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Toinvestigate liver carcinogenesis and other causes of death by collecting clinical data, including the Fib-4 index, from patients with successfully eradicated hepatitis C virus (HCV) by direct-acting antivirals (DAA) treatment.Patients ( n = 690), who achieved a sustained virologic response (SVR) between 2014 and 2021, were identified and followed up for approximately 6.8 years; 71 incident hepatocellular carcinoma (HCC) cases were identified. The Fib-4 index was calculated at DAA-treatment initiation and HCV eradication, and its relationship with carcinogenesis and prognosis was analyzed.The Fib-4 index was initially calculated and divided into three groups: Fib-41.45, 1.45 ≤ Fib-43.25, and 3.25 ≤ Fib-4 to develop HCC over time. On analysis, no carcinogenic cases were observed at Fib-41.45. In patients with a Fib-4 index ≥3.25, the initial HCC carcinogenic rate was higher than that in patients with Fib-4=1.45-3.25, and a significant difference was obtained between the two groups [ P = 0.0057 (1.45 vs.3.25); P = 0.0004 (1.45-3.25 vs.3.25)]. Regarding all 18 death and Fib-4 at treatment initiation, a significant difference was observed after stratification into two groups [Fib-43.25 and 3.25 ≤ Fib-4; P = 0.0136 (3.25 vs. ≥3.25)]. Significant differences were obtained in another analysis of 13 deaths, not due to HCC.The high Fib-4 index calculated at baseline and SVR12 significantly correlated not only with liver carcinogenesis but also with all mortality rates, including those due to causes other than liver cancer. Our findings suggest that improving liver fibrosis by eradicating HCV improves prognosis related to all etiologies.

The association between thrombolytic therapy and the outcome in patients with portal vein thrombosis (PVT) remains controversial. This study aimed to evaluate the outcome in patients with PVT who received antithrombin III-based therapy.This study was a retrospective, multicenter study to investigate the liver-related events and the survival rates in 240 patients with PVT who received the therapy.The patients comprised 151 men and 89 women, with a median age of 69 years. The rate of favorable response, defined as maximum area of PVT changed to ≤75%, was 67.5% (162/240). The cumulative rates of liver-related events at 1, 2, and 3 years were 38.2%, 53.9%, and 68.5%, respectively. The multivariate analysis showed that viable hepatocellular carcinoma, absence of maintenance therapy, non-responder, and PVT progression were significantly associated with liver-related events. The PVT progression was observed in 23.3% (56/240). The multivariate analysis identified older age, absence of maintenance therapy, and non-responder as independent factors associated with PVT progression. The multivariate analysis revealed that younger age, no hepatocellular carcinoma, presence of maintenance therapy, and lower Model for End-stage Liver Disease-Sodium score significantly contributed to 3-year survival. Of the 240 patients, 13 (8.9%) prematurely discontinued treatment due to any adverse events.This study suggests that maintenance therapy, favorable response, and absence of PVT progression may suppress or control liver-related events in antithrombin III-based therapy for patients with PVT. Specifically, maintenance therapy could suppress not only liver-related events, but also PVT progression and improve the prognosis.

With the increase in the number of patients with sustained virologic response (SVR) in whom hepatitis C virus (HCV) was eradicated by the anti-HCV therapy, there are now many individuals in whom serum HCV RNA is absent despite positive serum HCV antibodies. However, in general clinical practice, HCV infection remains usually screened by measurement of serum HCV antibodies and patients with SVR can be misunderstood regarding HCV infection status.In the multicenter study, we conducted interviews with administered questionnaires to SVR individuals who had regular hospital visits after SVR. The prevalence of experiencing an incorrect diagnosis of HCV infection after SVR was assessed. Individuals who experienced this misunderstanding were further asked where they experienced it and how it made them feel.In a survey of 2,246 SVR individuals, 197 individuals (8.8%) were misunderstood as having persistent HCV infection by medical doctors due to positive HCV antibody, despite the absence of HCV viremia. These misunderstandings occurred most prevalently at a private clinic (55.3%). More than half (53.3%) of these individuals felt anxious about their HCV infection with becoming unsure about their HCV eradication status.Misunderstanding HCV status is commonly occurred in SVR individuals. Specialists in hepatology and infectious diseases should broadly emphasize the fact that most patients with HCV antibodies are now HCV-free because of the use of anti-HCV therapy.

