Endoscopic ultrasound-guided tissue acquisition for focal liver lesions in patients with a history of multiple primary malignant neoplasms.

Objective: This study aimed to investigate the usefulness of endoscopic ultrasound-guided tissue acquisition (EUS-TA) for diagnosing focal liver lesions in patients with a history of multiple primary malignant neoplasms. Methods: Among patients who underwent EUS-TA for focal liver lesions between 2016 and 2022, those with a history of multiple malignant neoplasms were included. A histologically confirmed malignant tumor within the past 5 years before EUS-TA was defined as a history of malignant neoplasm. The primary outcomes were diagnostic ability and adverse events of EUS-TA. Results: This study included 16 patients (median age, 73 [33-90] years), the median tumor size was 32 (6-51) mm, 14 had a history of double malignant neoplasms, whereas two had triple malignant neoplasms. Malignant neoplasms were detected histologically or cytologically in all cases. Immunohistochemistry was performed in 75% (12/16), and the final diagnosis of EUS-TA was metastatic liver tumor in 12 patients, and primary malignant liver tumor in four patients. The primary site could be identified in 11 of 12 metastatic tumor cases. The diagnostic yield of EUS-TA was 100% (16/16) for differentiating benign and malignant tumors and 94% (15/16) for confirming the histological type including the primary site of metastatic lesions. No adverse events were associated with the procedure. Conclusion: EUS-TA is a useful diagnostic modality for focal liver lesions in patients with a history of multiple malignant neoplasms, allowing for the differential diagnosis of primary and metastatic tumors and identification of the primary site of metastatic lesions.

The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) mortality rates continue to increase faster than those of other cancer types due to high heterogeneity, which limits diagnosis and treatment. Pathological and molecular subtyping have identified that HCC tumors with poor outcomes are characterized by intratumoral collagenous accumulation. However, the translational and post-translational regulation of tumor collagen, which is critical to the outcome, remains largely unknown. Here, we investigate the spatial extracellular proteome to understand the differences associated with HCC tumors defined by Hoshida transcriptomic subtypes of poor outcome (Subtype 1; S1; n = 12) and better outcome (Subtype 3; S3; n = 24) that show differential stroma-regulated pathways. Collagen-targeted mass spectrometry imaging (MSI) with the same-tissue reference libraries, built from untargeted and targeted LC-MS/MS was used to spatially define the extracellular microenvironment from clinically-characterized, formalin-fixed, paraffin-embedded tissue sections. Collagen α-1(I) chain domains for discoidin-domain receptor and integrin binding showed distinctive spatial distribution within the tumor microenvironment. Hydroxylated proline (HYP)-containing peptides from the triple helical regions of fibrillar collagens distinguished S1 from S3 tumors. Exploratory machine learning on multiple peptides extracted from the tumor regions could distinguish S1 and S3 tumors (with an area under the receiver operating curve of ≥0.98; 95% confidence intervals between 0.976 and 1.00; and accuracies above 94%). An overall finding was that the extracellular microenvironment has a high potential to predict clinically relevant outcomes in HCC.

