Diagnostic features of autoimmune hepatitis in SARS­CoV­2­vaccinated vs. unvaccinated individuals.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of lives, leading to significant morbidity and mortality. With >772 million cases and nearly seven million deaths reported worldwide to date, the development of vaccines has been a critical step in mitigating the impact of COVID-19. However, concerns have arisen regarding the potential for SARS-CoV-2 mRNA vaccination to trigger autoimmune diseases, including autoimmune hepatitis (AIH). The present single-center, retrospective study aimed to compare the clinical and pathological features of AIH in patients with or without a history of SARS-CoV-2 mRNA vaccination. A total of 72 patients with AIH were examined. Among them, 10 had received the SARS-CoV-2 mRNA vaccination prior to AIH onset. These patients exhibited more pronounced CD4+ T cell infiltration into the liver tissue compared with those who were unvaccinated. No significant differences in the levels of other liver enzymes, autoimmune antibodies, or CD8+ T cell infiltration were observed between the groups. Moreover, the AIH patients with a history of SARS-CoV-2 mRNA vaccination had more extensive CD4+ T cell infiltration in their liver tissues than the unvaccinated patients. These findings suggested that the immune response to SARS-CoV-2 mRNA vaccination may influence the pathogenesis of AIH, highlighting the need for further research into the relationship between SARS-CoV-2 mRNA vaccination and autoimmune liver diseases. Such studies will also help clarify the distinction between vaccine-induced liver injury and traditional AIH.

Similar Efficacy Between Atezolizumab Plus Bevacizumab Versus Hepatic Arterial Infusion Chemotherapy For Unresectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Retrospective Cohort Study.

BACKGROUND/AIM: The landscape of treatments for hepatocellular carcinoma (HCC), including immune checkpoint inhibitors, has expanded significantly. However, unresectable HCC patients with portal vein tumor thrombus (PVTT) continue to face a poor prognosis. This investigation examined the survival outcomes and determinants influencing survival rates in advanced HCC patients with PVTT undergoing treatment with atezolizumab plus bevacizumab (ATZ+BEV) or hepatic arterial infusion chemotherapy (HAIC). PATIENTS AND METHODS: Between December 2003 and June 2023, 48 advanced HCC with PVTT underwent treatment with either ATZ+BEV (16 patients) or HAIC (32 patients). RESULTS: The analysis revealed no significant disparities in overall survival (OS) or treatment efficacy between the ATZ+BEV and HAIC groups (ATZ+BEV: 10.0 months, HAIC: 15.3 months). Treatment with either ATZ+BEV or HAIC resulted in minimal alterations in the ALBI score and preserved hepatic function. Independent prognostic factors for OS, identified via multivariate logistic regression, included serum α-fetoprotein levels >400 ng/ml [hazard ratio (HR)=1.94; p=0.001], the existence of more than five tumors (HR=1.55; p=0.043), and the Child-Pugh score (HR=2.53; p=0.002). CONCLUSION: This investigation revealed no significant variance in OS and response rates between patients receiving ATZ+BEV and those treated with HAIC. The survival of advanced HCC patients with PVTT is intricately linked to the preservation of liver function, emphasizing the necessity for additional research to enhance treatment approaches for this patient population.

Systemic Chemotherapy for Advanced Hepatocellular Carcinoma in Patients With Child-Pugh class B.