Background Immune checkpoint inhibitors (ICIs) are effective for advanced hepatocellular carcinoma (HCC). However, there are few reports on the correlation between the clinical efficacy of ICIs and the development of immune-related adverse events (irAEs) in patients with HCC. The aim of this study was to investigate the association between irAE development and survival in patients with HCC treated with atezolizumab plus bevacizumab. Patients and Methods We enrolled 150 patients with advanced HCC treated with atezolizumab plus bevacizumab between October 2020 and October 2021 at 5 territorial institutions. We compared the efficacy of atezolizumab plus bevacizumab between patients who experienced irAEs (irAE group) and those who did not (non-irAE group). Results Thirty-two patients (21.3%) developed irAEs of any grade. Grade 3/4 irAEs were observed in 9 patients (6.0%). The median progression-free survivals (PFS) in the irAE and non-irAE groups were 273 and 189 days, respectively (P = .055). The median overall survivals (OS) in the irAE and non-irAE groups were not reached and 458 days, respectively (P = .036). Grade 1/2 irAEs significantly prolonged PFS (P = .014) and OS (P = .003). Grade 1/2 irAEs were significantly associated with PFS (hazard ratio [HR], 0.339; 95% confidence interval [CI], 0.166-0.691; P = .003) and OS (HR, 0.086; 95% CI, 0.012-0.641; P = .017) on multivariate analysis. Conclusion The development of irAEs was associated with increased survival in a real-world population of patients with advanced HCC treated with atezolizumab plus bevacizumab. Grade 1/2 irAEs were strongly correlated with PFS and OS.

In this study, we investigated the impact of simple measurement of psoas muscle index (PMI) on the tolerability of sorafenib treatment of switch from sorafenib to regorafenib.This retrospective study enrolled 109 patients with Child-Pugh A hepatocellular carcinoma (HCC) treated with sorafenib. Pretreatment PMI was calculated by measuring and multiplying the greatest anterior/posterior and transverse diameters of the psoas muscles on axial computed tomography images at the L3 vertebral level, and normalizing the sum of bilateral psoas muscle areas by the square of the height in meters. We, then, statistically analyzed the association between PMI and adverse events (AEs) to treatment, tolerability of sorafenib, time to treatment failure (TTF), and prognosis in patients stratified according to PMI.Patients were divided into high PMI (n = 41) and low PMI (n = 68) groups based on the cutoff PMI values (men: 7.04 cm2/m2; women: 4.40 cm2/m2) determined by receiver operating characteristic curve analysis to determine sorafenib tolerability. Frequencies of all types of severe AEs were higher in the low PMI group (50.0%) than in the high PMI group (29.3%; P = 0.045). The high PMI group (51.2%) had greater tolerance to sorafenib than the low PMI group (25.0%; P = 0.007). Moreover, in multivariable analysis, PMI was associated with sorafenib tolerability (odds ratio 0.26; P = 0.008) and was a prognostic factor affecting TTF (hazard ratio 1.77; P = 0.021).PMI might be a predictive marker of tolerance to treatment and TTF in HCC patients receiving sorafenib treatment.

