Hepatocellular Carcinoma Research Articles

Trends in Hepatocellular Carcinoma Mortality Rates in the US and Projections Through 2040

ImportanceThe burden of liver cancer varies worldwide. An upward trend in both hepatocellular carcinoma (HCC) incidence and mortality in the past 2 decades has been observed.ObjectiveTo assess observed HCC-related age-standardized mortality rates (ASMRs) in the US for 2006 to 2022 and provide ASMR projections through 2040.Design, Setting, and ParticipantsThis cross-sectional study used data from the National Vital Statistics System, which is accessible through the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research website. Data on deaths attributed to HCC (from January 1, 2006, to December 31, 2022) were obtained for adults 25 years or older and were stratified by liver disease etiology, age, sex, and race and ethnicity. Etiologies included alcohol-associated liver disease (ALD), hepatitis B virus (HBV), hepatitis C virus (HCV), and metabolic dysfunction–associated steatotic liver disease (MASLD).Main Outcomes and MeasuresThe main outcomes were (1) observed ASMRs of HCC per 100 000 persons using Joinpoint regression (National Cancer Institute) to assess trends during 2006 to 2022 and (2) ASMRs projected for 2023 to 2040 using Prophet and AutoARIMA modeling.ResultsThis study included 188 280 HCC-related deaths from 2006 to 2022. Most deaths occurred among males (77.4%). The annual percentage change was 4.1% (95% CI, 2.2% to 7.7%) for 2006 to 2009 and decreased to 1.8% (95% CI, 0.7% to 2.0%) for 2009 to 2022, with an overall observed ASMR of 5.03 per 100 000 persons in 2022 and a projected ASMR of 6.39 per 100 000 persons by 2040, with consistent trends for both sexes. By etiology, ASMRs decreased for HCV- and HBV-related mortality but increased for ALD- and MASLD-related mortality. In 2022, MASLD surpassed HBV as the third-leading cause of HCC-related death and was projected to overtake HCV in 2032 as the second-leading cause; ALD was projected to be the leading cause of HCC-related death in 2026. In 2022, the ASMR was higher among individuals aged 65 years or older compared with those aged 25 to 64 years (18.37 vs 1.79 per 100 000 persons). The American Indian or Alaska Native population had the largest increase in projected ASMR by 2040 (14.71 per 100 000 persons) compared with the Asian population (3.03 per 100 000 persons).Conclusions and RelevanceIn this cross-sectional study, ASMRs for ALD- and MASLD-related HCC death increased rapidly from 2006 to 2022; ALD-related HCC was projected to be the leading cause by 2026, with MASLD as the second-leading cause by 2032. These findings may serve as a reference for public health decision-making and timely identification of groups at high risk of HCC death.

Liver resection in patients with a history of local ablation for hepatocellular carcinoma has the risk of poor survival and serosal invasion

AbstractAimThe aim was to evaluate the impact of previous local ablation (LA) on long‐term prognoses and tumor histopathological findings following hepatectomy for hepatocellular carcinoma (HCC).MethodsThis retrospective study used data from patients who underwent initial hepatectomy for HCC at Ehime University Hospital between October 2003 and July 2021. Using data from a total of 234 patients, after excluding patients with distant metastasis or macroscopic residual tumors and patients with mixed HCC, a group of 39 patients who underwent post‐ablation liver resection (PALR) was compared with a group of 195 non‐PALR patients with respect to patient characteristics, perioperative data, pathological findings, and outcomes.ResultsNumber of tumors was significantly greater and diameter of tumor was smaller in PALR group than those of non‐PALR group. Both overall survival (OS) and recurrence‐free survival (RFS) were significantly poor in PALR group than those of non‐PALR (5‐year OS 54.1% vs. 66.9%, p = 0.024; 5‐year RFS 24.7% vs. 37.0%, p = 0.019). However, PALR was not selected as independent prognosticator in multivariate analyses. In PALR group, tumor size ≥3 cm was sole independent prognosticator in multivariate analyses. Multivariate analysis showed that PALR [odds ratio (OR), 8.989; 95% confidence interval (CI), 2.807–28.787], alpha‐fetoprotein level >40 ng/mL (OR, 2.923; 95% CI, 1.063–8.035), and des‐γ‐carboxyprothrombin level >170 mAU/mL (OR, 5.164; 95% CI, 1.622–16.438) were independent predictors of pathological serosal invasion.ConclusionsHepatectomy for patients with history of LA for HCC had a risk of serosal invasion and poor survival.

