Lusutrombopag Reduces the Risk of Hemoperitoneum Caused by Percutaneous Radiofrequency Ablation for Hepatocellular Carcinoma Compared with Platelet Transfusion.

INTRODUCTION: Patients with liver cirrhosis develop thrombocytopenia and an increased risk of bleeding events after invasive procedures. Lusutrombopag, a thrombopoietin receptor agonist, can increase the platelet count. This study assessed whether lusutrombopag reduces the risk of hemoperitoneum following percutaneous radiofrequency ablation for hepatocellular carcinoma, compared with platelet transfusion. METHODS: Participants in the present study comprised patients with severe thrombocytopenia (platelet count <50,000/µL) enrolled between November 2012 and March 2020, excluding patients with idiopathic thrombocytopenia or anticoagulant use. Hemoperitoneum rate, hemostasis rate, hemoglobin reduction rate, rate of achieving a platelet count ≥50,000/µL, and increases in platelet count and factors contributing to hemoperitoneum were retrospectively analyzed. RESULTS: This study enrolled 41 patients, comprising 18 patients administered lusutrombopag and 23 patients who received platelet transfusion. The major hemoperitoneum rate after RFA was tend to be lower in the lusutrombopag group (0%) than in the platelet transfusion group (21.7%). All of the major hemoperitoneum was observed in the platelet transfusion group. Hemoglobin reduction rate was lower in the lusutrombopag group (-0.17%) than in the platelet transfusion group (6.79%, p = 0.013). Hemostasis rate was lower in the lusutrombopag group (0%) than in the platelet transfusion group (21.7%, p = 0.045). The rate of achievement of platelet counts ≥50,000/µL the day after RFA was higher in the lusutrombopag group (100%) than in the platelet transfusion group (60.9%, p = 0.005). CONCLUSION: Lusutrombopag may be able to perform RFA more safely with respect to the hemoperitoneum caused by percutaneous radiofrequency ablation compared with platelet transfusion.

Moderate-carbohydrate diet without caloric or lipid restriction for Japanese adult patients with nonalcoholic fatty liver disease: A prospective cohort study.

AIM: Although a low-calorie diet with lipid restriction is recommended in clinical practice guidelines for nonalcoholic fatty liver disease (NAFLD), both compliance and adherence are poor. The present study aimed to evaluate the compliance, adherence, and effectiveness of a moderate-carbohydrate diet without caloric or lipid restrictions. METHODS: Participants comprised 300 patients with NAFLD with elevated ALT levels who received counseling in carbohydrate restriction (150-200 g/day). Complete response (CR) was defined as ALT normalization and partial response as a ≥30% reduction in ALT from baseline without CR. RESULTS: Dropout rates were 3% (10 of 300) after 6 months and 8% (23 of 300) after 12 months. Achievement rates of carbohydrate intake ≤200 g/day after 1, 3, 6, and 12 months were 80%, 81%, 80%, and 73%, respectively. CR and partial response rates were 60% and 31% after 6 months, and 65% and 25% after 12 months, respectively. Rates of achieving a ≥7% weight reduction after 6 and 12 months were 51% and 49%, respectively. Significant reductions in percentage body fat and visceral fat area were obtained, along with a significant increase in liver/spleen attenuation ratio. Serum lipids, uric acid, homeostatic model assessment for insulin resistance, hemoglobin A1c, C-reactive protein, ferritin, immunoglobulin, blood cell, shear wave velocity in the liver, and Mac-2-binding protein glycosylated isomers all decreased significantly. CONCLUSIONS: Compliance and adherence to a moderate-carbohydrate diet without caloric or lipid restriction is high. The sustained high effectiveness of this therapy would improve the pathophysiological state of NAFLD.

Risk Factors of Glecaprevir/Pibrentasvir-Induced Liver Injury and Efficacy of Ursodeoxycholic Acid.