Background Measurement of the tricuspid regurgitation pressure gradient (TRPG) by echocardiography is recommended as the most objective examination for the detection of portopulmonary hypertension (PoPH). This prospective study aimed to identify factors associated with a high TRPG in patients with cirrhosis and develop a screening method for identifying patients most likely to benefit from investigation with echocardiography.Results Four hundreds and eighty-six patients with cirrhosis underwent Doppler echocardiography, and were analyzed in the present study. Of the 486 patients, 51 (10.5%) had TRPG ≥35 mmHg. The median BNP was 39.5 (range, 3.3–712.0) pg/mL. Ninety-one (18.7%) patients reported shortness of breath. Multivariate analysis identified female, shortness of breath, and BNP ≥49 pg/mL as independent factors for TRPG ≥35 mmHg. The risk score for predicting TRPG ≥35 mmHg was calculated: risk score = −3.230 + 0.622 × gender (female: 1, male: 0) + 1.403 × shortness of breath (presence: 1, absence: 0) + 0.726 × BNP (≥ 49pg/mL: 1, −8).Conclusions We clarified the characteristics of patients with suspected PoPH, and developed a scoring model for identifying patients at high risk of PoPH, which may have utility in selecting patients with cirrhosis that may benefit from echocardiography.

BACKGROUND In hepatocellular carcinoma (HCC), detection and treatment prior to growth beyond 2 cm are important as a larger tumor size is more frequently associated with microvascular invasion and/or satellites. In the surveillance of very small HCC nodules (≤ 2 cm in maximum diameter, Barcelona clinical stage 0), we demonstrated that the tumor markers alpha-fetoprotein and PIVKA-Ⅱ are not so useful. Therefore, we must survey with imaging modalities. The superiority of magnetic resonance imaging (MRI) over ultrasound (US) to detect HCC was confirmed in many studies. Although enhanced MRI is now performed to accurately diagnose HCC, in conventional clinical practice for HCC surveillance in liver diseases, unenhanced MRI is widely performed throughout the world. While, MRI has made marked improvements in recent years. AIM To make a comparison of unenhanced MRI and US in detecting very small HCC that was examined in the last ten years in patients in whom MRI and US examinations were performed nearly simultaneously. METHODS In 394 patients with very small HCC nodules, those who underwent MRI and US at nearly the same time (on the same day whenever possible or at least within 14 days of one another) at the first diagnosis of HCC were selected. The detection rate of HCC with unenhanced MRI was investigated and compared with that of unenhanced US. RESULTS The sensitivity of unenhanced MRI for detecting very small HCC was 95.1% (97/102, 95% confidence interval: 90.9-99.3) and that of unenhanced US was 69.6% (71/102, 95% confidence interval: 60.7-78.5). The sensitivity of unenhanced MRI for detecting very small HCC was significantly higher than that of unenhanced US (P < 0.001). Regarding the location of HCC in the liver in patients in whom detection by US was unsuccessful, S7-8 was identified in 51.7%. CONCLUSION Currently, unenhanced MRI is a very useful tool for the surveillance of very small HCC in conventional clinical follow-up practice.

Hepatocellular carcinoma (HCC) can de novo develop in patients with chronic hepatitis C even after the achievement of sustained virologic response (SVR). We characterized de novo HCC after SVR, comparing it with HCC that developed in patients during persistent hepatitis C virus (HCV) infection. Characteristics, survival rates, and recurrence rates after curative treatment in 178 patients who developed initial HCC after SVR diagnosed between 2014 and 2020 were compared with those of 127 patients with initial HCC that developed during persistent HCV infection diagnosed between 2011 and 2015; HCC was detected under surveillance in both groups. HCC was less advanced and liver function worsened less in patients with SVR than in patients with persistent HCV. The survival rate after diagnosis was significantly higher for patients with SVR than for patients with persistent HCV (1-, 3-, and 5-year survival rates, 98.2%, 92.5%, and 86.8% versus 89.5%, 74.7%, and 60.8%, respectively; P < 0.001). By contrast, the recurrence rate after curative treatment was similar between groups (1-, 3-, and 5-year recurrence rates, 11.6%, 54.6%, and 60.4% versus 24.0%, 46.7%, and 50.4%, respectively; P = 0.7484). Liver function improved between initial HCC diagnosis and recurrence in patients with SVR (P = 0.0191), whereas it worsened in the control group (P < 0.001). In addition, patients with SVR could receive curative treatment for recurrence more frequently than patients with persistent HCV (80.4% versus 47.8%, respectively; P = 0.0008). Conclusion: Survival of patients with de novo HCC after SVR was significantly higher than that of patients in whom HCC developed during persistent HCV infection, despite similar rates of recurrence after curative treatment. A higher prevalence of curative treatment for recurrent HCC and improved liver function contributed to this result.