USP11 promotes lipogenesis and tumorigenesis by regulating SREBF1 stability in hepatocellular carcinoma

USP11 promotes lipogenesis and tumorigenesis by regulating SREBF1 stability in hepatocellular carcinoma

Risk of Hepatocellular Carcinoma with Glucagon-like Peptide-1 receptor agonist treatment in patients: a systematic review and meta-analysis

Risk of Hepatocellular Carcinoma with Glucagon-like Peptide-1 receptor agonist treatment in patients: a systematic review and meta-analysis

Identification of a novel molecular classification for hepatocellular carcinoma based on disulfideptosis-related genes and its potential prognostic significance

Identification of a novel molecular classification for hepatocellular carcinoma based on disulfideptosis-related genes and its potential prognostic significance

The Evolving Landscape of Hepatocellular Carcinoma Mortality in the US

The Evolving Landscape of Hepatocellular Carcinoma Mortality in the US

Retracted] lncRNA DQ786243 promotes hepatocellular carcinoma cell invasion and proliferation by regulating the miR‑15b‑5p/Wnt3A axis

Retracted] lncRNA DQ786243 promotes hepatocellular carcinoma cell invasion and proliferation by regulating the miR‑15b‑5p/Wnt3A axis

High expression of BBOX1 in paracancerous tissue is associated with poor prognosis in hepatocellular carcinoma patients

High expression of BBOX1 in paracancerous tissue is associated with poor prognosis in hepatocellular carcinoma patients

Comparative analysis of efficacy and safety between D-TACE + HAIC + lenvatinib and D-TACE + lenvatinib in the treatment of unresectable massive hepatocellular carcinoma

Comparative analysis of efficacy and safety between D-TACE + HAIC + lenvatinib and D-TACE + lenvatinib in the treatment of unresectable massive hepatocellular carcinoma

TMSB4X is a regulator of inflammation-associated ferroptosis, and promotes the proliferation, migration and invasion of hepatocellular carcinoma cells

TMSB4X is a regulator of inflammation-associated ferroptosis, and promotes the proliferation, migration and invasion of hepatocellular carcinoma cells

Abstract C015: IL-27R signaling modulates protective versus pathogenic T cell responses in hepatocellular carcinoma

