Comprehensive DNA methylation profiling of COVID-19 and hepatocellular carcinoma to identify common pathogenesis and potential therapeutic targets.

BACKGROUND & AIMS: The effects of SARS-CoV-2 infection can be more complex and severe in patients with hepatocellular carcinoma (HCC) as compared to other cancers. This is due to several factors, including pre-existing conditions such as viral hepatitis and cirrhosis, which are commonly associated with HCC. METHODS: We conducted an analysis of epigenomics in SARS-CoV-2 infection and HCC patients, and identified common pathogenic mechanisms using weighted gene co-expression network analysis (WGCNA) and other analyses. Hub genes were identified and analyzed using LASSO regression. Additionally, drug candidates and their binding modes to key macromolecular targets of COVID-19 were identified using molecular docking. RESULTS: The epigenomic analysis of the relationship between SARS-CoV-2 infection and HCC patients revealed that the co-pathogenesis was closely linked to immune response, particularly T cell differentiation, regulation of T cell activation and monocyte differentiation. Further analysis indicated that CD4+ T cells and monocytes play essential roles in the immunoreaction triggered by both conditions. The expression levels of hub genes MYLK2, FAM83D, STC2, CCDC112, EPHX4 and MMP1 were strongly correlated with SARS-CoV-2 infection and the prognosis of HCC patients. In our study, mefloquine and thioridazine were identified as potential therapeutic agents for COVID-19 in combined with HCC. CONCLUSIONS: In this research, we conducted an epigenomics analysis to identify common pathogenetic processes between SARS-CoV-2 infection and HCC patients, providing new insights into the pathogenesis and treatment of HCC patients infected with SARS-CoV-2.

Impact of the COVID-19 pandemic on liver transplant waitlist outcome in France.

The objective of this study was to investigate the impact of the COVID-19 pandemic on the outcome of patients on the liver transplantation (LT) waitlist in 2020 in France, in particular, the incidence of deaths and delisting for worsening condition, depending on the allocation score component. The 2020 cohort of patients on the waiting list was compared with the 2018/2019 cohorts. 2020 saw fewer LTs than in either 2019 or 2018 (1128, 1356, and 1325, respectively), together with fewer actual brain dead donors (1355, 1729, and 1743). In 2020, deaths or delisting for worsening condition increased significantly versus 2018/2019 (subdistribution hazard ratio 1.4, 95% confidence interval [CI] 1.2-1.7), after adjustment for age, place of care, diabetes, blood type, and score component, although COVID-19-related mortality was low. This increased risk mainly concerned patients with hepatocellular carcinoma (1.52, 95% CI 1.22-1.90), with 650 MELD exception points (2.19, 95% CI 1.08-4.43), and especially those without HCC and MELD scores from 25 to 30 (3.36 [95% CI 1.82-6.18]). In conclusion, by significantly decreasing LT activity in 2020, the COVID-19 pandemic increased the number of waitlist deaths and delisting for worsening condition, and significantly more for particular components of the score, including intermediate severity cirrhosis.

ACE2 negatively regulates the Warburg effect and suppresses hepatocellular carcinoma progression via reducing ROS-HIF1α activity.

Aerobic glycolysis has pleiotropic roles in the pathogenesis of hepatocellular carcinoma (HCC). Emerging studies revealed key promoters of aerobic glycolysis, however, little is known about its negative regulators in HCC. In this study, an integrative analysis identifies a repertoire of differentially expressed genes (DNASE1L3, SLC22A1, ACE2, CES3, CCL14, GYS2, ADH4, and CFHR3) that are inversely associated with the glycolytic phenotype in HCC. ACE2, a member of the rennin-angiotensin system, is revealed to be downregulated in HCC and predicts a poor prognosis. ACE2 overexpression significantly inhibits the glycolytic flux as evidenced by reduced glucose uptake, lactate release, extracellular acidification rate, and the expression of glycolytic genes. Opposite results are noticed in loss-of-function studies. Mechanistically, ACE2 metabolizes Ang II to Ang-(1-7), which activates Mas receptor and leads to the phosphorylation of Src homology 2-containing inositol phosphatase 2 (SHP-2). SHP2 activation further blocks reactive oxygen species (ROS)-HIF1α signaling. Addition of Ang-(1-7) or the antioxidant N-acetylcysteine compromises in vivo additive tumor growth and aerobic glycolysis induced by ACE2 knockdown. Moreover, growth advantages afforded by ACE2 knockdown are largely glycolysis-dependent. In clinical settings, a close link between ACE2 expression and HIF1α or the phosphorated level of SHP2 is found. Overexpression of ACE2 significantly retards tumor growth in patient-derived xenograft model. Collectively, our findings suggest that ACE2 is a negative glycolytic regulator, and targeting the ACE2/Ang-(1-7)/Mas receptor/ROS/HIF1α axis may be a promising therapeutic strategy for HCC treatment.