By analyzing possible factors contributing to imaging misevaluation of arterial phase (AP) vascularity, we aimed to provide a more proper way to detect AP hypervascularity of hepatocellular carcinomas (HCCs) using the noninvasive imaging modalities magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS). We retrospectively recruited 164 pathologically confirmed HCC lesions from 128 patients. Using CEUS with Sonazoid (SCEUS) and gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid MRI (EOB-MRI), AP vascularity of the lesions was evaluated and inconsistencies in interpretation were examined. Indicators of margin, echogenicity, and halo and mosaic signs of lesions on grayscale US; depth of lesions on SCEUS; and tumoral homogeneity, signal contrast ratio of lesions to the surrounding area on precontrast and AP images on EOB-MRI, and histological grade were investigated. When precontrast images were used to adjust the AP enhancement ratio, the proportion of inconsistent interpretations of AP vascularity declined from 26.2% (43/164; 29 non-hypervascularity instances using EOB-MRI and 14 using SCEUS) to 16.5% (27/164; 7 using EOB-MRI and 20 using SCEUS). Greater lesion depth (P = 0.017), ill-defined tumoral margin (P = 0.028), absence of halo sign (P = 0.034), and histologically early HCC (P = 0.007) on SCEUS, and small size (P = 0.012) and heterogeneity (P = 0.013) of lesions and slight enhancement (low AP enhancement ratio) (P = 0.018 and 0.009 before and after adjustment) on EOB-MRI, may relate to undetectable hypervascularity. SCEUS and EOB-MRI may show discrepancies in evaluating AP vascularity in the case of deep, ill-defined, heterogeneous, slightly enhanced lesions, and histologically early HCCs. We recommend adjusting AP with precontrast images in EOB-MRI, and combining both modalities to detect hypervascularity.

INTRODUCTION Entecavir (ETV) and tenofovir alafenamide (TAF) are both first-line hepatitis B virus (HBV) therapies, but ETV-to-TAF switch outcome data are limited. We aimed to assess outcomes up to 96 weeks after ETV-to-TAF switch. METHODS ETV-treated (≥12 months) chronic hepatitis B patients switched to TAF in routine practice at 15 centers (United States, Korea, Japan, and Taiwan) were included. Primary outcome was complete viral suppression (CVS) rate (HBV DNA

BACKGROUND The oral nucleos(t)ide analogue, entecavir (ETV) was demonstrated to reduce the rate of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)-associated liver cirrhosis. However, the reduction of HCC differs in various regions of the world. AIM To investigate the reduction of HCC development due to ETV therapy by meta-analysis. METHODS We surveyed the differences in HCC development following ETV treatment based on published articles using PubMed (2004-2019). RESULTS The regions with the most marked reduction in HCC development due to ETV therapy were Spain (1.0%/year) and Canada (Southern part, 1.3%/year), and the most ineffective areas were South Korea (3.6%-3.8%/year), China (3.3%/year), Taiwan (2.4%-3.1%/year), and Hong Kong (2.8%/year). Following ETV administration, the incidence of HCC in genotype D regions (1.89% ± 0.28%/year, mean ± SE) was significantly lower than that in genotype C regions (2.91% ± 0.24%/year, P < 0.01). With regard to the initial HBV-DNA level, in genotype C patients (average: 5.61 Log10IU/mL) this was almost the same as that in genotype D patients (average: 5.46 Log10IU/mL). Moreover, there was no association between the prevalence ratio of HBV and the incidence of HCC on ETV treatment. CONCLUSION The effectiveness of ETV in preventing HCC development in HBV-associated liver cirrhosis is genotype-dependent.