Probing Dual Covalent Irreversible Inhibition of EGFR/FGFR4 by Electrophilic-Based Natural Compounds to Overcome Resistance and Enhance Combination Therapeutic Potentials and Management of Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is one of the most prevalent cancer types in the world and accounts for the majority of cases of primary liver cancer. A crucial part of the carcinogenesis of HCC involves aberrant stimulation of the FGF19-FGFR4 signaling pathway. Therefore, FGFR4 inhibition has become a strategic therapeutic approach for the treatment of HCC. However, the clinical treatment procedure is significantly hampered by the prevalence of kinase inhibitors resistance. It was recently established that the activation of EGFR signaling was found to be one of the primary mechanisms mediating the acquired resistance to FGFR4 inhibitors, moreover, sensitivity to FGFR4 inhibitors was effectively restored by inhibiting EGFR. These results provide compelling evidence that dual inhibition of EGFR and FGFR4 could represent a viable therapeutic approach to overcome resistance, hence enhanced management of HCC. To this end, we proposed a dual irreversible inhibition strategy through covalent binding by naturally occurring electrophilic warhead-bearing compounds (curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A and andrographolide) to covalently target both EGFR and FGFR4 through cysteine residues, Cys797 and Cys552, respectively. Covalent docking and covalent molecular dynamics (MM/MDcov) simulations combined with thermodynamic binding free energy calculations were performed, and the results were compared against known potent and selective covalent EGFR and FGFR4 inhibitors with available X-ray crystal structures, Afatinib and BLU9931, respectively. Curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A, and andrographolide showed relative binding free energies of -22.85, -17.14, -12.98, -21.81, and - 19.00 kcal/mol against EGFR and - 41.06, -29.45, -24.76, -40.11, and - 37.55 kcal/mol against FGFR4, respectively. The mechanisms of binding were emphasized by hydrogen bonding and binding forces analysis as well as active site physicochemical profiling. The findings of this study identified that curcumin, syringolin A and andrographolide-but not eupalmerin acetate or deoxyelephantopin -could be viable dual EGFR and FGFR4 covalent irreversible inhibitors and could be implemented in HCC combination therapy protocols alone or in conjunction with other chemotherapeutic agents. Investigations of this study conclusively indicate dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for enhanced management of HCC.

Mucin 1 expression is regulated by hsa_circ_0055054/microRNA­122­5p and promotes hepatocellular carcinoma development.

The abnormal expression of mucin 1 (MUC1) is a major cause of poor prognosis in patients with hepatocellular carcinoma (HCC). Competitive endogenous RNA demonstrates a novel regulatory mechanism that can affect the biological behavior of tumors. In the present study, the regulatory functions of hsa_circ_0055054 as well as those of microRNA (miR/miRNA) 122-5p on MUC1 expression and its role in HCC cell proliferation, migration and invasion, were evaluated. MUC1 expression was assessed using western blotting and reverse transcription-quantitative PCR. The phenotypic functions of the HCC cell lines were evaluated following MUC1 knockdown using Cell Counting Kit-8, wound healing and Transwell assays. Bioinformatics tools were used to identify specific miRNAs and circular (circ)RNAs that interact with and can regulate MUC1. The stability of circRNAs was assessed using a Ribonuclease R assay. The binding of circRNA/miRNA/MUC1 was assessed using dual-luciferase reporter assays and cellular function tests. Finally, in vivo experiments were performed using animal models. The results demonstrated that in MHCC97L cells, MUC1 and hsa_circ_0055054 were expressed at high levels while miR-122-5p was downregulated. The proliferation, migration and invasion of MHCC97L cells were suppressed by low MUC1 expression. hsa_circ_0055054 knockdown or miR-122-5p overexpression both led to a decrease in MUC1 expression. In MHCC97L cells with a low MUC1 expression caused by hsa_circ_0055054 knockdown, miR-122-5p inhibition resulted in the increased proliferation, migration and invasion of MHCC97L cells. In combination, the results of the present study indicate that hsa_circ_0055054 knockdown in MHCC97L cells leads to an increased expression of miR-122-5p and decreased expression of MUC1, which results in the inhibition of MHCC97L cell proliferation, migration and invasion.

Association between gut microbiota and hepatocellular carcinoma and biliary tract cancer: A mendelian randomization study.

BACKGROUND: An increasing number of studies have begun to discuss the relationship between gut microbiota and diseases, yet there is currently a lack of corresponding articles describing the association between gut microbiota and hepatocellular carcinoma (HCC) and biliary tract cancer (BTC). This study aims to explore the relationship between them using Mendelian randomization (MR) analysis method. AIM: To assess the relationship between gut microbiota and HCC and BTC. METHODS: We obtained Genome-wide association study (GWAS) data for the gut microbiome from the intestinal microbiota genomic library (MiBioGen, https://mibiogen.gcc.rug.nl/). Additionally, we accessed data pertaining to HCC and BTC from the IEU open GWAS platform (https://gwas.mrcieu.ac.uk/). Our analysis employed fundamental instrumental variable analysis methods, including inverse-variance weighted, MR and Egger. To ensure the dependability of the results, we subjected the results to tests for multiple biases and heterogeneity. RESULTS: During our investigation, we discovered 11 gut microbiota linked to an increased risk to BTC and HCC. The former included the genus Eubacterium hallii group (P = 0.017), Candidatus Soleaferrea (P = 0.034), Flavonifractor (P = 0.021), Lachnospiraceae FCS020 (P = 0.034), the order Victivallales (P = 0.018), and the class Lentisphaeria (P = 0.0.18). The latter included the genus Desulfovibrio (P = 0.042), Oscillibacter (P = 0.023), the family Coriobacteriaceae (P = 0.048), the order Coriobacteriales (P = 0.048), and the class Coriobacteriia (P = 0.048). Furthermore, in BTC, we observed 2 protective gut microbiota namely the genus Dorea (P = 0.041) and Lachnospiraceae ND3007 group (P = 0.045). All results showed no evidence of multiplicity or heterogeneity. CONCLUSION: This study explores a causal link between gut microbiota and HCC and BTC. These insights may enhance the mechanistic knowledge of microbiota-related HCC and BTC pathways, potentially informing therapeutic strategies.