Although glecaprevir/pibrentasvir (GP) therapy is recommended as a first-line treatment for hepatitis C virus (HCV) infection, serious drug-induced liver injury occasionally develops. The present study aimed to elucidate real-world risk factors for GP-induced liver injury and to evaluate the efficacy of add-on ursodeoxycholic acid (UDCA) for liver injury. We analyzed 236 HCV patients who received GP therapy. GP-induced liver injury was defined as any elevation to grade ≥ 1 in total bilirubin (TB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), or γ-glutamyl transferase (γ-GT) during treatment without other cause. The frequency of GP-induced liver injury was 61.9% (146/236). Serious elevation to grade ≥ 3 in TB, AST, ALT, ALP, and γ-GT was identified in 3.8% (9/236), 0%, 0%, 0%, and 0.4% (1/209), respectively. Therapy discontinuation and dose reduction were seen in one patient each. Multivariate analysis revealed age and TB as independent risk factors for GP-induced liver injury. In patients with grade ≥ 2 hyperbilirubinemia, TB after onset significantly decreased in the add-on UDCA group but not in the no UDCA group. Careful attention to GP-induced liver injury is warranted for elderly patients with cirrhosis. Add-on UDCA could suppress the aggravation of GP-induced liver injury.

Safety and efficacy of switching to pemafibrate from bezafibrate in patients with chronic liver disease.

AIM: Although fibrates were developed as lipid-lowering drugs, their efficacy against liver dysfunction in patients with cholestatic liver diseases, such as primary biliary cholangitis, primary sclerosing cholangitis, and fatty liver disease, has also been reported. Although fibrates act on some peroxisome proliferator-activated receptors (PPARs), pemafibrate is a novel selective PPAR-α modulator. The present study aimed to evaluate the safety and efficacy of switching from bezafibrate to pemafibrate in patients with chronic liver disease. METHODS: We analyzed 58 patients with chronic liver disease who switched from bezafibrate to pemafibrate because of minor adverse effects and/or incomplete response. RESULTS: This study included 41 patients with cholestatic liver disease and 17 patients with non-alcoholic fatty liver disease. Reasons for switching to pemafibrate were renal function decline in 31 patients, hemoglobin decline in 17 patients, creatine kinase (CK) elevation in 11 patients, incomplete response of liver dysfunction in 39 patients, and incomplete response of hyperlipidemia in 13 patients. After 3 months, although no significant change in CK was seen, hemoglobin and estimated glomerular filtration rate were significantly increased, and creatinine was significantly decreased. Significant decreases in hepatobiliary enzymes were seen in patients with cholestatic liver diseases, but not in patients with non-alcoholic fatty liver disease. No significant changes in serum lipids were observed. No patients discontinued pemafibrate due to adverse events. CONCLUSIONS: Switching to pemafibrate could improve adverse effects due to bezafibrate, and appeared effective against liver dysfunction in cholestatic liver disease patients with incomplete response to bezafibrate.

New next-generation microwave thermosphere ablation for small hepatocellular carcinoma.

BACKGROUND/AIMS: In July 2017, the Emprint™ next-generation microwave ablation system using thermosphere technology (Covidien, Boulder, CO, USA) was approved for use in Japan. This system can produce a predictable spherical ablation zone at higher temperatures than radiofrequency ablation (RFA). The aim of the present study was to elucidate whether this new microwave thermosphere ablation (MTA) could safely improve outcome compared to RFA, which is the standard of care for small hepatocellular carcinoma (HCC). METHODS: This retrospective study analyzed 513 patients with 630 HCCs (≤3 cm) who were performed by percutaneous RFA (174 patients, 214 HCCs) or MTA (339 patients, 416 HCCs) between January 2016 and March 2020. RESULTS: Median ablation time was significantly shorter for MTA (240 seconds) than for RFA (721 seconds; P<0.001). A significant difference in 3-year local tumor progression rate was evident between the RFA group (22%) and MTA group (8%; P<0.001). Multivariable analysis revealed ablation procedure and tumor diameter as independent factors contributing to local tumor progression (MTA; P<0.001; hazard ratio, 0.565; 95% confidence interval, 0.437-0.731). In patients with primary HCC, a significant difference in overall survival was evident (RFA vs. MTA, 3-year, 77% vs. 95%, P=0.029). Ablation procedure and Child-Pugh score were independent factors contributing to survival. The total complication rate was significantly lower for MTA (8%) than for RFA (14%, P<0.05), particularly for bile duct injury (3% vs. 9%, respectively; P<0.05). CONCLUSION: Next-generation MTA for small HCC could provide safer, more curative treatment in a shorter ablation time than RFA.

Measurements of Serum Mac-2-Binding Protein Glycosylation Isomer and Shear Wave Velocity in Health Checkups Are Useful in Screening for Non-Alcoholic Steatohepatitis.