Katsuaki Ogushi,1,* Makoto Chuma,1,* Haruki Uojima,2 Hisashi Hidaka,2 Kazushi Numata,1 Satoshi Kobayashi,3 Shunji Hirose,4 Nobuhiro Hattori,5 Tomoaki Fujikawa,6 Takahide Nakazawa,2 Naohisa Wada,2 Shuitirou Iwasaki,2 Taito Fukushima,3 Yusuke Sano,3 Makoto Ueno,3 Kuniyuki Kawano,3 Kota Tsuruya,4 Masako Shomura,4 Tsunamasa Watanabe,5 Kotaro Matsunaga,5 Yosuke Kunishi,7 Yusuke Saigusa,8 Kuniyasu Irie,9 Shogo Iwabuchi,6 Makoto Kako,10 Manabu Morimoto,3 Tatehiro Kagawa,4 Katsuaki Tanaka,11 Shin Maeda9 1Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan; 2Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan; 3Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan; 4Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; 6Department of Gastroenterology, Shonan Fujisawa General Hospital, Fujisawa, Japan; 7Department of Gastroenterology, Kanagawa Prefectural Ashigarakami Hospital, Kanagawa, Japan; 8Department of Biostatistics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 9Department of Gastroenterology, Yokohama City University Hospital, Yokohama, Japan; 10Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Japan; 11Gastroenterology Division, Hadano Red Cross Hospital, Hadano, Japan*These authors contributed equally to this workCorrespondence: Makoto Chuma Gastroenterological CenterYokohama City University Medical Center, 4-57 Urafune-Cho, Minami-Ku, Yokohama, Kanagawa 2320024, JapanTel +81 45 261 5656Fax +81 45 253 9955Email chuma@yokohama-cu.ac.jpPurpose: To assess the safety, efficacy and prognostic impact of clinical factors related to lenvatinib treatment in Child-Pugh class A (CP-A) and class B (CP-B) patients with unresectable hepatocellular carcinoma (u-HCC).Methods: Patients with u-HCC who were treated with lenvatinib at multiple centers in Japan were retrospectively analyzed for treatment outcomes according to their respective CP status. Radiological objective response (OR) was assessed using modified response evaluation criteria in solid tumors (mRECIST) guidelines.Results: Baseline demographic parameters were comparable between 126 (69.6%) patients with CP-A disease and 55 patients (30.4%) with CP-B disease. Frequency of lenvatinib-related adverse events, including decreased appetite (P=0.034), diarrhea (P=0.040), elevated serum bilirubin (P=0.016) and vomiting (P=0.009), were higher in CP-B than in CP-A patients. Relative dose intensity (RDI) was significantly higher in CP-A (0.69) than CP-B patients (0.50, P < 0.001). Furthermore, OR rate (44.0%) was markedly higher in CP-A5 patients as compared to CP-A6 (25.5%), CP-B7 (22.2%), and CP-B8 patients (5.3%), respectively (P=0.002). In multivariable analysis, performance status (0 vs 1, 2, P=0.026), CP class (A vs B, P=0.045) and RDI (≥ 0.7 vs < 0.7, P=0.034) were identified as factors associated with response to lenvatinib treatment. Overall survival (OS) at 12 months was significantly different between CP-A (66.3%) and CP-B patients (30.0%, P=0.002), and between CP 5– 7 (59.2%) and CP 8 patients (34.8%, P=0.003). In multivariable analysis, CP class (A vs B, P=0.007) and Barcelona clinic liver cancer (BCLC) stage (B vs C, P=0.002) were associated with OS following lenvatinib treatment.Conclusion: Lenvatinib treatment offers significant benefits in patients with good liver function in real-world practice. The various characteristics identified in this study might be helpful as clinical predictors of response to lenvatinib and survival in clinical practice. Further studies are required to address eligibility for lenvatinib treatment in CP 7 patients.Keywords: lenvatinib, tyrosine kinase inhibitor, hepatocellular carcinoma, Child-Pugh, adverse events, overall survival