Omics-imaging signature-based nomogram to predict the progression-free survival of patients with hepatocellular carcinoma after transcatheter arterial chemoembolization.

BACKGROUND: Enhanced magnetic resonance imaging (MRI) is widely used in the diagnosis, treatment and prognosis of hepatocellular carcinoma (HCC), but it can not effectively reflect the heterogeneity within the tumor and evaluate the effect after treatment. Preoperative imaging analysis of voxel changes can effectively reflect the internal heterogeneity of the tumor and evaluate the progression-free survival (PFS). AIM: To predict the PFS of patients with HCC before operation by building a model with enhanced MRI images. METHODS: Delineate the regions of interest (ROI) in arterial phase, portal venous phase and delayed phase of enhanced MRI. After extracting the combinatorial features of ROI, the features are fused to obtain deep learning radiomics (DLR)_Sig. DeLong's test was used to evaluate the diagnostic performance of different typological features. K-M analysis was applied to assess PFS in different risk groups, and the discriminative ability of the model was evaluated using the C-index. RESULTS: Tumor diameter and diolame were independent factors influencing the prognosis of PFS. Delong's test revealed multi-phase combined radiomic features had significantly greater area under the curve values than did those of the individual phases (P < 0.05).In deep transfer learning (DTL) and DLR, significant differences were observed between the multi-phase and individual phases feature sets (P < 0.05). K-M survival analysis revealed a median survival time of high risk group and low risk group was 12.8 and 14.2 months, respectively, and the predicted probabilities of 6 months, 1 year and 2 years were 92%, 60%, 40% and 98%, 90%,73%, respectively. The C-index was 0.764, indicating relatively good consistency between the predicted and observed results. DTL and DLR have higher predictive value for 2-year PFS in nomogram. CONCLUSION: Based on the multi-temporal characteristics of enhanced MRI and the constructed Nomograph, it provides a new strategy for predicting the PFS of transarterial chemoembolization treatment of HCC.

New HCC Subtypes Based on CD8 Tex-Related lncRNA Signature Could Predict Prognosis, Immunological and Drug Sensitivity Characteristics of Hepatocellular Carcinoma.

Purpose: Hepatocellular carcinoma has become one of the severe diseases threatening human health. T cell exhaustion is deemed as a reason for immunotherapy resistance. However, little is known about the roles of CD8 Tex-related lncRNAs in HCC. Materials and Methods: We processed single-cell RNA sequencing to identify CD8 Tex-related genes. CD8 Tex-related lncRNAs were identified based on their correlations with mRNAs. Unsupervised clustering approach was used to identify molecular clusters of CD8 Tex-related lncRNAs. Differences in prognosis and immune infiltration between the clusters were explored. Machine learning algorithms were used to construct a prognostic signature. Samples were classified as low- and high-risk groups based on their risk scores. We identified prognosis-related lncRNAs and constructed a ceRNA network. In vitro experiments were conducted to investigate the impacts of CD8 Tex-related lncRNAs on proliferation and apoptosis of HCC cells. Results: We clarified cell types within two HCC single-cell datasets. We identified specific markers of CD8 Tex cells and analyzed their potential functions. Twenty-eight lncRNAs were identified as CD8 Tex-related. Based on CD8 Tex-related lncRNAs, samples were categorized into two distinct clusters, which exhibited significant differences in survival rates and immune infiltration. Ninety-six algorithm combinations were employed to establish a prognostic signature. RSF emerged as the one with the highest C-index. Patients in high- and low-risk groups exhibited marked differences in prognosis, enriched pathways, mutations and drug sensitivities. MCM3AP-AS1, MAPKAPK5-AS1 and PART1 were regarded as prognosis-related lncRNAs. A ceRNA network was constructed based on CD8 Tex-related lncRNAs and mRNAs. Experiments on cell lines and organoids indicated that downregulation of MCM3AP-AS1, MAPKAPK5-AS1 and PART1 suppressed cell proliferation and induced apoptosis. Conclusion: CD8 Tex-related lncRNAs played crucial roles in HCC progression. Our findings provided new insights into the regulatory mechanisms of CD8 Tex-related lncRNAs in HCC.

Parents's knowledge and awareness about hepatitis B can influence the vaccination of their children.

BACKGROUND: Birth-dose (Hep-BD) followed by three additional doses (Hep-B3) of hepatitis B virus (HBV) vaccine are key to eliminating HBV by 2030. Unfortunately, Hep-BD and Hep-B3 coverage in our country is poor. AIM: To studied the parent's knowledge and awareness about HBV infection, its prevention, consequences and vaccination. METHODS: Parents of 6 months to 8 years old children were interviewed to assess their knowledge & awareness about hepatitis B, its transmission, prevention, illness caused by this, and vaccination. Eighteen close-ended questions were administered, and responses were recorded as 'yes', 'no', or 'not sure'. HBV knowledge score was calculated based on the sum of correct answers. Each correct response scored one point and incorrect, missing or 'not sure' responses received no points. Categorical data are presented as number (%) and numerical data are expressed as median. Data were compared using Chi2 tests and level of significance was kept as P < 0.05. RESULTS: Parents (58.3% mothers) of 384 children (89.9% age < 5 years; 82% age-appropriately vaccinated) were included. Three hundred and twenty-two (83.9%) children were Hep-B3 vaccinated. 94.3%, 87.5%, and 29.2% parents knew about polio, tetanus, and hepatitis B vaccine. Overall, 41.2%, 15.8%, and 23% parents knew about hepatitis B transmission, consequences of infection, and prevention respectively. Only 7.6% parents knew about three-dose schedule of hepatitis B vaccination. Only 23% parents believed that vaccine could prevent HBV, 15.7% knew that HBV affects liver. Parents of Hep-B3 vaccinated children were significantly more aware about HBV than the parents of unvaccinated children (P < 0.05 for 17/18 questions). CONCLUSION: The knowledge and awareness among the parents about hepatitis B is poor. The Increasing knowledge/awareness about HBV among parents may improve Hep-B3 vaccination coverage.

Identification of most representative hub-genes for diagnosis, prognosis, and therapies of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally. To reduce HCC-related mortality, early diagnosis and therapeutic improvement are essential. Hub differentially expressed genes (HubGs) may serve as potential diagnostic and prognostic biomarkers, also offering therapeutic targets for precise therapies. Therefore, we aimed to identify top-ranked hub genes for the diagnosis, prognosis, and therapy of HCC. METHODS: Through a systematic literature review, 202 HCC-related HubGs were derived from 59 studies, yet consistent detection across these was lacking. Then, we identified top-ranked HubGs (tHubGs) by integrated bioinformatics analysis, highlighting their functions, pathways, and regulators that might be more representative of the diagnosis, prognosis, and therapies of HCC. RESULTS: In this study, eight HubGs (CDK1, AURKA, CDC20, CCNB2, TOP2A, PLK1, BUB1B, and BIRC5) were identified as the tHubGs through the protein-protein interaction (PPI) network and survival analysis. Their differential expression in different stages of HCC, validated using The Cancer Genome Atlas (TCGA) Program database, suggests their potential as early HCC markers. The enrichment analyses revealed some important roles in HCC-related biological processes (BPs), molecular functions (MFs), cellular components (CCs), and signaling pathways. Moreover, the gene regulatory network analysis highlighted key transcription factors (TFs) and microRNAs (miRNAs) that regulate these tHubGs at transcriptional and post-transcriptional. Finally, we selected three drugs (CD437, avrainvillamide, and LRRK2-IN-1) as candidate drugs for HCC treatment as they showed strong binding with all of our proposed and published protein receptors. CONCLUSIONS: The findings of this study may provide valuable resources for early diagnosis, prognosis, and therapies for HCC.

An Efficacy and Safety Comparison of Regorafenib and Nivolumab in Unresectable Hepatocellular Cancer Patients: A Systematic Review.

OBJECTIVE: This systematic review aimed to compare the efficacy and safety of regorafenib and nivolumab, two FDA-approved second-line treatments for unresectable Hepatocellular Carcinoma (HCC). METHODS: Literature comparing the efficacy and safety of regorafenib and nivolumab in unresectable HCC patients was systematically searched across seven databases, including: PubMed, SCOPUS, Cochrane Database of Systematic Reviews, ScienceDirect, EBSCOhost, EMBASE, and ProQuest, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The search was done on April 2nd, 2023. Study quality and risk of bias were assessed using the Agency for Healthcare Research and Quality (AHRQ) and ROBINS-1 tools. The selected studies were included in the qualitative data synthesis. RESULTS: Three trials found that HCC patients taking nivolumab had statistically insignificantly longer OS, TTP, and progression-free survival than those on regorafenib. Nivolumab increased ORR, with largely partial responses, and mixed DCR, with little statistical significance. All three studies showed that nivolumab had fewer side effects and improved tolerance. DISCUSSION: Three retrospective cohort studies with a total of 383 regorafenib-receiving cohorts and 230 nivolumab-receiving cohorts were included in the qualitative analysis. Nivolumab was found to be superior in regards of longer overall survival, longer time to progression, higher objective response rate, and lower adverse event occurrence. However, statistical significance was not achieved in most of the parameters. CONCLUSIONS: The use of nivolumab is preferable as the second-line systemic therapy for unresectable HCC. More high-quality studies are urgently needed to generate quantitative analysis, and to encourage the formation of guidelines for second-line systemic therapy.

Enhanced anticancer activity of silver doped zinc oxide magnetic nanocarrier loaded with sorafenib for hepatocellular carcinoma treatment.

Drug delivery is the process or method of delivering a pharmacological product to have therapeutic effects on humans or animals. The use of nanoparticles to deliver medications to cells is driving the present surge in interest in improving human health. Green nanodrug delivery methods are based on chemical processes that are acceptable for the environment or that use natural biomaterials such as plant extracts and microorganisms. In this study, zinc oxide-superparamagnetic iron oxide-silver nanocomposite was synthesized via green synthesis method using Fusarium oxysporum fungi mycelia then loaded with sorafenib drug. The synthesized nanocomposites were characterized by UV-visibile spectroscopy, FTIR, TEM and SEM techniques. Sorafenib is a cancer treatment and is also known by its brand name, Nexavar. Sorafenib is the only systemic medication available in the world to treat hepatocellular carcinoma. Sorafenib, like many other chemotherapeutics, has side effects that restrict its effectiveness, including toxicity, nausea, mucositis, hypertension, alopecia, and hand-foot skin reaction. In our study, 40 male albino rats were given a single dose of diethyl nitrosamine (DEN) 60 mg/kg b.wt., followed by carbon tetrachloride 2 ml/kg b.wt. twice a week for one month. The aim of our study is using the zinc oxide-superparamagnetic iron oxide-silver nanocomposite that was synthesized by Fusarium oxysporum fungi mycelia as nanocarrier for enhancement the sorafenib anticancer effect.

Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy.

BACKGROUND: The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. METHODS: Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification-mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. RESULTS: We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). CONCLUSIONS: Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.

DEB-TACE versus cTACE for unresectable HCC with B1-type bile duct invasion after successful biliary drainage: A propensity score matching analysis.

BACKGROUND: Transarterial chemoembolization (TACE) is the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Given the lack of specific recommendations for conventional TACE (cTACE) and drug-eluting bead TACE (DEB-TACE) in patients having unresectable HCC with tumor infiltrating the common hepatic duct or the first-order branch of the bile ducts (B1-type bile duct invasion; B1-BDI) after biliary drainage, we retrospectively compared the safety and efficacy of DEB-TACE with cTACE in this patient population. MATERIALS AND METHODS: Using data from five tertiary medical centers (January 2017-December 2021), we compared complications, overall survival (OS), time to progression (TTP), and tumor response rate between patients having unresectable HCC with B1-BDI who underwent DEB-TACE or cTACE after successful biliary drainage. X-tile software calculated the pre-TACE total bilirubin (TBil) cutoff value, indicating optimal timing for sequential TACE after drainage. Propensity score matching (PSM) was performed. RESULTS: The study included 108 patients with unresectable HCC (B1-BDI) who underwent DEB-TACE and 114 who received cTACE as initial treatment. After PSM (n = 53 for each group), the DEB-TACE group had a longer TTP (8.9 vs. 6.7 months, p = 0.038) and higher objective response rate (64.2% vs. 39.6%, p = 0.011) than did the cTACE group, although OS was comparable (16.7 vs. 15.3 months, p = 0.115). The DEB-TACE group exhibited fewer post-procedural increments in the mean albumin-bilirubin score, TBil, and alanine aminotransferase (ALT), along with a significantly lower incidence of serious adverse events within 30 days (hepatic failure, ALT increase, and TBil increase) than the cTACE group (all p < 0.05). The pre-TACE TBil cutoff value was 99 µmol/L; patients with higher values (>99 µmol/L) had poorer OS in both groups (p < 0.05). CONCLUSION: DEB-TACE is safe and effective after successful biliary drainage in unresectable HCC with B1-BDI, potentially better than cTACE in terms of liver toxicity, TTP, and ORR. Lowering TBil below 99 µmol/L through successful drainage may create ideal conditions for sequential TACE.

Exosomal mRNA in plasma serves as a predictive marker for microvascular invasion in hepatocellular carcinoma.

BACKGROUND AND AIM: There is a pressing need for non-invasive preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). This study investigates the potential of exosome-derived mRNA in plasma as a biomarker for diagnosing MVI. METHODS: Patients with suspected HCC undergoing hepatectomy were prospectively recruited for preoperative peripheral blood collection. Exosomal RNA profiling was conducted using RNA sequencing in the discovery cohort, followed by differential expression analysis to identify candidate targets. We employed multiplexed droplet digital PCR technology to efficiently validate them in a larger sample size cohort. RESULTS: A total of 131 HCC patients were ultimately enrolled, with 37 in the discovery cohort and 94 in the validation cohort. In the validation cohort, the expression levels of RSAD2, PRPSAP1, and HOXA2 were slightly elevated while CHMP4A showed a slight decrease in patients with MVI compared with those without MVI. These trends were consistent with the findings in the discovery cohort, although they did not reach statistical significance (P > 0.05). Notably, the expression level of exosomal PRPSAP1 in plasma was significantly higher in patients with more than 5 MVI than in those without MVI (0.147 vs 0.070, P = 0.035). CONCLUSION: This study unveils the potential of exosome-derived PRPSAP1 in plasma as a promising indicator for predicting MVI status preoperatively.

Impact of DAA Treatment for HCV on Hepatocellular Carcinoma in a Predominately African American Population.

PURPOSE: This study tested the hypothesis that our predominately AA medical center population would demonstrate a decline in HCV-driven HCC diagnosis following the initiation of DAA treatment in 2014. Also evaluated was whether achieving an SVR prior to diagnosis of HCC improved outcomes in patients who had an HCV diagnosis after completion of treatment. METHODS: All patients with HCC seen at the Detroit Medical Center from 2009 to 2021 were identified using ICD-10 codes, and medical records were evaluated. Outcomes were evaluated as either alive or death/hospice as of December of 2022. RESULTS: There were 461 patients with HCC of whom 433 (94%) had racial information in the database (AA = 351; non-AA = 82). HCC incidence regardless of race peaked in 2017, with a subsequent decline through 2021. HCV as a risk factor was higher in AA as compared to non-AA (85% vs. 53% p = 0.0001). Outcome (alive vs. death/hospice) was better for SVR patients compared to untreated patients (54% vs. 19%; p = 0.0009). HCC patients who achieved SVR also had better liver function at diagnosis as defined by Child-Pugh score (74% vs. 49% Class A p = 0.04) at the time of diagnosis. CONCLUSIONS: Racial disparity in HCC etiology was confirmed with AA more likely to have HCV than non-AA. The reduction in HCC patients with HCV confirms the impact of DAA treatment and prior successful treatment of HCV yields better outcomes. Increasing HCV treatment rates especially in AA patients will have a major impact on HCC development and treatment outcomes. WHAT IS KNOWN: • African Americans are more likely to have HCV infection as compared to non-AA. • Hepatocellular carcinoma is increasing in incidence in the US. • The role of HCV in the development of HCC remains to be further investigated. WHAT IS NEW: • HCC diagnosis in a single urban medical center study increased from 2009 as a result of HCV as a risk factor. • HCC declined post 2018 due primarily to a reduction in HCV infection as the risk factor. • African Americans were more likely to have HCV as the risk factor as compared to non-AA patients who were more likely to have no known risk factor on record (i.e., cryptogenic).

Decision-Tree Models Indicative of Microvascular Invasion on MRI Predict Survival in Patients with Hepatocellular Carcinoma Following Tumor Ablation.

Purpose: Histological microvascular invasion (MVI) is a risk factor for poor survival and early recurrence in hepatocellular carcinoma (HCC) after surgery. Its prognostic value in the setting of locoregional therapies (LRT), where no tissue samples are obtained, remains unknown. This study aims to establish CT-derived indices indicative of MVI on liver MRI with superior soft tissue contrast and evaluate their association with patient survival after ablation via interstitial brachytherapy (iBT) versus iBT combined with prior conventional transarterial chemoembolization (cTACE). Patients and Methods: Ninety-five consecutive patients, who underwent ablation via iBT alone (n = 47) or combined with cTACE (n = 48), were retrospectively included between 01/2016 and 12/2017. All patients received contrast-enhanced MRI prior to LRT. Overall (OS), progression-free survival (PFS), and time-to-progression (TTP) were assessed. Decision-tree models to determine Radiogenomic Venous Invasion (RVI) and Two-Trait Predictor of Venous Invasion (TTPVI) on baseline MRI were established, validated on an external test set (TCGA-LIHC), and applied in the study cohorts to investigate their prognostic value for patient survival. Statistics included Fisher's exact and t-test, Kaplan-Meier and cox-regression analysis, area under the receiver operating characteristic curve (AUC-ROC) and Pearson's correlation. Results: OS, PFS, and TTP were similar in both treatment groups. In the external dataset, RVI showed low sensitivity but relatively high specificity (AUC-ROC = 0.53), and TTPVI high sensitivity but only low specificity (AUC-ROC = 0.61) for histological MVI. In patients following iBT alone, positive RVI and TTPVI traits were associated with poorer OS (RVI: p < 0.01; TTPVI: p = 0.08), PFS (p = 0.04; p = 0.04), and TTP (p = 0.14; p = 0.03), respectively. However, when patients with combined cTACE and iBT were stratified by RVI or TTPVI, no differences in OS (p = 0.75; p = 0.55), PFS (p = 0.70; p = 0.43), or TTP (p = 0.33; p = 0.27) were observed. Conclusion: The study underscores the role of non-invasive imaging biomarkers indicative of MVI to identify patients, who would potentially benefit from embolotherapy via cTACE prior to ablation rather than ablation alone.

Breaking the Barriers of Therapy Resistance: Harnessing Ferroptosis for Effective Hepatocellular Carcinoma Therapy.

Ferroptosis is a type of cell death that relies on iron and is distinguished by the occurrence of lipid peroxidation and the buildup of reactive oxygen species. Ferroptosis has been demonstrated to have a significant impact on the advancement and resistance to treatment of hepatocellular carcinoma (HCC), thereby highlighting its potential as a viable therapeutic target. Ferroptosis was observed in HCC tissues in contrast to normal liver tissue. The inhibition of ferroptosis has been found to increase the viability of HCC cells and decrease their susceptibility to various anticancer therapies, including chemotherapy, radiotherapy, and immune checkpoint blockade. The administration of drugs that directly modulate ferroptosis regulators or induce excessive production of lipid-reactive oxygen species has demonstrated the potential to enhance the responsiveness of drug-resistant HCC cells to treatment. However, the precise mechanism underlying this phenomenon remains ambiguous. This review presents a comprehensive overview of the crucial role played by ferroptosis in enhancing the efficacy of treatment for hepatocellular carcinoma (HCC). The main aim of this study is to examine the feasibility of utilizing ferroptosis as a therapeutic approach to improve the efficacy of HCC treatment and overcome drug resistance.

Dual-tracer PET/CT in the management of hepatocellular carcinoma.

Background & Aims: Combined 18F-fluorodeoxyglucose (FDG) and 11C-acetate (dual-tracer) positron-emission tomography/computed tomography (PET/CT) is being increasingly performed for the management of hepatocellular carcinoma (HCC), although its role is not well defined. Therefore, we evaluated its effectiveness in (i) staging, (ii) characterization of indeterminate lesions on conventional imaging, and (iii) detection of HCC in patients with unexplained elevations in serum alpha-fetoprotein (AFP) levels. Methods: We retrospectively assessed 525 consecutive patients from three tertiary centers between 2014 and 2020. For staging, we recorded new lesion detection rates, changes in the Barcelona Clinic Liver Cancer (BCLC) classification, and treatment allocation due to dual-tracer PET/CT. To characterize indeterminate lesions and unexplained elevation of serum AFP levels, the sensitivity and specificity of dual-tracer PET/CT in diagnosing HCC were evaluated. A multidisciplinary external review and a cost-benefit analysis of patients for metastatic screening were also performed. Results: Dual-tracer PET/CT identified new lesions in 14.3% of 273 staging patients, resulting in BCLC upstaging in 11.7% and treatment modifications in 7.7%. It upstaged 8.1% of 260 patients undergoing metastatic screening, with estimated savings of US$495 per patient. It had a sensitivity and specificity of 80.7% (95% CI 71.2-88.6%) and 94.8% (95% CI 90.4-98.6%), respectively, for diagnosing HCC in 201 indeterminate lesions. It detected HCC in 45.1% of 51 patients with unexplained elevations in serum AFP concentrations. External review revealed substantial agreement between local and external image interpretation and patient assessment (n = 273, κ = 0.822; 95% CI 0.803-0.864). Conclusions: Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP. Impact and implications: Compared to CT or MRI, dual-tracer positron-emission tomography/computed tomography (PET/CT) led to upstaging in 12% of patients with hepatocellular carcinoma (HCC) undergoing staging, resulting in treatment modification in 8% of cases and a cost saving of US$495 per patient. It also accurately detected HCC in high-risk cases where CT or MRI were equivocal or normal. Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP.

Relationship Between Sleep Quality and Quality of Life: Analysis of Hepatocellular Carcinoma Survivors.

BACKGROUND:  We analyzed the correlation between the Pittsburgh Sleep Quality Index (PSQI) subcategories (sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbance, sleep medications, and daytime dysfunction) and a comprehensive measure of quality of life (QOL), the 36-Item Short Form Survey (SF-36) items, in patients with hepatocellular carcinoma (HCC) to determine the components that require intervention to improve QOL. METHODS: A total of 75 patients with recurrent HCC admitted to our hospital between May 2021 and May 2023 were included in this study. The QOL score was used for the SF-36 items, and the sleep disorder score was used for PSQI questionnaires. RESULTS: Correlations were found between sleep quality, sleep disturbance, and SF-36 for all QOL items and between sleep onset time and SF-36 for six QOL items: bodily pain, mental health, physical functioning, role-emotional, role-physical, and vitality. Correlations between daytime dysfunction and SF-36 were found for all QOL items, except for physical functioning. No correlation was found between sleep duration, sleep efficiency, sleep medications, and SF-36 for any QOL item. CONCLUSION: Sleep duration, sleep efficiency, and sleep medications may not contribute to QOL improvement in patients with HCC and sleep disturbances. Factors that improve sleep quality and sleep difficulty may contribute to QOL improvement. Therapeutic interventions aimed at improving general health and social functioning for sleep latency and physical functioning for daytime arousal difficulty are required.