IDDF2023-ABS-0005 Hepatocellular carcinoma (HCC) treatment experience using smart fusion in dialysis patients

BackgroundApproximately 700 dialysis patients are seen at our hospital. Among them are patients with HCC that develop viral hepatitis. Advances in ultrasound systems have improved the accuracy of HCC treatment and diagnosis. This time, we had the opportunity to use microwaves for dialysis patients using Smart Fusion and needle navigation installed in APLIOi800 so that we will report it.MethodsTen dialysis patients were treated from January 2018 to February 2023. An Emprint (Covidien, USA) antenna was used for treatment. Canon APLIOi800(Canon, Tochigi, Japan) was used. The built-in function is Smart Fusion. This method can display ultrasound imaging and volume data from other modalities, such as CT and MRI, in association with positional information using a magnetic sensor. Needle navigation has a function that can confirm the position of the needle. It is possible to treat even when the tumor is overprinted and the visualization is poor due to bubbles. Informed consent was obtained from all patients and the treatment was performed.ResultsIt was possible to visualize all tumors. In this study, CT images were used in 0 cases, and MRI was used in 1 Case. No serious side effects occurred after treatment.ConclusionsUsing this method, it was thought that dialysis patients could be safely and accurately treated.

IDDF2023-ABS-0299 Effectiveness of relink initiatives to re-engage diagnosed-but-untreated HCV-positive patients with direct-acting antiviral treatment

BackgroundHepatitis C virus (HCV) infection is a major cause of chronic liver disease that can progress to cirrhosis and hepatocellular carcinoma. The WHO has identified HCV infection as a public health threat and set a global target for HCV elimination by 2030. Simple pangenotypic direct-acting antiviral regimens allow most patients to be cured with minimal pretreatment and on-treatment monitoring. To achieve the WHO goal, patients including previously diagnosed HCV-positive patients who have been lost to follow-up, need to be linked to care. Studies report that up to 60% of patients who test positive for HCV antibodies are lost to follow-up and not treated. This loss has been further exacerbated by the COVID-19 pandemic, and many patients put off receiving care. Here, we explore the effectiveness of care re-engagement programs for patients with HCV.MethodsWe assessed ReLink programs (sponsored by Gilead Sciences, Inc.), designed to identify and re-engage HCV-positive patients with medical care and start/restart HCV treatment. We evaluated these programs by analyzing the number of patients, steps in the care cascade where patients were lost to follow-up, and the efficacy of the engagement program (determined by the number relinked and treated).ResultsSix programs assessed 44,964 patient records, identifying 11,163 patients lost to follow-up and eligible for contact. The main reason for the loss of follow-up was the inability to contact patients. Overall, 3726 patients were relinked with care, and 701 were treated. Several key points were identified for improving patient engagement with care, including the use of electronic databases to identify patients lost to follow-up, securing reliable contact information for patients, and partnership with medical societies.ConclusionsActive case finding, patient navigation, and care coordination in these programs led to increased engagement and treatment rates. Engaging HCV-positive patients with care is urgent, as many may already have developed more advanced liver disease. Adopting and adapting effective strategies from these programs may be a feasible way to improve patient outcomes and increase treatment numbers, thus contributing to meeting the WHO goal of HCV elimination.

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.

Nationwide Trends and the Influence of Age and Gender in the In-Patient Care of Patients with Hepatocellular Carcinoma in Germany between 2010 and 2020.

This study analyzes nationwide trends in HCC hospitalizations focusing on interventional liver-directed treatments and the influence of age and gender. Using data from the German Federal Statistical Office all hospitalizations for HCC between 2010 and 2020 were included. Uni- and multivariable logistic regression analyses were performed to identify variables independently associated with the use of liver-directed therapies. Due to the COVID-19 pandemic, data from 2020 were analyzed separately. A total of 134,713 hospitalizations (2010-2019) were included, increasing by 3.4% annually (12,707 to 13,143). The mean in-hospital stay (-15.0% [7.2 to 6.1 days]) and mortality (-23.2% [6.8 to 5.2%]) decreased while transarterial, surgical, and percutaneous ablative interventions increased by 38.6, 31.5, and 19.3%, respectively. In-hospital mortality was 7.7% in admissions with surgical treatment, while it was 0.6 and 0.5% for transarterial and percutaneous interventions. Mortality was higher in females (6.2 vs. 5.7%). Females (OR 0.89 [0.86,0.91], p < 0.001) and patients ≥80 years (OR 0.81 [0.79,0.84], p < 0.001) were less likely to receive liver-directed treatments. Liver-directed therapies were increasingly performed while in-hospital mortality and in-hospital stay decreased. Minimally invasive approaches showed lower mortality, shorter in-hospital stay, and lower costs compared to surgery. Proportionately, more women and older patients were hospitalized, receiving fewer liver-directed treatments while their mortality was higher.