BACKGROUND In a phase III trial of lenvatinib as first-line treatment for advanced unresectable hepatocellular carcinoma (uHCC), the drug proved non-inferior to sorafenib in terms of the overall survival, but offered better progression-free survival. However, the effects of lenvatinib in uHCC patients with a tumor thrombus in the main portal vein and/or a high tumor burden (tumor occupancy more than 50% of the total liver volume), remain unclear, because these were set as exclusion criteria in the aforementioned trial. CASE SUMMARY A 53-year-old man (case 1) and 66-year-old woman (case 2) with uHCC presented to us with a tumor thrombus in both the main portal vein and inferior vena cava, a high tumor burden accompanied by a tumor diameter greater than > 100 mm, and distant metastasis, with the residual liver function classified as grade 2A according to the modified Albumin–Bilirubin grading. We started both patients on lenvatinib. The therapeutic effect, as evaluated by the modified Response Evaluation Criteria in Solid Tumors, was rated as partial response in both case 1 and case 2 (at 8 wk and 4 wk after the start of lenvatinib administration, respectively). The therapeutic effect was sustained for 6 mo in case 1 and 20 mo in case 2. Fever occurred as an adverse event in both case 1 and 2, and hyperthyroidism and thrombocytopenia in only case 2, neither of which, however, necessitated treatment discontinuation. CONCLUSION Even in hepatocellular carcinoma patients with poor prognostic factors, if the liver function is well-preserved, lenvatinib is effective and safe.

Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naive patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10–5; genotype 2 vs. 3, p = 3.28 × 10–5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1–3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4–5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512–148.550), p value (p = 4.06 × 10–5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153–13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4–5 (41.6% [79/190]) than CKD stage 1–3 (26.1% [319/1220]) patients (p = 2.00 × 10–5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10–18) patients. G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

Background: Lenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated whether or not NO influence a therapeutic response and adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC).Methods: This study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO3–) to nitrite (NO2–) with nitrate reductase, followed by quantitation of NO2– based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of maximal therapeutic response and SAE on the change rate of NO from baseline after administration of lenvatinib.Results: After lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (P = 0.193). However, the change rate of NO was significantly higher in patients with AEs than in those without AEs (P = 0.013). When a reduction in NO rate of < 0.8 was defined as a clinically significant reduction of NO (CSRN), the CSRN group had significantly worse progression-free survival (PFS) and overall survival (OS) than the non-CSRN group (P = 0.040 and P = 0.005, respectively)ConclusionDecreased NO levels were associated with the occurrence of AEs and worse prognosis after lenvatinib administration. Change rate in serum NO can be used as predictive markers in patients receiving lenvatinib therapy for HCC.

Purpose: To assess the utility of measurement of the computed tomography (CT) attenuation value (CTav) in predicting tumor necrosis in hepatocellular carcinoma (HCC) patients who achieve a complete response (CR), defined using modified Response Evaluation Criteria in Solid Tumors (mRECIST), after lenvatinib treatment. Method: We compared CTav in arterial phase CT images with postoperative histopathology in four patients who underwent HCC resection after lenvatinib treatment, to determine CTav thresholds indicative of histological necrosis (N-CTav). Next, we confirmed the accuracy of the determined N-CTav in 15 cases with histopathologically proven necrosis in surgical specimens. Furthermore, the percentage of the tumor with N-CTav, i.e. the N-CTav occupancy rate, assessed using Image J software in 30 tumors in 12 patients with CR out of 571 HCC patients treated with lenvatinib, and its correlation with local recurrence following CR were examined. Results: Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off value of CTav of 30.2 HU, with 90.0% specificity and 65.0% sensitivity in discriminating between pathologically identified necrosis and degeneration, with a CTav of less than 30.2 HU indicating necrosis after lenvatinib treatment (N30-CTav). Furthermore, the optimal cut-off value of 30.6% for the N30-CTav occupancy rate by ROC analysis was a significant indicator of local recurrence following CR with 76.9% specificity and sensitivity (area under the ROC curve; 0.939), with the CR group with high N30-CTav occupancy (>30.6%) after lenvatinib treatment showing significantly lower local recurrence (8.3% at 1 year) compared with the low (30.6% might be a predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.

