using these identified parameters, a new scoring system (0 to 2 points) was established. Patients in the high-score group (2 points) could be identified as having a significantly higher risk of HCC development, and the respective 1- and 2-year cumulative incidence rates of HCC were 6.1% and 14.4%. CONCLUSIONS: A high FIB-4 index and a high post-treatment AFP at the end of DAA treatment were the independent predictors for developing HCC after DAA treatment. For patients with these risk factors, extra attention to the possibility of HCC development is needed.