Effect of COVID-19 Pandemic on Patients Who Have Undergone Liver Transplantation Because of Hepatocellular Carcinoma.

BACKGROUND AND AIM: Many clinical studies have shown that the COVID-19 case fatality rate is higher in older patients, those with comorbidities, those with immunosuppressive conditions, and those who stay in the intensive care unit. This study aims to evaluate the clinical outcomes of 66 liver transplant (LT) patients with primary liver cancer who were exposed to COVID-19 infection. METHODS: Demographic and clinical data of 66 patients with primary liver cancer (hepatocellular carcinoma = 64, hepatoblastoma = 1, cholangiocarcinoma = 1) who underwent LT in our institute and were exposed to COVID-19 infection between March 2020 and November 2021 were analyzed in this cross-sectional study. The following data of the patients were recorded: age, sex, body mass index (kg/m2), blood group, underlying primary liver disease, smoking, tumor characteristics, post-transplant immunosuppressive agents, COVID-19 symptoms, hospitalization, intensive care unit stay, intubation, and other clinical features. RESULTS: There were 55 (83.3%) male and 11 (16.7%) female patients, with a median age of 58 years. Sixty-four patients were exposed to COVID-19 only once, whereas the remaining 2 patients were exposed 2 and 4 times, respectively. After exposure to COVID-19, it was determined that 37 patients used antiviral drugs, 25 were hospitalized, 9 were followed in the intensive care unit, and 3 were intubated. One intubated patient was under hospital follow-up because of biliary complications before exposure to COVID-19, and this patient died from sepsis. CONCLUSION: The low mortality rate of LT patients with primary liver cancer exposed to COVID-19 infection can be attributed to background immunosuppression that prevents cytokine storm. However, it is appropriate to support this study with multicenter studies to make strong comments on this issue.

Time to surgery is not an oncological risk factor in HCC patients undergoing liver resection.

PURPOSE: Given limitations of the health care systems in case of unforeseeable events, e.g., the COVID pandemic as well as trends in prehabilitation, time from diagnosis to surgery (time to surgery, (TTS)) has become a research issue in malignancies. Thus, we investigated whether TTS is associated with oncological outcome in HCC patients undergoing surgery. METHODS: A monocentric cohort of 217 patients undergoing liver resection for HCC between 2009 and 2021 was analyzed. Individuals were grouped according to TTS and compared regarding clinical characteristics. Overall survival (OS) and recurrence-free survival (RFS) was compared using Kaplan-Meier analysis and investigated by univariate and multivariable Cox regressions. RESULTS: TTS was not associated with OS (p=0.126) or RFS (p=0.761) of the study cohort in univariate analysis. In multivariable analysis age (p=0.028), ASA (p=0.027), INR (0.016), number of HCC nodules (p=0.026), microvascular invasion (MVI; p<0.001), and postoperative complications (p<0.001) were associated with OS and INR (p=0.005), and number of HCC nodules (p<0.001) and MVI (p<0.001) were associated with RFS. A comparative analysis of TTS subgroups was conducted (group 1, ≤30 days, n=55; group 2, 31-60 days, n=79; group 3, 61-90 days, n=45; group 4, >90 days, n=38). Here, the median OS were 62, 41, 38, and 40 months (p=0.602 log rank) and median RFS were 21, 26, 26, and 25 months (p=0.994 log rank). No statistical difference regarding oncological risk factors were observed between these groups. CONCLUSION: TTS is not associated with earlier tumor recurrence or reduced overall survival in surgically treated HCC patients.

OPTN/SRTR 2021 Annual Data Report: Liver.