Background/Aim: Numerous agents, including immune checkpoint inhibitors, are now available for hepatocellular carcinoma (HCC) treatment. Most trials involving systemic chemotherapy have included patients with Child-Pugh class A, while excluding or minimally enrolling those with Child-Pugh class B, due to liver dysfunction-related mortality. This study aimed to identify prognostic factors for survival in Child-Pugh class B patients receiving sorafenib (SOR), lenvatinib (LEN), atezolizumab plus bevacizumab (ATZ+BEV), or hepatic arterial infusion chemotherapy (HAIC). Patients and Methods: From December 2003 to June 2023, 137 patients with advanced HCC receiving systemic chemotherapies (SOR: n=43, LEN: n=16, ATZ+BEV: n=18, HAIC: n=60) were enrolled. Results: Overall survival (OS) and response rates did not differ significantly across treatments (SOR: 8.3 months, LEN: 10.2 months, ATZ+BEV: 8.5 months, HAIC: 7.3 months). Patients on HAIC and LEN had a lower rate of discontinuing treatment within three months compared to those on ATZ+BEV and SOR. HAIC was associated with fewer changes in ALBI score and better preservation of liver function. Multivariate logistic regression identified serum α-fetoprotein >400 ng/ml [hazard ratio (HR)=1.94; p=0.001], tumor count >5 (HR=1.55; p=0.043), and Child-Pugh score (HR=2.53; p=0.002) as independent predictors of OS. Conclusion: OS and response rates were similar across systemic chemotherapies. Prognosis for HCC in Child-Pugh class B patients was associated with liver function, necessitating further research for optimal treatment.

Neutrophil-to-Lymphocyte Ratio Predicts Immune-related Adverse Events in Patients With Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab.

Background/Aim: Atezolizumab in combination with bevacizumab is an approved systemic chemotherapy regimen for advanced hepatocellular carcinoma (HCC). However, immune checkpoint inhibitors (ICIs), such as atezolizumab, frequently lead to immune-related adverse events (irAEs). The identification of biomarkers that can predict the occurrence of irAEs is crucial for the optimal management of patients undergoing ICI treatment. Patients and Methods: Between October 2020 and June 2023, we conducted a study involving 69 patients with advanced HCC who received treatment with atezolizumab plus bevacizumab. We conducted an analysis of blood-based biomarkers to identify independent risk factors associated with irAEs. Results: In our study, 12 out of 69 patients (17.4%) experienced irAEs. Our investigation into blood-based biomarkers revealed that a neutrophil-to-lymphocyte ratio (NLR) <2.04 at three weeks after the initiation of treatment had high predictive power (area under the curve: 0.77) for irAEs. Furthermore, multivariate logistic analysis identified NLR at three weeks (hazard ratio=0.23; p=0.037) and non-viral infection (hazard ratio=4.47; p=0.037) as independent factors contributing to the occurrence of irAEs. Patients who developed irAEs demonstrated a more favorable overall response rate (75.0% vs. 28.1%, p=0.005), disease control rate (91.6% vs. 52.6%, p=0.016), and progression-free survival (12.1 months vs. 6.0 months, p=0.010) than those who did not experience irAEs. Conclusion: An NLR <2.04 at three weeks after the initiation of treatment may serve as a valuable biomarker for predicting irAEs in patients with HCC undergoing atezolizumab plus bevacizumab therapy.

Combined Ultrasound and Computed Tomography Guidance in Radiofrequency Ablation for Hepatocellular Carcinoma Reduces Local Recurrence Rate.

Background/Aim: In radiofrequency ablation (RFA) treatment of hepatocellular carcinoma (HCC), the therapeutic effect depends on the appropriate position of the electrode. To improve the accuracy of the electrode needle position, we currently perform RFA with combined ultrasound sonography (US) and computed tomography (CT) guidance. The purpose of this study was to evaluate the effectiveness of this US/CT-guided RFA method. Patients and Methods: This retrospective study recruited 97 patients with single tumors treated with transcatheter arterial chemoembolization and monopolar RFA between January 2013 and December 2017. Among these, 50 patients were treated with RFA under US/CT guidance (US/CT-guided group) and 47 were treated with RFA under US guidance alone (US-guided group). We analyzed the efficacy of US/CT guidance compared with US guidance alone. Results: The 1-, 2-, and 3-year local recurrence rates for the US/CT-guided and US-guided groups were 4.1%, 6.3%, and 8.6%, and 19.6%, 31.6%, and 41.9%, respectively. The local recurrence rate was lower in the US/CT-guided group (p=0.0030). Cox proportional hazards model for multivariate analysis demonstrated that the independent risk factors associated with local recurrence were tumor size (p=0.0028) and US/CT guidance (p=0.0037). Conclusion: US/CT-guided RFA for HCC reduced the local recurrence rate compared with US-guided RFA alone.

Factors Contributing to the Prognosis after Second-line Therapy with Ramucirumab in Advanced Hepatocellular Carcinoma.

Objective Multiple therapeutic agents exist for advanced hepatocellular carcinoma (HCC), but prognostic factors in second-line and subsequent therapies are unclear. Ramucirumab is a molecular-targeted agent effective against hepatocytes with alpha-fetoprotein (AFP) >400 ng/mL after sorafenib failure. We examined the prognostic factors and efficacy of ramucirumab with prior therapy other than sorafenib. Methods In our retrospective multicenter study, 33 patients were treated with ramucirumab for HCC with prior therapy other than sorafenib, including 1 patient who received 2 lines of ramucirumab. We analyzed background factors, liver reserve, the prognosis, and treatment duration and efficacy. Results The median albumin-bilirubin (ALBI) value showed little change during ramucirumab treatment. The ALBI value improved in 32% of patients, and their prognoses were better than in those who did not improve. Response and efficacy rates were not as high as those in the REACH-2 study but were similar when limited to patients with 2,500 ng/mL AFP. Thirteen patients received further treatment after ramucirumab failure and they had a significantly better prognosis from ramucirumab administration and also had a significantly better prognosis from the start of the first tyrosine kinase inhibitor than who did not received further treatment. In univariate and multivariate analyses of prognostic factors, the continuation of treatment with another drug after ramucirumab failure and a good ALBI value at initiation were significant. The presence of a ramucirumab response and treatment duration were not associated with the prognosis. A good ALBI value at initiation and ALBI value improvement during treatment were also identified as independent factors associated with eligibility for further treatment after ramucirumab failure. The treatment line did not correlate with the availability of treatment with another drug after treatment failure. Conclusions ALBI value improvement with ramucirumab treatment allows for subsequent treatment after failure and an improved overall prognosis.

[A case of multiple osteonecrosis caused by acute-on-chronic pancreatitis].

A 61-year-old man was admitted due to alcoholic liver cirrhosis, portal vein thrombosis, hepatocellular carcinoma, and chronic pancreatitis. The patient's portal vein thrombosis improved with anticoagulant therapy. Serum amylase gradually increased, but there was no abdominal pain. The patient was placed under observation. The pain in both ankle and knee joints appeared on nine days after admission. Multiple osteonecrotic lesions of both elbows, both knees and both ankle joints were examined using 99mTc bone scintigraphic examinations. Magnetic resonance of the right ankle joint showed osteonecrosis. The pain of the right ankle joint improved with a decrease of serum amylase. We report that this is a rare case of multiple osteonecrosis caused by exacerbation of chronic pancreatitis.

Therapeutic efficacy of atezolizumab plus bevacizumab for hepatocellular carcinoma with WNT/ß-catenin signal activation.

Atezolizumab plus bevacizumab therapy has high response rates in patients with advanced hepatocellular carcinoma (HCC). It has been reported that HCC with immune exclusion associated with the signal activation of WNT/ß-catenin is resistant to immune checkpoint inhibitors; however, to the best of our knowledge, the effectiveness of atezolizumab plus bevacizumab for HCC with WNT/ß-catenin signal activation has not been reported. The present study aimed to analyze the efficacy of atezolizumab plus bevacizumab for HCC with WNT/ß-catenin signal activation. A total of 24 patients who underwent liver tumor biopsy for HCC were classified into WNT/ß-catenin signal activation and inactivation groups according to the expression levels of ß-catenin and glutamine synthetase, which are indicative of WNT/ß-catenin signal activation. The differences in the clinical responses to treatment between the groups were analyzed. A total of 15 patients had HCC with WNT/ß-catenin signal activation, whereas 9 patients had HCC with WNT/ß-catenin signal inactivation. There were no significant differences between both groups regarding objective responses (P=0.519) and disease control (P=0.586). In the WNT/ß-catenin signal activation group, the median progression-free survival rate was 6.9 months compared with 6.2 months in the WNT/ß-catenin signal inactivation group (P=0.674). Although a small number of patients was included in the present study, the present findings suggested that the efficacy of atezolizumab plus bevacizumab might be unaffected by WNT/ß-catenin signal activation.

Hepatitis C virus eradication ameliorates the prognosis of advanced hepatocellular carcinoma treated with sorafenib.

The risk of hepatocellular carcinoma (HCC) occurrence following hepatitis C virus (HCV) eradication has been previously reported, but the impact of HCV eradication on advanced HCC patient survival remains unclear. Therefore, the present study aimed to evaluate the effect of HCV eradication on the survival outcome of patients with advanced HCC treated with sorafenib. One hundred and three HCV-related advanced HCC patients who were treated with sorafenib were enrolled in this study. Of these, 43 patients were administered antiviral therapy before sorafenib treatment (HCV eradication group), while 60 patients remained HCV-infected (HCV non-eradication group). We analysed the impact of HCV eradication on survival in advanced HCC treated with sorafenib. Median overall survival (OS) was significantly longer in the HCV eradication group than in the HCV non-eradication group (24.0 months vs. 14.1 months; p = 0.001). Although there was no significant difference in the albumin-bilirubin (ALBI) score at the start of treatment between the HCV eradication group and the non-eradication group (p = 0.065), the ALBI score at 2 months after initiation of sorafenib treatment was significantly decreased in the HCV non-eradication group (p < 0.001), but not in the HCV eradication group (p = 0.121). Multivariate logistic analysis revealed HCV eradication (hazard ratio [HR], 0.5; p = 0.006) and ALBI score at the start of treatment (HR, 2.47; p = 0.002) as factors that may contribute to OS. HCV eradication may serve an important role in the survival outcome of advanced HCC patients treated with sorafenib.

Multicentric recurrence of intraductal papillary neoplasm of bile duct after spontaneous detachment of primary tumor: A case report.

BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) rarely recurs in a multicentric manner. We encountered a patient with multiple recurrences of the gastric subtype of IPNB one year after spontaneous detachment of the primary tumor during peroral cholangioscopy (POCS). CASE SUMMARY: A 68-year-old woman on maintenance hemodialysis because of lupus nephritis had several cardiovascular diseases and a pancreatic intraductal papillary mucinous neoplasm (IPMN). She was referred to our department for dilation of the common bile duct (CBD) and a tumor in the lumen, detected using ultrasonography. She had no complaints, and blood tests of hepatobiliary enzymes were normal. Magnetic resonance cholangiopancreatography (MRCP) showed a papillary tumor in the CBD with a filling defect detected using endoscopic retrograde cholangiography (ERC). Intraductal ultrasonography revealed a papillary tumor and stalk at the CBD. During POCS, the tumor spontaneously detached with its stalk into the CBD. Pathology showed low-intermediate nuclear atypia of the gastric subtype of IPNB. After 1 year, follow-up MRCP showed multiple tumors distributed from the left hepatic duct to the CBD. ERC and POCS showed multicentric tumors. She was alive without hepatobiliary symptoms at least two years after initial diagnosis of IPNB. CONCLUSION: The patient experienced gastric subtype of IPNB without curative resection. Observation may be reasonable for patients with this subtype.

Therapeutic efficacy of lenvatinib for hepatocellular carcinoma with iso-high intensity in the hepatobiliary phase of Gd-EOB-DTPA-MRI.