Abstract Liver cancer is the 3rd leading cause of cancer death. Hepatocellular carcinoma (HCC) is the major form of primary liver cancer, with a growing incidence rate estimated to surge by 50% in the coming twenty years. Although some success has been achieved with immune checkpoint blockade inhibitors, many HCC patients do not respond well to the treatments. Therefore, it is critical to better understand immune mechanisms regulating HCC to identify new biomarkers and develop novel immunotherapies for HCC patients. HCC is driven by chronic liver diseases and is frequently associated with chronic inflammation in the liver. Cytokines are small mediators of inflammation that play an essential role in inflammatory diseases and tumorigenesis. IL27 is a member of the IL6/IL12 superfamily with context-dependent roles in various inflammatory disorders and cancer. IL27 receptor (R) is expressed by most immune cells and several non-immune cells and plays pivotal roles in the regulation of immune responses. Recent work from our lab shows that IL27R signaling suppresses anti-cancer immune response in HCC, acting via the control of innate cytotoxic cells, and Il27ra -/- mice develop significantly less HCC. However, how IL27R signaling regulates T cell subsets in HCC in vivo remains elusive. Here, using diethylnitrosamine (DEN)-induced mouse model of HCC we found a reduction of regulatory T cells (Tregs) in tumor-bearing Il27ra-/-mice along with lowered HCC burden. ScRNA sequencing of CD45+ cells isolated from HCC tumors indicated a less proliferative phenotype of Tregs and more cytotoxic and less exhausted CD8 T cells in mice with Il27ra deficiency. Pathway analysis suggested that IL27R-deficient Tregs were more quiescent, as characterized by the downregulation of various metabolic pathways. Our newly generated Foxp3 cre Il27ra flox mice show a significant reduction of DEN-driven HCC accompanied by an increase of tumor-infiltrating activated CD8 T cells compared to IL27R sufficient controls. Treg-specific deletion of IL27R caused the upregulation of TCF1 in Tregs which has been recently demonstrated to control Treg immune-suppressive functions in colorectal cancer. Meanwhile, tumor-infiltrating effector CD8 T cells were increased in Foxp3 cre+ Il27ra flox mice relative to their Foxp3 cre- Il27ra flox littermate controls. Interestingly, CD8 T cell specific deletion of IL27R did not impact HCC growth in CD8 cre Il27ra flox mice. Overall, our data suggest that IL27R signaling suppresses anti-HCC immunity by enhancing the pro-tumorigenic Tregs and suppressing anti-tumor effector CD8 T cell functions. Citation Format: Zhengzheng Shi, Jiani Zhu, Aleksandra Mazitova, Anastasiia Marchenko, Sergei Grivennikov, Ekaterina Koltsova. IL-27R signaling modulates protective versus pathogenic T cell responses in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C015.

Postoperative Outcomes of Laparoscopic Hepatic Resection Combined With Radiofrequency Ablation for Two or Three Hepatocellular Carcinomas: A Case Series of Nine Patients

Postoperative Outcomes of Laparoscopic Hepatic Resection Combined With Radiofrequency Ablation for Two or Three Hepatocellular Carcinomas: A Case Series of Nine Patients

Unexpected Anti-tumor Effect of Selective Internal Radiation Therapy and Radiofrequency Ablation Followed by Immune Checkpoint Inhibitors for Hepatocellular Carcinoma

Introduction: Hepatocellular carcinoma (HCC) has become an increasingly serious health problem worldwide. Combining immune checkpoint inhibitors (ICIs) for HCC with local treatments can produce synergistic effects. Although the abscopal effect was noted in 1953, most studies on this phenomenon have been conducted in the context of external beam radiotherapy (EBRT). The incidence of the abscopal effect induced by selective internal radiation therapy (SIRT) alone is lower. This research reports a case of a patient with multifocal HCC who received SIRT plus radiofrequency ablation (RFA) followed by ICI therapy. During the subsequent course of ICI therapy, an anti-tumor effect was detected in the left hepatic lobe, far from the site targeted by the local treatments. Case Presentation: The abscopal effect has recently attracted widespread attention because ICIs can enhance this phenomenon. However, little is known about the relationship between inducing the abscopal effect and local treatment against HCC. A 76-year-old male patient presented with multifocal HCC. During hepatic angiography, MRI showed multiple HCCs in both lobes of the liver. Selective internal radiation therapy was performed on a tumor with a diameter of approximately 80 millimeters in the right lobe. A month later, RFA was conducted on another tumor in the right lobe, approximately 30 mm in diameter, and ICI therapy was administered on the second day post-RFA. Hepatic arterial phase imaging of contrast-enhanced magnetic resonance performed 10 months after SIRT showed the disappearance of the tumor in the left liver lobe. Conclusions: This case highlights that the combination of multiple local treatment methods with ICI therapy can enhance the anti-tumor immune response and benefit patients with multifocal

Antagonism of the ATP-gated P2X7 receptor inhibits the proliferation of hepatocellular carcinoma cells.

The P2X7 receptor, an ATP-gated ion channel which belongs to the P2X receptor family, plays critical roles in recognizing extracellular adenosine 5'-triphosphate (ATP) and is widely expressed in most tumor cells as well as inflammatory cells. Previously, the P2X7 receptor has been demonstrated to modulate the progression of various malignancies, including glioblastoma, pancreatic cancer, lung cancer, leukemia, and lymphoma. However, the biological function and prognostic values of P2X7 receptor in hepatocellular carcinoma remain to be determined. Here, we investigated the expression level of P2X7 receptor in patients with hepatocellular carcinoma. Then MTS and EdU assays were carried out to study the role of P2X7 receptor blockade in the proliferation of hepatocellular carcinoma cells. In addition, the underlying mechanism was further elucidated by bulk RNAseq. Compared to the control group, the P2X7 receptor was significantly up-regulated in the hepatocellular carcinoma group. Interestingly, A740003 and A438079, two selective antagonists at P2X7 receptor, significantly blocked Ca2+ influx and decreased the proliferative rate of hepatocellular carcinoma cells. Furthermore, the expression level of chondroitin sulfate synthase 1 (CHSY1), an enzyme that mediates the polymerization step of chondroitin sulfate, was reduced by both A740003 and A438079. In conclusion, inhibition of the P2X7 receptor attenuated the proliferation of hepatocellular carcinoma cells, and this process was largely modulated by CHSY1. Thus, our findings reveal a previously unknown role for P2X7 receptor in the proliferation of hepatocellular carcinoma cells and imply that the P2X7 receptor may represent a new target for the treatment of hepatocellular carcinoma.

Enhancing Radiofrequency Ablation for Hepatocellular Carcinoma: Nano-Epidrug Effects on Immune Modulation and Antigenicity Restoration.

Radiofrequency ablation (RFA), a critical therapy for hepatocellular carcinoma (HCC), carries a significant risk of recurrence and metastasis, particularly owing to mechanisms involving immune evasion and antigen downregulation via epigenetic modifications. This study introduces a "nano-epidrug" named MFMP. MFMP, which is composed of hollow mesoporous manganese dioxide (MnO2) nanoparticles, FIDAS-5 as an MAT2A inhibitor, macrophage membrane, and anti-PD-L1 (aPD-L1), targets HCC cells. By selectively binding to these cells, MFMP initially reverses immune suppression via PD-L1 inhibition. After endocytosis, MFMP disassembles in the tumor microenvironment, releasing FIDAS-5 and Mn2+. FIDAS-5 prevents cGAS methylation, whereas Mn2+ aids STING pathway restoration. In addition, FIDAS-5 reduces m6A RNA modification, suppressing EGFR expression. These changes enhance HCC antigenicity to promote cytotoxic T cell recognition and cytotoxic killing. Furthermore, MFMP mediates immunogenic cell death in HCC by synergizing with RFA through cGAS DNA demethylation, EGFR mRNA demethylation, and TBK1 protein phosphorylation, thereby inhibiting recurrence and metastasis and enhancing immune memory. Thus, MFMP is a potential adjunctive therapy requiring clinical validation.

Bioinformatics combined with network pharmacology and experimental validation to identify key biomarkers of hepatocellular carcinoma and corresponding compounds in Radix Astragali and Pueraria Mirifica.

The occurrence and death rates of primary hepatocellular carcinoma (HCC) are increasing, and there remains a shortage of effective oral medications with minimal side effects. We aim to identify potential biomarkers and compounds from Radix Astragali (RA) and Pueraria Mirifica (PM) to treat liver cancer and improve prognosis. Differentially expressed genes (DEGs) associated with HCC were identified by bioinformatics analysis of three datasets, GSE112791, GSE101685, and GSE45114. Using public databases to predict the bioactive components and possible targets of RA and PM. Target crossover from Gene Expression Omnibus (GEO) and public databases were used to identify potential biomarkers for HCC. Subsequently, validation and prognostic value analyses were performed using the Gene Expression Profile Interaction Analysis (GEPIA) platform. The Cytoscape software created a network of "compound targets" to pinpoint compounds linked to the biomarkers. Molecular docking techniques were utilized to validate the connection between these compounds and the identified biomarkers. Ultimately, the HepG2 liver cancer cell line was chosen to assess the inhibitory effect of Hederagenin (HDG) and to confirm the expression of ADH1B through Western blot analysis. In this study, four key biomarkers (NR1I2, ADH1B, NQO1, GHR) were identified. Molecular docking showed that these four core targets could form stable conformations with the corresponding compounds. As the drug concentration decreases, the inhibitory effect on HepG2 diminishes, and the survival rate of HepG2 cells significantly declines following the administration of 100 µmol/L HDG. Compared to the control, the expression of ADH1B protein is significantly increased in HepG2 cells treated with 100 µmol/L HDG. The study identified four key biomarkers (ADH1B, GHR, NQO1, NR1I2) that have prognostic ability for HCC. This study provides biomarkers and potential targeted monomeric medicines for treating HCC.

Correlation between thyroid dysfunction and efficacy of immune checkpoint inhibitors in patients with advanced solid tumors.

Immune checkpoint inhibitors (ICIs) are currently the first line of tumor immunotherapy for the treatment of a wide range of tumors. However, the main side effect of immune checkpoint inhibitors is that they cause immune-related adverse events (irAEs) in patients. The relationship between the occurrence of immune side effects in patients and efficacy is controversial. The objective of this study was to confirm the relationship between patients who develop thyroid dysfunction after immune checkpoint inhibitors and efficacy. This study was a retrospective real-world clinical study, and a total of 50 patients with advanced tumors treated with immune checkpoint inhibitors at Anqing People's Hospital from 2020.8 to 2022.5 were retrospectively collected. Among them, 30 patients with hypothyroidism and 20 patients with normal or hyperthyroidism occurred, and the treatment effects and prognostic differences between the two groups were compared. After PD1 treatment in all patients, there were 10 cases of partial remission(PR), 18 cases of stable disease(SD) and 2 cases of progressive disease(PD) in patients who developed hypothyroidism, with a disease control rate(DCR) of 93.3% and objective remission rate(ORR) of 33.3%. There were 0 complete remission (CR) patient, 3 PR patients, 11 SD patients, 6 PD patients, 70.0% DCR and 15.0% ORR in patients who did not develop hypothyroidism. The DCR and ORR of patients who developed hypothyroidism were better than those of non-hypothyroid patients, and the difference was statistically significant (P < 0.05). Kaplan-Meier survival analysis showed that progression-free survival (PFS) reached 9.2months (95% CI 7.726-10.779) in patients who developed hypothyroidism and did not hypothyroidism patients have a PFS of 7.3months (95% CI 5.604-8.505), with a statistically significant difference (P = 0.0341 < 0.05). Further subgroup analysis revealed that among patients who developed hypothyroidism, PFS was 3.3months (95% CI 0.630-5.440) in patients with cholangiocarcinoma, 6.89months (95% CI 5.604-8.505) in patients with non-small cell lung cancer, > 12months in patients with hepatocellular carcinoma, and 11.05months (95% CI 9.308-12.792) in patients with esophageal cancer months and PFS for patients with gastric cancer was 9.74months (95% CI 6.979-12.502). When patients with advanced tumors were treated with immune checkpoint inhibitors, DCR and ORR were higher in patients who developed hypothyroidism, and patients had better PFS. The benefits were greater in patients with gastric, esophageal, and hepatocellular carcinomas.

Enhancing deep-seated hepatocellular carcinoma detection: assessing the added value of high mechanical index setting in sonazoid-based contrast-enhanced ultrasound during post-vascular phase.

This retrospective study aimed to investigate the role of an additional high mechanical index (MI) setting scan during the post-vascular phase (PVP) in detecting deep-seated hepatocellular carcinoma (HCC) lesions. A total of 805 confirmed HCCs, which underwent Sonazoid-based contrast-enhanced ultrasound (CEUS) between January 2014 and October 2021, were included. Low MI scan was initially employed for lesion detection during the PVP, followed by high MI scan. Propensity score matching (PSM) was utilized to address confounding variables. Of the 805 study lesions, 668 were detected as perfusion defects at the initial low MI setting, while 137 remained undetected. Among these 137 undetected lesions, 77 were identified at the subsequent high MI setting, whereas 60 remained undetected. Lesions that were larger (18.69±11.27mm vs. 16.55±7.42mm, p = 0.006), more superficial (6.06±2.41cm vs. 7.40±2.74cm, p < 0.001), and hypoechoic (482/668 vs. 62/137, p < 0.001) were detectable at the initial low MI setting. Male patients benefited more from the additional high MI scan (63/97 vs. 14/40, p < 0.001). Lesions identified with additional high MI were larger (18.30±8.76mm vs. 14.30±4.34mm, p < 0.001) and deeper than undetected ones (8.48±2.48cm vs. 6.02±2.43cm, p < 0.001). After PSM, depth was shown to be an independent predictor in multivariate analysis (odds ratio: 1.557, 95% confidence interval: 1.249-1.941). The depth cutoff was 7.75 cm, with a sensitivity of 0.681, specificity of 0.851, and area under the curve of 0.774. The additional high MI setting scan during the PVP of Sonazoid-based CEUS leads to enhanced detection of deep-seated HCCs.

Safety of local thermal ablation in hepatocellular carcinoma patients with cirrhosis and severe thrombocytopenia.

Generally, invasive treatment is contraindication for patients with severe thrombocytopenia, because it may increase risk of bleeding. However, many early hepatocellular carcinoma (HCC) patients with cirrhosis have platelet counts (PC) less than 50 × 109/L due to hypersplenism. These patients are often accompanied by hepatic insufficiency, which makes hepatectomy impossible, and local thermal ablation (LTA) has become a major treatment. The aim of our study is to investigate the correlation between severe thrombocytopenia and bleeding after LTA in HCC patients with cirrhosis, and evaluate risk factors of bleeding. 473 patients with cirrhosis who underwent LTA for HCC from 2016 to 2020 were enrolled, and 709 ablations were performed in total. Based on preoperative PC, cases were divided into three groups, namely,group A (PC > 50 × 109/L), group B (30 × 109/L < PC ≤ 50 × 109/L) and group C (PC ≤ 30 × 109/L). The incidence of bleeding after LTA was compared among the three groups. Logistic regression was used to explore the risk factors for bleeding after ablation. The overall incidence of bleeding complications was 4.4%, and no significant difference was observed between group A, B, and C (3.9% vs. 6.4% vs. 3.3%, P = 0.410). In multivariate analysis, tumor diameter (OR = 2.657 per 1cm, P < 0.001), and multiple lesions (≥ 3) (OR = 3.723, P = 0.006) were found to be independent predictors of bleeding after LTA. In small HCC patients with cirrhosis and hypersplenism, the PC range 30-50 × 109/L will not increase the risk of bleeding after LTA. Tumor diameter and number of lesions are independent predictors for bleeding after LTA in HCC patients.

Methotrexate and triformyl cholic acid functionalized magnetic graphene oxide nanocomposite for multi-targeting chemo-photothermal therapy of hepatocellular carcinoma

Methotrexate and triformyl cholic acid functionalized magnetic graphene oxide nanocomposite for multi-targeting chemo-photothermal therapy of hepatocellular carcinoma