Liver-related mortality rates in patients with non-alcoholic steatohepatitis (NASH) increase with advancing liver fibrosis stage. The present study aimed to elucidate whether adding non-invasive liver fibrosis tests to a comprehensive health checkup system is useful for NASH screening. Both serum Mac-2-binding protein glycosylation isomer (M2BPGi) and point shear wave elastography (pSWE) using ultrasonography were performed for 483 health checkup subjects who consented to participate in this prospective study. Outcomes in positive subjects were surveyed 1 year later. Eighty-eight subjects (18%) showed positive results for at least one liver fibrosis test, with 63 subjects positive for pSWE, 33 subjects positive for M2BPGi, and 72 subjects showing no significant elevation of liver enzymes. The secondary consultation rate for positive subjects was 52% (46/88). However, as 15 of those 46 subjects visited a non-liver-specialist and could not undergo detailed examination, the secondary examination rate was only 35% (31/88). For the 31 subjects who received secondary examination, NASH was diagnosed in 14 subjects, other chronic liver disease (CLD) in 6 subjects, and no CLD in 11 subjects. Additional liver fibrosis tests using M2BPGi and pSWE appear useful in health checkups when screening for CLD, especially for NASH.

Feeding artery ablation before radiofrequency ablation for hepatocellular carcinoma may reduce critical recurrence.

BACKGROUND AND AIM: Percutaneous radiofrequency ablation (RFA) is a minimally invasive and curative local treatment for hepatocellular carcinoma (HCC). However, serious concerns remain regarding critical recurrences such as metastasis, dissemination, and/or seeding due to RFA. In August 2006, we introduced selective feeding artery ablation before tumor ablation to reduce the risk of critical recurrence by blocking tumor blood flow. The aim of the present study was to clarify whether feeding artery ablation before tumor ablation can reduce the risk of critical recurrence after RFA. METHODS: This study retrospectively analyzed 279 patients with primary, solitary, and hypervascular HCC ≤5 cm in diameter who were treated with RFA alone between April 2001 and August 2013. Critical recurrence was defined as intra- or extrahepatic metastasis, dissemination, or seeding that was difficult to treat radically. RESULTS: Of the 279 HCC patients, 157 patients were treated with conventional RFA alone, and 122 patients underwent RFA with prior feeding artery ablation. Although no significant differences were seen in the rates of local tumor progression-free survival, overall recurrence-free survival, or overall survival between a conventional RFA group and a prior feeding artery ablation group, significant differences were seen in rates of critical recurrence-free survival and cancer-specific survival (5-year, 69 vs 81%, P = 0.01 and 76 vs 88%, P = 0.03, respectively). On multivariate analysis, prior feeding artery ablation, tumor diameter, and alpha-fetoprotein were independent factors related to critical recurrence. CONCLUSIONS: Feeding artery ablation before tumor ablation may reduce the risk of critical recurrence.

Sofosbuvir plus ribavirin is tolerable and effective even in elderly patients 75-years-old and over.

BACKGROUND: Although clinical use of sofosbuvir plus ribavirin has been approved for patients infected with genotype 2 hepatitis C virus, patients ≥ 75-years-old have not been included in previous clinical trials. AIM: To evaluate the real-world safety and efficacy of sofosbuvir plus ribavirin for elderly patients (≥ 75-years-old) compared to nonelderly patients, we conducted a post-marketing prospective cohort study. METHODS: We treated 265 patients with genotype 2 hepatitis C virus using standard approved doses of sofosbuvir (400 mg/d) plus ribavirin adjusted by body weight, administered orally for 12 wk. RESULTS: Sustained virological response rates for the overall cohort, patients < 65-years-old, ≥ 65-years-old but < 75-years-old, and ≥ 75-years-old were 97% (258/265), 98% (93/95), 97% (84/87), and 98% (81/83), respectively (P = 0.842). Logistic regression analyses identified history of hepatocellular carcinoma treatment and alpha-fetoprotein as factors significantly associated with sustained virological response. Alpha-fetoprotein was the only independent factor identified. Sustained virological response rate was significantly lower for patients with hepatocellular carcinoma treatment (91%) than for patients without history of hepatocellular carcinoma treatment (98%, P = 0.004). One patient (0.4%) discontinued treatment due to drug-induced pneumonia. Dose reduction or interruption of ribavirin was required for 12.1% (32/265) of patients because of anemia, including 7.7% (14/182) of patients < 75-years-old and 21.7% (18/83) of patients ≥ 75-years-old (P = 0.002). CONCLUSION: Although ribavirin dose reduction or interruption was required with advanced age, sofosbuvir plus ribavirin appears tolerable and highly effective even in patients ≥ 75-years-old.

Prognostic value of 18F-fluorodeoxyglucose positron emission tomography in patients with small hepatocellular carcinoma treated by radiofrequency ablation.

BACKGROUND: 18F-fluorodeoxyglucose (18F-FDG) uptake in hepatocellular carcinoma (HCC) is significantly associated with early recurrence and survival after curative surgical resection. However, there are no reports regarding the relationship between 18F-FDG uptake and outcomes after radiofrequency ablation (RFA). A prospective cohort study was conducted to evaluate the prognostic value of 18F-FDG positron emission tomography (PET) in HCC patients after RFA. METHODS: A total of 121 consecutive patients with primary HCC (≤3 tumors, of diameter ≤ 3 cm) without vascular invasion on imaging were examined by 18F-FDG-PET computed tomography prior to RFA. An HCC with a component of 18F-FDG uptake visibly stronger than that of surrounding liver was defined as 18F-FDG-PET positive. RESULTS: The median follow-up period was 1267 days. There were 110 18F-FDG-PET negative and 11 positive tumors. The cumulative 1-year recurrence rates in the 18F-FDG negative and positive groups were 30 and 64% (P = 0.017), respectively, and cumulative 1-year metastatic recurrence rates were 6 and 36% (P < 0.001), respectively. The cumulative 5-year survival rates were 88 and 22% (P < 0.001), respectively. Multivariate analysis revealed 18F-FDG-PET positivity and tumor size as independent factors related to metastatic recurrence and survival after RFA. CONCLUSIONS: 18F-FDG-PET positivity was significantly associated with outcomes after RFA. RFA should not be readily selected as the first-line treatment for small HCC that includes a component of visually strong 18F-FDG uptake.

Combination with portosystemic shunt occlusion and antiviral therapy improves prognosis of decompensated cirrhosis.

BACKGROUND AND AIM: Portosystemic shunt occlusion using endovascular treatment can transiently improve liver function in patients with decompensated cirrhosis. In recent years, viral hepatitis can be easily controlled. The present study aimed to clarify the safety and efficacy of endovascular treatment in decompensated cirrhotic patients, and to elucidate whether viral treatment improves the prognosis after shunt occlusion. METHODS: Among 98 cirrhotic patients who received portosystemic shunt occlusion from January 2007 to June 2016, we retrospectively analyzed 61 decompensated cirrhotic patients. RESULTS: Forty-five patients had viral hepatitis. Recovery rates of liver function to Child A within 6 months in viral hepatitis, non-viral hepatitis, and overall were 78% (35/45), 81% (13/16), and 79% (48/61), respectively. Recovery rates according to baseline Child-Pugh score were as follows: score 7, 88% (15/17); score 8, 89% (24/27); score 9, 69% (9/13); and score ≥ 10, 0% (0/4). Three-year reprogression rates to decompensated cirrhosis for non-virus, non-sustained viral negativity (SVN), and SVN groups were 23 100, and 0%, respectively (P < 0.01). Three-year survival rates for those were 63, 62, and 91%, respectively (P < 0.01). Eight-year survival rate for SVN group was also 91%. Multivariate analysis revealed age, baseline ammonia level, baseline Child class, and SVN as independent contributors to survival. CONCLUSIONS: SVN in patients with viral hepatitis appears prerequisite to maintaining recovered liver function by shunt occlusion and to improving prognosis. Combination therapy with shunt occlusion and antiviral treatment should be considered as a first-line treatment for decompensated cirrhotic patients with viral hepatitis and large portosystemic shunt growth.

Trends and Efficacy of Interferon-Free Anti-hepatitis C Virus Therapy in the Region of High Prevalence of Elderly Patients, Cirrhosis, and Hepatocellular Carcinoma: A Real-World, Nationwide, Multicenter Study of 10 688 Patients in Japan.

BACKGROUND: We investigated changes in patient characteristics, rate of sustained virologic response (SVR), and factors associated with SVR after anti-hepatitis C virus (HCV) therapy with direct-acting antiviral (DAA) regimens in real-world practice in Japan, where patients with HCV are characterized by older age and high prevalence of cirrhosis and hepatocellular carcinoma (HCC). METHODS: Changes in patient characteristics and SVR rates were evaluated from medical records among 10 688 patients who started interferon (IFN)-free DAA therapy between September 2014 and June 2018 in a nationwide, multicenter study. Factors associated with failure of SVR were analyzed. In particular, effects of cirrhosis or history of HCC on SVR were assessed by exact matching. RESULTS: Patient age was becoming younger and baseline liver fibrosis was becoming milder over time. Overall SVR rate was 95.4%. The SVR rates increased over time in patients without a history of IFN-free DAA therapy. Multivariate analysis revealed that cirrhosis was unfavorably associated with achievement of SVR in both patients with genotype 1 (odds ratio, 1.68; 95% confidence interval [CI], 1.27-2.21) and genotype 2 (odds ratio, 1.69; 95% CI, 1.01-2.78). Comparisons after exact matching showed that the SVR rate was significantly lower in patients with cirrhosis than without it, whereas patients with and without a history of HCC had similar SVR rates. CONCLUSIONS: Background characteristics of patients who undergo IFN-free DAA therapy are changing in Japan. Patients without a history of IFN-free DAA therapy have high SVR rates. Exact matching confirmed that cirrhosis significantly influences the achievement of SVR in real-world settings.

A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation.

BACKGROUND: Thrombocytopenia represents an obstacle for invasive procedures in chronic liver disease (CLD) patients. We aimed to estimate the appropriate dose and evaluate the efficacy and safety of lusutrombopag for the treatment of thrombocytopenia before percutaneous liver radiofrequency ablation (RFA) for primary hepatic cancer in patients with CLD. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, 61 CLD patients with platelet count < 50 × 103/µL at screening were randomized to placebo or lusutrombopag 2, 3, or 4 mg once daily for 7 days, followed by a 28-day post-treatment assessment period. The primary efficacy endpoint was the proportion of patients who did not require platelet transfusion before RFA. The pre-specified key secondary efficacy endpoint was the proportion of responders. Adverse events (AEs) and thrombosis-related AEs were evaluated. RESULTS: The proportion of patients who did not require platelet transfusion before RFA and that of responders were significantly higher (p < 0.01) in the 2-mg (80.0, 66.7%), 3-mg (81.3, 68.8%), and 4-mg groups (93.3, 80.0%) compared with the placebo group (20.0, 6.7%) and showed a dose-dependent effect. The incidence of AEs was 97.8 and 100% in the lusutrombopag (all groups) and placebo groups, respectively; no dose-related increase was observed. Four patients experienced thrombosis-related events (one each in the placebo and 2-mg groups, and two in the 4-mg group). A total of 16 (18%) adverse drug reactions occurred in the safety analysis set. CONCLUSIONS: Lusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count. CLINICAL TRIAL REGISTRATION: The study is registered at JapicCTI-121944.

Real-world virological efficacy and safety of elbasvir and grazoprevir in patients with chronic hepatitis C virus genotype 1 infection in Japan.

BACKGROUND: The real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1. METHODS: The rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics. RESULTS: Overall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment. CONCLUSIONS: The EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen.

Lansoprazole prevents the progression of liver fibrosis in non-alcoholic steatohepatitis model rats.

OBJECTIVES: We previously demonstrated that lansoprazole provided hepatoprotection in a drug-induced hepatitis animal model partially through the Nrf2/HO-1 pathway. Here, we examined whether lansoprazole could also provide hepatoprotection in a rat model of non-alcoholic steatohepatitis (NASH). METHODS: Six-week-old rats were fed a normal chow or a choline-deficient amino acid-defined (CDAA) diet to establish a rat model of NASH. The groups fed a CDAA diet for 5 weeks were subcutaneously administered either a vehicle or a lansoprazole suspension for 4 weeks beginning the second week of the experiment. KEY FINDINGS: Bridging fibrosis was observed in the livers of almost all the NASH model rats (six of seven), but it was not always observed in NASH model rats (one of seven) continuously administered lansoprazole. The serum aspartate aminotransferase level elevated by the CDAA diet was significantly decreased following lansoprazole administration. Lansoprazole also increased the expression of Nrf2, but not HO-1, in the liver of NASH model rats. Lansoprazole decreased the level of activated TGF-ß protein. Furthermore, interleukin-6 gene and protein expression were decreased. CONCLUSIONS: Lansoprazole inhibits hepatic fibrogenesis, at least during the early stages, in CDAA diet-induced NASH model rats. The mechanisms might be associated with cytokine suppression but not the inhibition of reactive oxygen species.