Previous studies have reported that hepatocellular carcinoma (HCC) harboring WNT/ß-catenin mutations exhibits iso-high intensity by gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-MRI, i.e. EOB-MRI) during the hepatobiliary phase (HBP), thus indicating that EOB-MRI may help clinicians identify an immune exclusion class, which might not respond to treatment with immune checkpoint inhibitors. The present study analyzed the efficacy of lenvatinib for HCC with iso-high intensity during the HBP of EOB-MRI. Overall, 52 patients who underwent EOB-MRI for 140 HCC nodules were classified into iso-high-intensity and low-intensity groups during the HBP of EOB-MRI. The clinical and histological characteristics, and different responses to treatment of both groups were analyzed. The expression levels of ß-catenin and glutamine synthetase, indicative of WNT/ß-catenin mutations, were enhanced in the HCC with iso-high-intensity group. Nine patients had iso-high intensity, whereas 43 patients had low intensity. Tumor size was larger, and the levels of antagonist-II or vitamin K absence were higher in the iso-high-intensity group. Furthermore, 3/9 patients in the iso-high-intensity group had objective responses compared with 13/43 patients in the low-intensity group. Disease control was observed in 5/9 patients in the iso-high-intensity group and 26/43 patients in the low-intensity group. Median overall survival was 29.8 months for the iso-high-intensity group compared with 20.8 months for the low-intensity group. In the iso-high-intensity group, the median progression-free survival rate was 6.7 months compared with 5.6 months in the low-intensity group. No differences in best percentage change from baseline tumor size were observed in either group. Although few patients were included in this study, the present findings suggested that the efficacy of lenvatinib was unaffected by signal intensity during the HBP of EOB-MRI.

Serum α-fetoprotein level at treatment completion is a useful predictor of hepatocellular carcinoma occurrence more than one year after hepatitis C virus eradication by direct-acting antiviral treatment.

Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved liver function of HCV patients. The risk of hepatocellular carcinoma (HCC) occurrence following HCV eradication has been previously reported, but HCC may have been missed following imaging diagnosis before DAA administration in previous studies. Therefore, the present study aimed to identify definite predictors of HCC occurrence ≥1 year after DAA treatment. Among 956 patients receiving DAAs for HCV infection, 567 patients who achieved sustained virologic response with no history of HCC treatment were enrolled in this study between September 2014 and July 2021. The incidence of HCC in HCV-infected patients ≥1 year following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinical characteristics and blood test results. In the present study, 25 patients developed HCC. The incidence of HCC was 1.4%, 3.2%, 4.9% and 6.8% at 2, 3, 4 and 5 years, respectively, from the end of treatment with DAAs. Multivariate logistic analysis revealed serum α-fetoprotein level at end of treatment (EOT-AFP) >3.8 ng/ml ≥1 year following treatment with DAAs (HR, 9.7; p < .0001) as an independent factor that may contribute to HCC occurrence following DAA treatment. In conclusion, serum EOT-AFP level may serve an important role in determining the risk of HCC occurrence ≥1 year after DAA treatment. Regular examinations are required even if serum EOT-AFP level is low at treatment completion.

[A case of pembrolizumab-induced sclerosing cholangitis that was responsive to high-dose steroid therapy].

An 80-year-old woman was treated with pembrolizumab for non-small cell lung carcinoma. The hepatobiliary enzymes of the patient were elevated before the start of the ninth treatment cycle. The patient was diagnosed with pembrolizumab-induced sclerosing cholangitis based on magnetic resonance cholangiopancreatography and liver biopsy. Liver dysfunction improved with steroid therapy, and hepatobiliary enzymes increased again. The patient was treated with methylprednisolone (1000mg/day for 3 days) followed by oral prednisolone (1mg/kg/day). The patient's hepatobiliary enzymes subsequently decreased, and the oral prednisolone was tapered. Another liver biopsy, which showed a decrease in the hepatic CD8+ T cell count, was performed. Liver dysfunction did not recur although steroid therapy was discontinued after 1 year of administration.

A case of granulocyte colony-stimulating factor-producing intrahepatic sarcomatoid cholangiocarcinoma.

Here, we report a rare case of intrahepatic sarcomatoid cholangiocarcinoma that expressed granulocyte colony-stimulating factor (G-CSF). An 87-year-old man who presented with a continuous high-grade fever and cough over two weeks, and increased inflammatory response was admitted to our hospital. Laboratory tests revealed marked granulocytosis and high serum levels of G-CSF and interlukin-6. Imaging studies showed a huge liver mass in his right lobe and intrahepatic metastasis. He died of progressive disease. Pathological findings of the primary liver tumor at autopsy showed sarcomatous change; the specimen was positive for cytokeratins (AE1/AE3, cytokeratin-7, cytokeratin-19) and G-CSF. Few cases of G-CSF-producing intrahepatic sarcomatoid cholangiocarcinoma have been reported.