In 2021, liver transplant volume continued to grow, with a record 9,234 transplants performed in the United States, 8,665 (93.8%) from deceased donors and 569 (6.2%) from living donors. There were 8,733 (94.6%) adult and 501 (5.4%) pediatric liver transplant recipients. An increase in the number of deceased donor livers corresponded to an increase in the overall transplant rate and shorter waiting times, although still 10.0% of livers that were recovered were not transplanted. Alcohol-associated liver disease was the leading indication for both waitlist registration and liver transplant in adults, outpacing nonalcoholic steatohepatitis, while biliary atresia remained the leading indication for children. Related to allocation policy changes implemented in 2019, the proportion of liver transplants performed for hepatocellular carcinoma has decreased. Among adult candidates listed for liver transplant in 2020, 37.7% received a deceased donor liver transplant within 3 months, 43.8% within 6 months, and 53.3% within 1 year. Pretransplant mortality improved for children following implementation of acuity circle-based distribution. Short-term graft and patient survival outcomes up to 1 year worsened for adult deceased and living donor liver transplant recipients, which is a reversal of previous trends and coincided with the onset of the COVID-19 pandemic in early 2020. Longer-term outcomes among adult deceased donor liver transplant recipients were unaffected, with overall posttransplant mortality rates of 13.3% at 3 years, 18.6% at 5 years, and 35.9% at 10 years. Pretransplant mortality improved for children following implementation of acuity circle-based distribution and prioritization of pediatric donors to pediatric recipients in 2020. Pediatric living donor recipients had superior graft and patient survival outcomes compared with deceased donor recipients at all time points.

Iron as a therapeutic target in chronic liver disease.

It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.

Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review.

Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.

Use of Contrast Media During CT-guided Thermal Ablation of Colorectal Liver Metastasis for Procedure Planning is Associated with Improved Immediate Outcomes.

PURPOSE: The aim of this study was to analyze the impact of using intra-procedural pre-ablation contrast-enhanced CT prior to percutaneous thermal ablation (pre-ablation CECT) of colorectal liver metastases (CLM) on local outcomes. MATERIALS AND METHODS: This retrospective analysis of a prospectively collected liver ablation registry included 144 consecutive patients (median age 57 years IQR [49, 65], 60% men) who underwent 173 CT-guided ablation sessions for 250 CLM between October 2015 and March 2020. In addition to oncologic outcomes, technical success was retrospectively evaluated using a biomechanical deformable image registration software for 3D-minimal ablative margin (3D-MAM) quantification. Bayesian regression was used to estimate effects of pre-ablation CECT on residual unablated tumor, 3D-MAM, and local tumor progression-free survival (LTPFS). RESULTS: Pre-ablation CECT was acquired in 71/173 (41%) sessions. Residual unablated tumor was present in one (0.9%) versus nine tumors (6.6%) ablated with versus without using pre-ablation CECT, respectively (p = 0.024). Pre-ablation CECT use decreased the odds of residual disease on first follow-up by 78% (CI95% [5, 86]) and incomplete ablation (3D-MAM ≤ 0 mm) by 58% (CI95% [13, 122]). The odds ratio for residual unablated tumor for larger CLM was lower when pre-ablation CECT was used (odds ratio 1.0 with pre-ablation CECT vs. 2.52 without). Pre-ablation CECT use was not associated with improvements on LTPFS. CONCLUSIONS: Pre-ablation CECT is associated with improved immediate outcomes by significantly reducing the incidence of residual unablated tumor and by mitigating the risk of incomplete ablation for larger CLM. We recommend performing baseline intra-procedural pre-ablation CECT as a standard imaging protocol. LEVEL OF EVIDENCE: Level 3 (retrospective cohort study).

A case report of hepatic angiomyolipoma, inflammatory subtype. Clinico-pathological characterization: a diagnostic challenge.

BACKGROUND: Angiomyolipoma is a benign mesenchymal neoplasm of a wide histological heterogeneity belonging to the PEComa "family." The liver, after the kidney, is their second most frequent location. However, inflammatory hepatic AMLs constitute a rare entity, with only fourteen documented cases until 2020. These neoplasms can overlap morphological features of IgG4-related diseases, being of great diagnostic relevance to demonstrating myomelanocytic-lineage differentiation of the neoplastic cells. CASE PRESENTATION: we present a new case of an inflammatory hepatic AML resembling an IgG4-related disease in a 35-year-old woman with a subcapsular 5 cm mass confined to segment VII of the right hepatic lobe. Although having reduced its size along the tumor's natural evolution, complete tumor resection was decided due to its hypermetabolic behavior (max. SUV = 12,6) assessed by PET-CT scan. Finally, the patient underwent a right hepatectomy due to spontaneous rupture and bleeding of the lesion during the intervention. All the diagnostic and therapeutic procedures occurred in the last months of the COVID-19 pandemic. CONCLUSIONS: This review aims to describe inflammatory hepatic AML histological and immunohistochemical features. We further sought to establish a clinicopathological contextualization of this tumoral subtype.