Real-world safety and efficacy of sofosbuvir and ledipasvir for elderly patients.

BACKGROUND AND AIM: In September 2015, sofosbuvir and ledipasvir were approved for clinical use in Japan for patients infected with genotype 1 hepatitis C virus. We conducted a postmarketing prospective cohort study to elucidate the safety and efficacy of this therapy in a real-world setting. METHODS: We treated 509 patients using standard doses of sofosbuvir and ledipasvir for 12 weeks. As sustained virological response (SVR) in 2 patients could not be evaluated, 507 patients were finally analyzed. Patients with daclatasvir plus asunaprevir failure were excluded. RESULTS: Four patients (0.8%) discontinued treatment due to adverse events. SVR rates for the overall cohort, patients <65 years old, ≥65 and <75 years old, and ≥75 years old were 98% (495/507), 98% (161/163), 96% (179/186), and 98% (155/158), respectively. SVR rates among cirrhotic patients, patients with moderate chronic kidney disease (CKD), patients with a history of hepatocellular carcinoma (HCC) treatment, patients with protease inhibitor (PI) triple therapy failure, and patients with resistance-associated substitutions (RASs) to nonstructural protein 5A (NS5A) were 97% (228/235), 98% (117/119), 95% (95/100), 94% (46/49), and 92% (44/48), respectively. In the comparison of factors between patients with and without SVR, high body weight, discontinuation of therapy, and NS5A RASs were significantly associated with non-SVR. CONCLUSIONS: In this real-world setting, sofosbuvir and ledipasvir were a safe treatment even in patients ≥75 years old. When patients without pre-existing NS5A RASs and daclatasvir plus asunaprevir failure are selected, extremely high SVR rates can be achieved irrespective of age.

The Real-World Safety and Efficacy of Daclatasvir and Asunaprevir for Elderly Patients.

BACKGROUND/AIMS: Although daclatasvir with asunaprevir was approved in Japan for interferon ineligible or intolerant patients, patients aged ≥75 years were excluded in the phase III trial. The present study aimed to evaluate the safety and efficacy of this therapy for elderly patients aged ≥75 years and to clarify whether an extremely high sustained virological response (SVR) rate can be achieved, even in a real-world setting when patients with resistance-associated substitutions (RASs) to nonstructural protein 5A (NS5A) inhibitors or prior simeprevir failure are excluded. METHODS: Daclatasvir (60 mg) and asunaprevir (100 mg) were orally administered daily for 24 weeks. Patients without pre-existing NS5A RASs and simeprevir failure were enrolled in this study. RESULTS: Overall, 110 patients were treated. The median age was 73 years old. The SVR rates of total patients, those aged ≥75 years, and those aged ＜75 years were 97% (107/110), 98% (46/47), and 97% (61/63), respectively. The treatment of two patients (2%) was discontinued because of adverse events. CONCLUSIONS: Daclatasvir with asunaprevir was a safe treatment, even in patients aged ≥75 years. When patients without pre-existing NS5A RASs and prior simeprevir failure were selected, an extremely high SVR rate could be achieved irrespective of age.

Irregular Defects in Hepatocellular Carcinomas During the Kupffer Phase of Contrast-Enhanced Ultrasonography with Perfluorobutane Microbubbles: Pathological Features and Metastatic Recurrence After Surgical Resection.

The present study aimed to elucidate the association between post-vascular-phase (Kupffer-phase) images from contrast-enhanced ultrasonography (CEUS) with perfluorobutane microbubbles and metastatic recurrences after the resection of hepatocellular carcinoma (HCC). The study examined 73 patients with solitary HCC ≤5 cm in diameter who underwent CEUS before resection. HCC was defined as irregular type (including an irregular defect on Kupffer-phase images) or non-irregular type. Intrahepatic metastatic recurrence was defined as >3 intrahepatic recurrences. Metastatic recurrence included both extrahepatic and intrahepatic recurrences. Frequencies of microscopic portal invasion and intrahepatic metastasis were significantly higher in the irregular group than in the non-irregular group. Cumulative 5-y metastatic recurrence rates in the irregular and non-irregular groups were 43% and 7% (p = 0.028), respectively. Multivariate analyses identified Kupffer-phase findings as a factor significantly related to metastatic recurrence. In conclusion, HCCs with an irregular defect during Kupffer-phase CEUS are characterized by more frequent microscopic vascular invasion and intrahepatic metastasis and are significantly associated with metastatic recurrence after resection.

Add-on Pegylated Interferon Alpha-2a Therapy in Chronic Hepatitis B Japanese Patients Treated with Entecavir.

Entecavir requires long-term administration. Pegylated interferon (PEG-IFN) therapy leads to significant reduction of hepatitis B surface antigen (HBs Ag) levels. This study aimed to assess the safety and efficacy of adding PEG-IFN-α-2a to entecavir toward cessation of entecavir. A total of 23 patients treated with entecavir underwent add-on PEG-IFN-α-2a therapy (90 µg per week) for 48 weeks. Viral response (VR) was defined as more than 50% reduction of baseline hepatitis B surface antigen (HBs Ag) level at 72 weeks from the start of therapy. Complete response (CR) was defined as the decline of HBs Ag levels <100 IU/mL. Hepatitis B e antigen (HBe Ag) seroconversion rate was 25% (2/8), and VR rate was 52% (12/23). CR was observed in four patients (17%). However, CR rate in baseline HBs Ag level <2000 IU/mL and HBe Ag negative patients was 50% (4/8). Univariate analysis showed that the percentage of HBs Ag level reduction at week 12 was significantly associated with VR. The area under the curve value was 0.848. Adding PEG-IFN-α-2a to entecavir has limited efficacy. The percentage reduction of HBs Ag level at week 12 may be a useful predictor for VR.

Simeprevir-Based Triple Therapy with Reduced Doses of Pegylated Interferon α-2a Plus Ribavirin for Interferon Ineligible Patients with Genotype 1b Hepatitis C Virus.

BACKGROUND/AIMS: The present study aimed to evaluate the safety and efficacy of simeprevir-based triple therapy with reduced doses of pegylated interferon (PEG-IFN) and ribavirin for interferon (IFN) ineligible patients, such as elderly and/or cirrhotic patients, and to elucidate the factors contributing to a sustained virologic response (SVR). METHODS: One hundred IFN ineligible patients infected with genotype 1b hepatitis C virus (HCV) were treated. Simeprevir (100 mg) was given orally together with reduced doses of PEG-IFN-α 2a (90 µg), and ribavirin (200 mg less than the recommended dose). RESULTS: The patients' median age was 70 years, and 70 patients were cirrhotic. Three patients (3%) discontinued treatment due to adverse events. The SVR rate was 64%. Factors that significantly contributed to the SVR included the γ-glutamyl transferase and α-fetoprotein levels, interleukin- 28B (IL28B) polymorphism status, and the level and reduction of HCV RNA at weeks 2 and 4. The multivariate analysis showed that the IL28B polymorphism status was the only independent factor that predicted the SVR, with a positive predictive value of 77%. CONCLUSIONS: Simeprevir-based triple therapy with reduced doses of PEG-IFN and ribavirin was safe and effective for IFN ineligible patients infected with genotype 1b HCV. IL28B polymorphism status was a useful predictor of the SVR.

Rapid On-Site Evaluation by Endosonographers during Endoscopic Ultrasonography-Guided Fine-Needle Aspiration for Diagnosis of Gastrointestinal Stromal Tumors.

BACKGROUND/AIMS: Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has been used to diagnose gastrointestinal submucosal tumors (SMTs). Although rapid on-site evaluation (ROSE) has been reported to improve the diagnostic accuracy of EUS-FNA for pancreatic lesions, on-site cytopathologists are not routinely available. Given this background, the usefulness of ROSE by endosonographers themselves for pancreatic tumors has also been reported. However, ROSE by endosonographers for diagnosis of SMT has not been reported. The aim of this study was to evaluate the diagnostic accuracy of EUS-FNA with ROSE by endosonographers for SMT, focusing on diagnosis of gastrointestinal stromal tumor (GIST), compared with that of EUS-FNA alone. METHODS: Twenty-two consecutive patients who underwent EUS-FNA with ROSE by endosonographers for SMT followed by surgical resection were identified. Ten historical control subjects who underwent EUS-FNA without ROSE were used for comparison. RESULTS: The overall diagnostic accuracy for SMT was significantly higher in cases with than without ROSE (100% vs. 80%, p=0.03). The number of needle passes by FNA with ROSE by endosonographers tended to be fewer, although accuracy was increased (3.3±1.3 vs. 5.9±3.8, p=0.06). CONCLUSIONS: ROSE by endosonographers during EUS-FNA for SMT is useful for definitive diagnosis, particularly for GIST.