Inferior outcomes of liver transplantation for hepatocellular carcinoma during early-COVID-19 pandemic in the United States.

BACKGROUND: Early in the coronavirus disease 2019 (COVID-19) pandemic, there was a significant impact on routine medical care in the United States, including in fields of transplantation and oncology. AIM: To analyze the impact and outcomes of early COVID-19 pandemic on liver transplantation (LT) for hepatocellular carcinoma (HCC) in the United States. METHODS: WHO declared COVID-19 as a pandemic on March 11, 2020. We retrospectively analyzed data from the United Network for Organ Sharing (UNOS) database regarding adult LT with confirmed HCC on explant in 2019 and 2020. We defined pre-COVID period from March 11 to September 11, 2019, and early-COVID period as from March 11 to September 11, 2020. RESULTS: Overall, 23.5% fewer LT for HCC were performed during the COVID period (518 vs 675, P < 0.05). This decrease was most pronounced in the months of March-April 2020 with a rebound in numbers seen from May-July 2020. Among LT recipients for HCC, concurrent diagnosis of non-alcoholic steatohepatitis significantly increased (23 vs 16%) and alcoholic liver disease (ALD) significantly decreased (18 vs 22%) during the COVID period. Recipient age, gender, BMI, and MELD score were statistically similar between two groups, while waiting list time decreased during the COVID period (279 days vs 300 days, P = 0.041). Among pathological characteristics of HCC, vascular invasion was more prominent during COVID period (P < 0.01), while other features were the same. While the donor age and other characteristics remained same, the distance between donor and recipient hospitals was significantly increased (P < 0.01) and donor risk index was significantly higher (1.68 vs 1.59, P < 0.01) during COVID period. Among outcomes, 90-day overall and graft survival were the same, but 180-day overall and graft were significantly inferior during COVID period (94.7 vs 97.0%, P = 0.048). On multivariable Cox-hazard regression analysis, COVID period emerged as a significant risk factor of post-transplant mortality (Hazard ratio 1.85; 95%CI: 1.28-2.68, P = 0.001). CONCLUSION: During COVID period, there was a significant decrease in LTs performed for HCC. While early postoperative outcomes of LT for HCC were same, the overall and graft survival of LTs for HCC after 180 days were significantly inferior.

7th Turkey in vitro Diagnostics (IVD) Symposium

The proceedings contain 75 papers. The topics discussed include: development of different product groups in the cleaning industry with synthesized nanosilver;investigation of the antimetastatic potential of thymbra spicata in human breast adenocarcinoma cells combined with standard chemotherapy;the effect of toll-interancing protein on inflammatory status of hepatocellular carcinoma cell line;surgery and inflammation: surgical inflammation;biochemistry of inflammation;its mediators and activities;pathophysiology of inflammation;classic and new biomarkers of inflammation;thymol reduces the lipopolysaccharide-induced acute kidney inflammation by modulating lysosomal stress;metabolic shift of the kynurenine pathway in inflammatory conditions;and evaluation of HBA1C level in patients with COVID-19.

704/DNA vaccines leverage cytoplasmic DNA stimulation to promote anti-HIV neutralizing antibody production in mice and strong immune response against alpha-fetoprotein in non-human primates.