Chylothorax due to hepatic alveolar echinococcosis with infiltration of diaphragm and left pleura: a case report.

BACKGROUND: Alveolar echinococcosis (AE) is an endemic parasitic zoonosis in Germany. In most cases, the liver is the primary organ affected. CASE PRESENTATION: A 59-year old female patient presented with increasing exertional dyspnea and unintentional weight loss. A computed tomography (CT) scan showed a left-sided chylous pleural effusion and multiple intrahepatic masses with infiltration of the diaphragm and the pleura. The findings were initially misinterpreted as hepatocellular carcinoma (HCC) with infiltrating growth. Liver biopsy of one of the masses showed no evidence of malignancy, but an amorphous necrosis of unclear origin. HCC was further ruled out by magnetic resonance imaging (MRI). However, MRI findings were highly suspicious for hepatothoracic dissemination and complications due to AE. Typical histologic findings in a repeated and more specific examination of the liver tissue and a positive serology for echinococcosis confirmed the diagnosis of AE. As the hepatic and pulmonary manifestations were considered inoperable in a curative matter, an anti-parasitic treatment with albendazole was initiated. A video-assisted thoracoscopic surgery (VATS) with removal of the chylous effusion as well as a talc pleurodesis was performed to relieve the patient from dyspnea. Two months later, the patient was asymptomatic and a positron emission tomography (PET)-CT-scan with [18 F] fluoro-2-deoxy-d-glucose (FDG) showed a remarkable diminution of the hepatic manifestation. CONCLUSIONS: This case demonstrates a rare presentation of alveolar echinococcosis with a focus on pulmonary symptoms, emphasizing the importance of evaluation for pulmonary involvement in patients with AE and respiratory symptoms.

Telephone-Only Visits Preserved Hepatocellular Cancer Screening Rates in Patients with Cirrhosis Early in the COVID-19 Pandemic.

BACKGROUND: The coronavirus 2019 (COVID-19) pandemic required an immediate and large-scale transition to telemedicine. Telemedicine includes phone visits and video visits. Studies suggest that hepatocellular cancer (HCC) screening rates fell at the beginning of the COVID-19 pandemic. If left unaddressed, HCC morbidity/mortality may increase following the pandemic due to inadequate screening. AIMS: To assess the impact of phone-only visits on HCC screening rates in patients with cirrhosis. METHODS: Utilizing ICD-10 codes, 2 cohorts of patients with cirrhosis were identified. The pre-pandemic cohort had index visit between 1/1/2019 and 6/30/2019 (n = 290). The pandemic cohort (n = 112) was evaluated between 4/7/2020 and 6/7/2020. Each cohort was followed for 6 months from their index visit to determine HCC screening rate. Demographics and socioeconomic data from the American Community Survey database were compiled and compared between the cohorts. RESULTS: HCC screening rates in the pre-pandemic and pandemic cohorts were 72.4% and 69.6%, respectively, p = 0.67. No differences in HCC screening rates were observed between the two cohorts when stratified by demographic and socioeconomic factors. CONCLUSIONS: Use of phone-only visits was associated with adherence to HCC screening similar to that seen with in-person visits. The lack of influence on screening rates by racial/socioeconomic factors suggest telephone-only visits do not exacerbate healthcare disparities. In times of public health of crisis, telephone-only visits may provide the necessary access to hepatology care to ensure HCC screening regimens remain in-place for at-risk patients.

The Impact of the COVID-19 Pandemic on Hepatocellular Carcinoma Time to Treatment Initiation: A National Cancer Database Study.

BACKGROUND: The COVID-19 pandemic strained oncologic care access and delivery, yet little is known about how it impacted hepatocellular carcinoma (HCC) management. Our study sought to evaluate the annual effect of the COVID-19 pandemic on time to treatment initiation (TTI) for HCC. METHODS: The National Cancer Database was queried for patients diagnosed with clinical stages I-IV HCC (2017-2020). Patients were categorized based on their year of diagnosis as "Pre-COVID" (2017-2019) and "COVID" (2020). TTI based on stage and type of treatment first received was compared by the Mann-Whitney U test. A logistic regression model was used to evaluate factors of increased TTI and treatment delay (> 90 days). RESULTS: In total, 18,673 patients were diagnosed during Pre-COVID, whereas 5249 were diagnosed during COVID. Median TTI for any first-line treatment modality was slightly shorter during the COVID year compared with Pre-COVID (49 vs. 51 days; p < 0.0001), notably in time to ablation (52 vs. 55 days; p = 0.0238), systemic therapy (42 vs. 47 days; p < 0.0001), and radiation (60 vs. 62 days; p = 0.0177), but not surgery (41 vs. 41 days; p = 0.6887). In a multivariate analysis, patients of Black race, Hispanic ethnicity, and uninsured/Medicaid/Other Government insurance status were associated with increased TTI by factors of 1.057 (95% CI: 1.022-1.093; p = 0.0013), 1.045 (95% CI: 1.010-1.081; p = 0.0104), and 1.088 (95% CI: 1.053-1.123; p < 0.0001), respectively. Similarly, these patient populations were associated with delayed treatment times. CONCLUSIONS: For patients diagnosed during COVID, TTI for HCC, while statistically significant, had no clinically significant differences. However, vulnerable patients were more likely to have increased TTI.

Investigating the correlation between COVID-19 and the progression of chronic liver disease.

INTRODUCTION: The novel coronavirus disease 2019 has thrown light on various heterogeneous afflictions of newly emerging viruses on the human body. Early reports demonstrated direct effect of novel coronavirus on the liver, but subsequently, this did not stand up to validation. The SARS-CoV-2 virus affects the liver differentially; in healthy compared to those with preexisting liver disease. AREAS COVERED: This exhaustive paper reviews the current, literature on mechanisms by which COVID-19 affects the healthy liver and those with preexisting liver disease such as alcohol-related and nonalcoholic fatty liver, autoimmune liver disease, chronic liver disease and cirrhosis, hepatocellular carcinoma, viral hepatitis, and liver transplant recipients, with special mention on drug-and herb-induced liver injury with COVID-19 therapies. Search methodology: the review (Dec. 2022 - Jan. 2023) is based on PubMed (NLM) search using the keyword 'COVID' with supplementary searches using 'fibrosis;' 'liver;' 'cirrhosis;' 'CLD;' 'NAFLD;' 'NASH;' 'hepatocellular carcinoma;' 'hepatitis;' 'fatty liver;' 'alcohol;' 'viral;' 'transplant;' and 'liver failure.' EXPERT OPINION: Direct liver tropism of SARS-CoV-2 does not cause liver damage. Adverse events following infection depend on the severity of liver disease, the severity of COVID-19, and other risk factors such as metabolic syndrome and older age. Alcohol-related liver disease independently predicts adverse outcomes.

Effect of COVID-19 Pandemic-Related Delays in Chemoembolization on the Survival of Patients with Hepatocellular Carcinoma.

Background and Aims: COVID-19 has led to potential delays in liver cancer treatment, which may have undesirable effects on the prognosis of patients. We aimed to quantify the COVID-19 pandemic impact on the survival of patients with hepatocellular carcinoma (HCC) who underwent transarterial chemoembolization (TACE). Methods: A retrospective study was conducted in patients with HCC who underwent TACE at a tertiary care center during the prelockdown (March to July 2019) and lockdown (March to July 2020) periods. Demographic data, tumor characteristics, functional status, and vital status were collected from the hospital medical records. The endpoints were TACE interval, treatment response, and survival after TACE. Cox proportional hazards regression determined the significant preoperative factors influencing survival. Results: Compared to prelockdown, a significant delay occurred during the lockdown in repeated TACE treatments (76.7 vs. 63.5 days, P=0.007). The trend suggested a significant decrease in patients with HCC in the repeated TACE group (-33.3%). After screening, 145 patients were included (prelockdown (n = 87), lockdown (n = 58)). There was no significant difference in the 1-month objective response rate between the prelockdown and lockdown groups (65.5% vs. 64.4%, P=1.00). During follow-up, 56 (64.4%) and 34 (58.6%) deaths occurred in the prelockdown and lockdown groups, respectively (P=0.600). Multivariate analysis revealed no association between the lockdown group and decreased survival (HR 0.88, 95% CI 0.57-1.35, P=0.555). Conclusions: The impact of the COVID-19 pandemic on liver cancer care resulted in significant decreases and delays in repeated TACE treatments in 2020 compared to 2019. However, treatment delays did not seem to significantly impact survival.