AIM Direct-acting antivirals (DAAs) are currently available even for patients with decompensated cirrhosis. Reportedly, hepatic functional reserve improved in the short term after achievement of sustained virologic response (SVR). We aimed to clarify the outcomes after achievement of SVR in patients with decompensated cirrhosis who were treated by DAAs in real-world clinical practice. METHODS A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted in 86 patients with decompensated cirrhosis, who were evaluated for 48 weeks post-treatment. RESULTS The cohort included 8 patients with Child-Pugh class A, 56 with B, and 22 with C. The proportion of Child-Pugh class A patients increased from 9.1% at baseline to 44.1% at 48 weeks post-treatment, while that of class B and C patients decreased from 66.2% to 35.1% and from 24.7% to 14.3%, respectively. Among the patients with Child-Pugh class B and C, univariate analysis identified low total bilirubin, Child-Pugh score, Child-Pugh class B, ALBI score, and high serum albumin as factors associated with improvement to Child-Pugh class A. The optimal cut-off value of the factors for predicting improvement to Child-Pugh class A were 1.4 mg/dL for total bilirubin, 2.9 g/dL for serum albumin, 8 points for Child-Pugh score, and -1.88 for ALBI score. CONCLUSION Achievement of SVR with sofosbuvir/velpatasvir improved the liver functional reserve at 12 weeks post-treatment and maintained the stable effects until 48 weeks post-treatment in patients with decompensated cirrhosis. Specifically, the patients with less advanced conditions had the likelihood of improving to Child-Pugh class A at 48 weeks post-treatment. This article is protected by copyright. All rights reserved.

Purpose To assess the impact of clinical factors on the safety and efficacy of atezolizumab plus bevacizumab (ATZ+BV) treatment in patients with unresectable hepatocellular carcinoma (u-HCC). Method Ninety-four u-HCC patients who were treated with ATZ+BV at multiple centers were enrolled. We defined Child-Pugh (CP)-A patients who received ATZ+BV treatment as a 1st line therapy as the 'meets the broad sense of the IMbrave150 criteria' group (B-IMbrave150-in, n=46), and patients who received ATZ+BV treatment as a later line therapy or CP-B patients (regardless of whether ATZ+BV was a 1st line or later line therapy) as the B-IMbrave150-out group (n=48). Patients were retrospectively analyzed for adverse events (AEs) and treatment outcomes according to their clinical status characteristics, including neutrophil lymphocyte ratio (NLR) at baseline. Results The overall incidence of AEs was 87.2% (82/94 patients). The frequency of interruption of ATZ+BV treatment due to fatigue was higher in CP-B than CP-A patients (P=0.030). Objective response (OR) rates of the B-IMbrave150-in group (28.3%, 39.1%) were significantly higher than those of the B-IMbrave150-out group (8.3%, 18.8%; P=0.0157, 0.0401) using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST, respectively. In multivariate analysis, neutrophil lymphocyte ratio (NLR) (hazard ratio (HR), 4.591; P=0.0160) and B-IMbrave150 criteria (HR, 4.108; P=0.0261) were independent factors associated with the OR of ATZ+BV treatment using RECIST. Conclusion In real-world practice, ATZ+BV treatment might offer significant benefits in patients who meet B-IMbrave150 criteria or have low NLR. This article is protected by copyright. All rights reserved.