Genetic immunization is an attractive approach for prophylactic and therapeutic vaccination using synthetic vectors to deliver antigen-encoding nucleic acids. Recently, DNA delivered by a physical means or RNA by liposomes consisting of four different lipids demonstrated good protection in human phase III clinical trials and received Drugs Controller General of India and US FDA approval to protect against COVID-19, respectively. However, the development of a system allowing for efficient and simple delivery of nucleic acids while improving immune response priming has the potential to unleash the full therapeutic potential of genetic immunization. DNA-based gene therapies and vaccines have the potential for rapid development, as exemplified by the recent approval of Collategene, a gene therapy to treat human critical limb ischemia, and ZyCoV, a DNA vaccine delivered by spring-powered jet injector to protect against SARS-CoV2 infection. Recently, we reported amphiphilic block copolymer 704 as a promising synthetic vector for DNA vaccination in various models of human diseases. This vector allows dose sparing of antigen-encoding plasmid DNA. Here, we report the capacity of 704-mediated HIV and anti-hepatocellular carcinoma DNA vaccines to induce the production of specific antibodies against gp120 HIV envelope proteins in mice and against alpha-fetoprotein antigen in non-human primates, respectively. An investigation of the underlying mechanisms showed that 704-mediated vaccination did trigger a strong immune response by (1) allowing a direct DNA delivery into the cytosol, (2) promoting an intracytoplasmic DNA sensing leading to both interferon and NF-κB cascade stimulation, and (3) inducing antigen expression by muscle cells and presentation by antigen-presenting cells, leading to the induction of a robust adaptive response. Overall, our findings suggest that the 704-mediated DNA vaccination platform is an attractive method to develop both prophylactic and therapeutic vaccines.

Effect of the COVID-19 Pandemic on the Psychological Health of Patients Who Underwent Liver Transplantation Due to Hepatocellular Carcinoma.

BACKGROUND: The primary aim of this study was to compare liver transplant (LT) recipients with and without hepatocellular carcinoma (HCC) in terms of COVID-19-related depression, anxiety, and stress. METHOD: A total of 504 LT recipients with (HCC group; n = 252) and without HCC (non-HCC group; n = 252) were included in the present case-control study. Depression Anxiety Stress Scales (DASS-21) and Coronavirus Anxiety Scale (CAS) were used to evaluate the depression, stress, and anxiety levels of LT patients. DASS-21 total and CAS-SF scores were determined as the primary outcomes of the study. Poisson regression and negative binomial regression models were used to predict the DASS and CAS scores. The incidence rate ratio (IRR) was used as a coefficient. Both groups were also compared in terms of awareness of the COVID-19 vaccine. RESULTS: Poisson regression and negative binomial regression analyses for DASS-21 total and CAS-SF scales showed that the negative binomial regression method was the appropriate model for both scales. According to this model, it was determined that the following independent variables increased the DASS-21 total score: non-HCC (IRR: 1.26; p = 0.031), female gender (IRR: 1.29; p = 0.036), presence of chronic disease (IRR: 1.65; p < 0.001), exposure to COVID-19 (IRR: 1.63; p < 0.001), and nonvaccination (IRR: 1.50; p = 0.002). On the other hand, it was determined that the following independent variables increased the CAS score: female gender (IRR:1.75; p = 0.014) and exposure to COVID-19 (IRR: 1.51; p = 0.048). Significant differences were found between the HCC and non-HCC groups in terms of median DASS-21 total (p < 0.001) and CAS-SF (p = 0.002) scores. Cronbach's alpha internal consistency coefficients of DASS-21 total and CAS-SF scales were calculated to be 0.823 and 0.783, respectively. CONCLUSION: This study showed that the variables including patients without HCC, female gender, having a chronic disease, being exposed to COVID-19, and not being vaccinated against COVID-19 increased anxiety, depression, and stress. High internal consistency coefficients obtained from both scales indicate that these results are reliable.

Hepatocellular carcinoma surveillance in the telehealth era: A single-centre review.

BACKGROUND: Real-world hepatocellular carcinoma (HCC) surveillance uptake remains suboptimal, despite evidence that surveillance is associated with lower cancer-related mortality in patients with cirrhosis and chronic hepatitis B. We aimed to examine the impact of telehealth consultations on HCC surveillance rates within a specialist liver clinic. METHODS: We conducted a retrospective observational study within an Australian outreach liver clinic within a culturally diverse community, comparing standard consultations before the COVID-19 pandemic to telehealth consultations during the pandemic. The primary outcome was surveillance uptake defined as the percentage of time up-to-date with surveillance (PTUDS) with the 6-month interval following each scan considered up-to-date. RESULTS: Over 18 months of follow-up for each cohort, the median PTUDS was 86.5% in the standard consultation cohort and 85.5% in the telehealth consultation cohort (p = 0.12). HCC diagnoses did not differ between groups and hospitalisation and mortality rates were low. Using multivariate regression, increasing age, the need for an interpreter and being born in South-East Asia independently predicted PTUDS in the standard consultation cohort, whereas being born in Australia or New Zealand was predictive of a lower PTUDS. Current alcohol use and distance from the clinic predicted a lower PTUDS in the telehealth consultation cohort. In both groups, missed clinic attendances were strongly predictive of a lower PTUDS. CONCLUSION: Telehealth hepatology consultations effectively coordinate HCC surveillance and are associated with similar outcomes to standard consultations. Its implementation should be widely considered given its advantages with regards to accessibility for patients.

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.

Bioinformatics Analysis of Candidate Genes and Pathways Related to Hepatocellular Carcinoma in China: A Study Based on Public Databases.

Background and Objective: Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor of the digestive system worldwide. Chronic hepatitis B virus (HBV) infection and aflatoxin exposure are predominant causes of HCC in China, whereas hepatitis C virus (HCV) infection and alcohol intake are likely the main risk factors in other countries. It is an unmet need to recognize the underlying molecular mechanisms of HCC in China. Methods: In this study, microarray datasets (GSE84005, GSE84402, GSE101685, and GSE115018) derived from Gene Expression Omnibus (GEO) database were analyzed to obtain the common differentially expressed genes (DEGs) by R software. Moreover, the gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by using Database for Annotation, Visualization and Integrated Discovery (DAVID). Furthermore, the protein-protein interaction (PPI) network was constructed, and hub genes were identified by the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape, respectively. The hub genes were verified using Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and Kaplan-Meier Plotter online databases were performed on the TCGA HCC dataset. Moreover, the Human Protein Atlas (HPA) database was used to verify candidate genes' protein expression levels. Results: A total of 293 common DEGs were screened, including 103 up-regulated genes and 190 down-regulated genes. Moreover, GO analysis implied that common DEGs were mainly involved in the oxidation-reduction process, cytosol, and protein binding. KEGG pathway enrichment analysis presented that common DEGs were mainly enriched in metabolic pathways, complement and coagulation cascades, cell cycle, p53 signaling pathway, and tryptophan metabolism. In the PPI network, three subnetworks with high scores were detected using the Molecular Complex Detection (MCODE) plugin. The top 10 hub genes identified were CDK1, CCNB1, AURKA, CCNA2, KIF11, BUB1B, TOP2A, TPX2, HMMR and CDC45. The other public databases confirmed that high expression of the aforementioned genes related to poor overall survival among patients with HCC. Conclusion: This study primarily identified candidate genes and pathways involved in the underlying mechanisms of Chinese HCC, which is supposed to provide new targets for the diagnosis and treatment of HCC in China.

Impact of COVID-19 on Liver Transplantation in Hong Kong and Singapore: A Modelling Study.

BACKGROUND: Liver transplantation (LT) activities during the COVID-19 pandemic have been curtailed in many countries. The impact of various policies restricting LT on outcomes of potential LT candidates is unclear. METHODS: We studied all patients on the nationwide LT waitlists in Hong Kong and Singapore between January 2016 and May 2020. We used continuous time Markov chains to model the effects of different scenarios and varying durations of disruption on LT candidates. FINDINGS: With complete cessation of LT, the projected 1-year overall survival (OS) decreased by 3•6%, 10•51% and 19•21% for a 1-, 3- and 6-month disruption respectively versus no limitation to LT, while 2-year OS decreased by 4•1%, 12•55%, and 23•43% respectively. When only urgent (acute-on-chronic liver failure [ACLF] or acute liver failure) LT was allowed, the projected 1-year OS decreased by a similar proportion: 3•1%, 8•41% and 15•20% respectively. When deceased donor LT (DDLT) and urgent living donor LT (LDLT) were allowed, 1-year projected OS decreased by 1•2%, 5•1% and 8•85% for a 1-, 3- and 6-month disruption respectively. OS was similar when only DDLT was allowed. Complete cessation of LT activities for 3-months resulted in an increased projected incidence of ACLF and hepatocellular carcinoma (HCC) dropout at 1-year by 49•1% and 107•96% respectively. When only urgent LT was allowed, HCC dropout and ACLF incidence were comparable to the rates seen in the scenario of complete LT cessation. INTERPRETATION: A short and wide-ranging disruption to LT results in better outcomes compared with a longer duration of partial restrictions. FUNDING: None to disclose.

Outcome of Kidney Transplants from Viremic and Non-Viremic Hepatitis C Virus Positive Donors into Negative Recipients: Results of the Spanish Registry.

Historically, donor infection with hepatitis-C virus (HCV) has been a barrier to kidney transplantation. However, in recent years, it has been reported that HCV positive kidney donors transplanted into HCV negative recipients offer acceptable mid-term results. However, acceptance of HCV donors, especially viremic, has not broadened in the clinical practice. This is an observational, multicenter, retrospective study including kidney transplants from HCV positive donors into negative recipients reported to the Spanish group from 2013 to 2021. Recipients from viremic donors received peri-transplant treatment with direct antiviral agents (DAA) for 8-12 weeks. We included 75 recipients from 44 HCV non-viremic donors and 41 from 25 HCV viremic donors. Primary non function, delayed graft function, acute rejection rate, renal function at the end of follow up, and patient and graft survival were not different between groups. Viral replication was not detected in recipients from non-viremic donors. Recipient treatment with DAA started pre-transplant avoids (n = 21) or attenuates (n = 5) viral replication but leads to non-different outcomes to post-transplant treatment with DAA (n = 15). HCV seroconversion was more frequent in recipients from viremic donors (73% vs. 16%, p < 0.001). One recipient of a viremic donor died due to hepatocellular carcinoma at 38 months. Donor HCV viremia seems not to be a risk factor for kidney transplant recipients receiving peri-transplant DAA, but continuous surveillance should be advised.

Comprehensive analysis of the novel omicron receptor AXL in cancers.

The SARS-CoV-2 is constantly mutating, and the new coronavirus such as Omicron has spread to many countries around the world. Anexelekto (AXL) is a transmembrane protein with biological functions such as promoting cell growth, migration, aggregation, metastasis and adhesion, and plays an important role in cancers and coronavirus disease 2019 (COVID-19). Unlike angiotensin-converting enzyme 2 (ACE2), AXL was highly expressed in respiratory system cells. In this study, we verified the AXL expression in cancer and normal tissues and found AXL expression was strongly correlated with cancer prognosis, tumor mutation burden (TMB), the microsatellite instability (MSI) in most tumor types. Immune infiltration analysis also demonstrated that there was an inextricable link between AXL expression and immune scores in cancer patients, especially in BLCA, BRCA and CESC. The NK-cells, plasmacytoid dendritic cells, myeloid dendritic cells, as one of the important components of the tumor microenvironment, were highly expressed AXL. In addition, AXL-related tumor neoantigens were identified and might provide the novel potential targets for tumor vaccines or SARS-Cov-2 vaccines research in cancer patients.

Elevated neutrophil extracellular traps by HBV-mediated S100A9-TLR4/RAGE-ROS cascade facilitate the growth and metastasis of hepatocellular carcinoma.

BACKGROUND: Neutrophil extracellular traps (NETs) are considered significant contributors to cancer progression, especially metastasis. However, it is still unclear whether NETs are involved in hepatitis B virus (HBV)-related hepatocarcinogenesis and have potential clinical significance during evaluation and management for hepatocellular carcinoma (HCC). In this study, we aimed to investigate the functional mechanism of NETs in HBV-related hepatocarcinogenesis and their clinical significance. METHODS: A total of 175 HCC patients with and without HBV infection and 58 healthy controls were enrolled in this study. NETs were measured in tissue specimens, freshly isolated neutrophils and blood serum from these patients, and the correlation of circulating serum NETs levels with malignancy was evaluated. The mechanism by which HBV modulates NETs formation was explored using cell-based studies. In addition, in vitro and in vivo experiments were further performed to clarify the functional mechanism of NETs on the growth and metastasis of HCC. RESULTS: We observed an elevated level of NETs in blood serum and tissue specimens from HCC patients, especially those infected with HBV. NETs facilitated the growth and metastasis of HCC both in vitro and in vivo, which were mainly dominated by increased angiogenesis, epithelial-mesenchymal transition (EMT)-related cell migration, matrix metalloproteinases (MMPs)-induced extracellular matrix (ECM) degradation and NETs-mediated cell trapping. Inhibition of NETs generation by DNase 1 effectively abrogated the NETs-aroused HCC growth and metastasis. In addition, HBV-induced S100A9 accelerated the generation of NETs, which was mediated by activation of toll-like receptor (TLR4)/receptor for advanced glycation end products (RAGE)-reactive oxygen species (ROS) signaling. Further, circulatory NETs were found to correlate with viral load, TNM stage and metastasis status in HBV-related HCC, and the identified NETs could predict extrahepatic metastasis, with an area under the ROC curve (AUC) of 0.83 and 90.3% sensitivity and 62.8% specificity at a cutoff value of 0.32. CONCLUSIONS: Our findings indicated that activation of RAGE/TLR4-ROS signaling by HBV-induced S100A9 resulted in abundant NETs formation, which subsequently facilitated the growth and metastasis of HCC cells. More importantly, the identified circulatory NETs exhibited potential as an alternative biomarker for predicting extrahepatic metastasis in HBV-related HCC.

Comprehensive Analysis of Cuproptosis-Related Genes in Prognosis and Immune Infiltration of Hepatocellular Carcinoma Based on Bulk and Single-Cell RNA Sequencing Data.

BACKGROUND: Studies on prognostic potential and tumor immune microenvironment (TIME) characteristics of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) are limited. METHODS: A multigene signature model was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The cuproptosis-related multivariate cox regression analysis and bulk RNA-seq-based immune infiltration analysis were performed. The results were verified using two cohorts. The enrichment of CRGs in T cells based on single-cell RNA sequencing (scRNA-seq) was performed. Real-time polymerase chain reaction (RT-PCR) and multiplex immunofluorescence staining were performed to verify the reliability of the conclusions. RESULTS: A four-gene risk scoring model was constructed. Kaplan-Meier curve analysis showed that the high-risk group had a worse prognosis (p < 0.001). The time-dependent receiver operating characteristic (ROC) curve showed that the OS risk score prediction performance was good. These results were further confirmed in the validation queue. Meanwhile, the Tregs and macrophages were enriched in the cuproptosis-related TIME of HCC. CONCLUSIONS: The CRGs-based signature model could predict the prognosis of HCC. Treg and macrophages were significantly enriched in cuproptosis-related HCC, which was associated with the depletion of proliferating T cells.

Perspectives on the Underlying Etiology of HCC and Its Effects on Treatment Outcomes.

Hepatocellular carcinoma (HCC) continues to be a serious medical problem with poor prognosis worldwide. The distribution of the major etiologies of HCC is changing due to the progress of anti-viral treatments, including hepatitis B virus (HBV) suppression by nucleoside/nucleotide analogues (NAs) and increased sustained virologic response (SVR) rates by direct-acting antivirals (DAAs) for hepatitis C virus (HCV), as well as the rising trend of nonviral liver disease. Although viral hepatitis remains the most common cause of HCC, non-alcoholic liver disease (NAFLD) with metabolic syndrome and alcohol-associated liver disease (ALD) are increasing. Effective and well-tolerated NAs treatment can slow the disease progression of chronic HBV infection to cirrhosis, end-stage liver disease, and reduce HCC risk. Treatment with NAs is also associated with significant improvement in the long-term survival of patients with HBV infection who already have HCC. DAAs have achieved viral elimination in almost all patients with HCV without significant adverse events, even in patients with decompensated liver cirrhosis and HCC. Similarly, DAA therapy can reduce disease progression, liver and non-liver complications, and improve the long-term survival of patients with chronic HCV infection with or without HCC. Meanwhile, NAFLD is a rapidly increasing cause of HCC along with the epidemics of obesity and type 2 diabetes globally. NAFLD-related HCC can occur in patients without cirrhosis and is known to have a lower survival rate than viral hepatitis-related HCC. Since there is currently no specific pharmacotherapy effective for NAFLD, lifestyle modification and prevention of complications are important to improve prognosis. Additionally, ALD is the second fastest-growing cause of HCC-related deaths, especially with an accelerated trend since the COVID-19 pandemic. This review provides an overview of the epidemiologic trends in the etiologies of HCC, and the progress of treatments for each etiology and the impact on outcome in the patients with HCC.

COVID-19: Has the Liver Been Spared?

The liver is a secondary and often collateral target of COVID-19 disease but can lead to important consequences. COVID-19 might directly cause a high number of complications in patients with pre-existing chronic liver disease, increasing their risk of hepatic decompensation. Moreover, it also determines indirect consequences in the management of patients with liver disease, especially in those suffering from decompensated cirrhosis and HCC, as well as in the execution of their follow-up and the availability of all therapeutic possibilities. Liver imaging in COVID-19 patients proved to be highly nonspecific, but it can still be useful for identifying the complications that derive from the infection. Moreover, the recent implementation of telemedicine constitutes a possible solution to both the physical distancing and the re-organizational difficulties arising from the pandemic. The present review aims to encompass the currently hypothesized pathophysiological mechanisms of liver injury in patients with COVID-19 mediated by both the direct invasion of the virus and its indirect effects and analyze the consequence of the pandemic in patients with chronic liver disease and liver tumors, with particular regard to the management strategies that have been implemented to face this worldwide emergency and that can be further improved.