Evaluating liver fibrosis is crucial for disease severity assessment, treatment decisions, and hepatocarcinogenic risk prediction among patients with chronic hepatitis C. In this retrospective multicenter study, we aimed to construct a novel model formula to predict cirrhosis. A total of 749 patients were randomly allocated to training and validation sets at a ratio of 2:1. Liver stiffness measurement (LSM) was made via transient elastography using FibroScan. Patients with LSM ≥12.5 kPa were regarded as having cirrhosis. The best model formula for predicting cirrhosis was constructed based on factors significantly and independently associated with LSM (≥12.5 kPa) using multivariate regression analysis. Among the 749 patients, 198 (26.4%) had LSM ≥12.5 kPa. In the training set, multivariate analysis identified logarithm natural (ln) type IV collagen 7S, ln hyaluronic acid, and ln Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA+-Mac-2 BP) as the factors that were significantly and independently associated with LSM ≥12.5 kPa. Thus, the formula was constructed as follows: score = −6.154 + 1.166 × ln type IV collagen 7S + 0.526 × ln hyaluronic acid + 1.069 × WFA+-Mac-2 BP. The novel formula yielded the highest area under the curve (0.882; optimal cutoff, −0.381), specificity (81.5%), positive predictive values (62.6%), and predictive accuracy (81.6%) for predicting LSM ≥12.5 kPa among fibrosis markers and indices. These results were almost similar to those in the validated set, indicating the reproducibility and validity of the novel formula. The novel formula scores were significantly, strongly, and positively correlated with LSM values in both the training and validation data sets (correlation coefficient, 0.721 and 0.762; p = 2.67 × 10−81 and 1.88 × 10−48, respectively). In conclusion, the novel formula was highly capable of diagnosing cirrhosis in patients with chronic hepatitis C and exhibited better diagnostic performance compared to conventional fibrosis markers and indices.

We evaluated the efficacy of fusion imaging combining contrast-enhanced ultrasonography (CEUS) images and arterial phase contrast-enhanced CT (CECT) or hepatobiliary phase magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (EOB-MRI) images for the early evaluation of the effectiveness of radiofrequency ablation (RFA) for small hypervascular hepatocellular carcinoma (HCC) with iso-echoic or unclear margins on conventional US. Forty HCCs (22 iso-echoic and 18 unclear margin lesions) with mean diameters of 13.7 mm were treated using RFA under the guidance of fusion imaging with CEUS. The adequacy of RFA was evaluated using fusion imaging with CEUS 1 day after RFA. CECT or EOB-MRI was performed 1 month after RFA. We reviewed the images obtained using both modalities. When the 1-month CECT or EOB-MRI scans were used as the reference standard, the sensitivity, specificity, and accuracy of the 1-day fusion imaging for the diagnosis of the adequate ablation of these HCCs were 97, 100, and 98%, respectively; the kappa value for the agreement between the findings using the two modalities was 0.655. Fusion imaging with CEUS appears to be a useful method for the early evaluation of the efficacy of RFA for the treatment of HCCs with iso-echoic or unclear margins on conventional US.

AIM Recently, a new method has been developed to diagnose hepatic steatosis with attenuation coefficients based on the ultrasound-guided attenuation parameter (UGAP). We investigated whether fibrosis identified by hepatic stiffness measurements based on magnetic resonance elastography (MRE) affects attenuation coefficient measurement using UGAP for the evaluation of hepatic steatosis. METHODS A total of 608 patients with chronic liver disease were analyzed. Correlations between magnetic resonance imaging-determined proton density fat fraction (PDFF) or MRE value and attenuation coefficients were evaluated. In addition, the interaction between hepatic fibrosis and the attenuation coefficient was analyzed. RESULTS The correlation coefficient (r) between PDFF values and attenuation coefficient values was 0.724, indicating a strong relationship. Conversely, the r between MRE values and attenuation coefficient values was -0.187, indicating almost no relationship. In the multiple regression assessment of the effect of PDFF and MRE on the attenuation coefficient based on UGAP, the P-values for PDFF, MRE, and PDFF × MRE were

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-naive, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen.