Stage Hepatocellular Carcinoma Research Articles

Evaluating immune cell abundance across hepatocellular carcinoma disease stages I-III: Findings from TCGA analysis.

621 Background: Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the sixth most prevalent cancer globally and a leading cause of cancer-related mortality. The tumor microenvironment (TME) in HCC, characterized by complex interactions between immune and tumor cells, significantly influences tumor progression and immune suppression. Understanding the immune landscape across the different stages of HCC can inform prognosis and therapeutic strategies. Methods: We analyzed RNA seq data from 333 HCC patients (disease stages I-III), from The Cancer Genome Atlas (TCGA), using the immune deconvolution algorithms CIBERSORT and xCell. Differential gene expression analysis was performed using the DESeq2 package in R. Immune cell abundance across various HCC stages was imputed, and survival analyses was conducted using Kaplan-Meier curves and log-rank tests. Results: Of the 19,514 genes analyzed, 2,774 were up-regulated and 947 were down-regulated in stage II and III in comparison to stage I. CIBERSORT and xCell analyses revealed significant variability in the immune cell composition between HCC stages. Notable differences were observed in the T cells (CD4 and CD8 subsets), B cells, plasma cells, and stromal components. ANOVA and post hoc tests identified significant stage-specific differences in several immune cell types. For the survival analysis, we categorized patients into low and high groups based on median cell abundances. Overall survival showed no statistically significant differences among the various groups for common myeloid and lymphoid progenitor cells. In contrast, disease-free survival demonstrated statistically significant differences across the groups for both cell types. Conclusions: This study emphasizes the tumor microenvironment's pivotal role in HCC, revealing that immune cell composition significantly influences disease-free survival, despite limited effects on overall survival. These findings advocate for further exploration into targeted immunotherapies and the development of predictive models that integrate immune landscape characteristics, ultimately aiming to enhance patient outcomes in HCC. Cell type xCell Cibersort Mean SD Mean SD T cell CD4 naive 0.00466 0.01994 1.31e-5 1.69e-4 T cell CD8 0.01368 0.03253 0.03161 0.04947 Eosinophil 3.96e-5 3.41e-4 1.67e-4 8.69e-4 Macrophage 0.02323 0.02441 0.02924 0.04345 Macrophage.M1 0.00914 0.01526 0.01806 0.02054 Macrophage.M2 0.02303 0.01697 0.05439 0.04815 B cell memory 0.00196 0.01418 0.00107 0.00733 B cell naive 0.00163 0.01034 0.01319 0.02148 Neutrophil 2.14e-4 0.00137 0.00112 0.00539 Immune score 0.04621 0.06817 - - Table presents various cell type abundances for each algorithm used.

Safety, efficacy, and outcomes of 90-yttrium radioembolization in combination with immune checkpoint inhibitors as a definitive first-line treatment approach in non-surgical hepatocellular carcinoma.

617 Background: Immune checkpoint inhibitors (ICI) have emerged as first line therapy for advanced-stage hepatocellular carcinoma (HCC). However, response rates remain modest (<20%). Combination treatments offer potential to improve initial response rates while extending duration of response. While early studies of 90 Yttrium transarterial radioembolization ( 90 Y)-ICI showed fewer adverse events (AE) and improved objective responses (OR) (30-40%), there were no improvements in time to progression (TTP) and overall survival (OS). This study evaluates safety, efficacy, and outcomes of first line 90 Y-ICI while evaluating the role of ICI regimen and treatment sequencing. Methods: A retrospective, multi-center study was conducted in BCLC A-C stage HCC patients (ECOG 0-1) receiving first line 90 Y-ICI with atezolizumab/bevacizumab (A+B) or tremelimumab/durvalumab (STRIDE). Treatment response was recorded at 90 Y follow-up. TTP, progression-free survival (PFS), and OS were primary endpoints, with AE and safety as secondary outcomes. Results: The study included 40 patients receiving 90 Y-ICI from 2021–2024, with a median follow-up of 12 months. The cohort was predominantly Child-Pugh A (96%) with HCV-related cirrhosis (76%), BCLC-C stage (51%), and a median target HCC size of 7.7 cm (IQR, 6-11 cm). Grade 3-4 AEs occurred in 15 patients (37%), leading to steroid use (12, 29%), treatment delays (13, 31%), or discontinuation (4, 10%). The first cycle target OR rate was 82% (32/39), with a 51% (20/39) complete response (CR) rate. The first cycle overall OR was 59% (23/39), with a 41% (16/39) CR rate. No significant differences were found in adverse events, delays, or discontinuations based on sequencing or regimen. Sequencing had no significant effect on target or overall OR with no downstream effect on TTP (P = 0.968) or PFS (P = 0.906). Similarly, there was no effect of ICI regimen on OR, TTP (P = 0.813) or PFS (P = 0.904), although the data trended toward higher response rates with the STRIDE regimen. Log-rank analysis revealed target CR was associated with improved TTP (P = 0.004) and PFS (P = 0.009), but not OS (P = 0.237). Achieving an overall CR was associated with further improvements in TTP (P < 0.001) and PFS (P < 0.001). The cohort 2-year OS was 55% with median OS not yet reached. Conclusions: First line 90 Y-ICI therapy in BCLC A-C stage HCC is an effective treatment strategy with AEs in the expected range of systemic therapy and low rates of treatment discontinuation. Sequencing and ICI regimen did not significantly impact AEs or treatment outcomes. However, patients achieving CR showed significantly improved TTP and PFS. Although follow-up is limited, these findings suggest achieving CR is key to optimal long-term outcomes. We anticipate long-term follow-up will demonstrate an OS benefit linked to first line CR rate.

IMMULAB: A phase II trial of immunotherapy with pembrolizumab in combination with local ablation for patients with early stage hepatocellular carcinoma (HCC)—The IKF-IMMULAB trial.

582 Background: Ablation of neoplastic tissue through radiofrequency ablation (RFA), microwave ablation (MWA), or brachytherapy is a potentially curative option for patients with early stage hepatocellular carcinoma (HCC); however, recurrence rates are high. While updated results from IMbrave050 do not support the use of adjuvant therapy following resection or local therapy, the potential of peri-interventional systemic treatment as a potentially more effective approach to increase recurrence free and long-term survival remains to be determined. We propose that peri-interventional treatment with pembrolizumab may improve outcomes following local ablative therapies. Methods: This single arm phase II trial investigates peri-interventional treatment with pembrolizumab combined with RFA/MWA or brachytherapy, or - as recommended for tumors ≥ 3 cm - by combination with TACE in early stage HCC with maintained liver function. 200 mg of pembrolizumab (q3w) was administered intravenously for 2 cycles followed by radiologic imaging and local therapy. Pembrolizumab was continued for up to 12 months. Primary endpoint was radiological response rate according to RECIST 1.1 prior to local therapy. Results: 30 pts (ECOG 0 or 1) were enrolled in 9 centers in Germany with a median age of 70 years (73.3% males, median tumor size 25 mm with minimum of 10 mm and maximum of 72 mm, 60% solitary lesions). All pts received at least 1 dose of study treatment and the median number of cycles was 13. ORR was 13.3% with 6.7% CR and 6.7% PR after two cycles. After a median follow-up of 34.5 months, median time to recurrence (TTR) was 16.43 months, with 8 pts remaining free of recurrence. mOS was not reached, with a 2y OS rate of 76% and a 3y OS rate of 66%. No new safety signs were observed. Subsequent local ablation was performed in 13 pts, and 10 pts started on systemic therapies (5 TKI, 3 ICI and 2 pts received TKI and ICI). Conclusions: In the IKF-IMMULAB trial the expected objective response rate of 30%, according to RECIST1.1., prior to local therapy was not reached. However, with recent evidence that radiologic response underestimates pathological response in ICI-treated HCC patients and supported by a 2y OS rate of 76% and a 3y OS rate of 66%, there is evidence for the efficacy of peri-interventional treatment with pembrolizumab without new safety signals. Clinical trial information: NCT03753659 .

Deep Learning and Hyperspectral Imaging for Liver Cancer Staging and Cirrhosis Differentiation.

Liver malignancies, particularly hepatocellular carcinoma (HCC), pose a formidable global health challenge. Conventional diagnostic techniques frequently fall short in precision, especially at advanced HCC stages. In response, we have developed a novel diagnostic strategy that integrates hyperspectral imaging with deep learning. This innovative approach captures detailed spectral data from tissue samples, pinpointing subtle cellular differences that elude traditional methods. A sophisticated deep convolutional neural network processes this data, effectively distinguishing high-grade liver cancer from cirrhosis with an accuracy of 89.45%, a sensitivity of 90.29%, and a specificity of 88.64%. For HCC differentiation specifically, it achieves an impressive accuracy of 93.73%, sensitivity of 92.53%, and specificity of 90.07%. Our results underscore the potential of this technique as a precise, rapid, and non-invasive diagnostic tool that surpasses existing clinical methods in staging liver cancer and differentiating cirrhosis.

Near-Infrared Fluorescent Probe for Simultaneously Imaging Ferrous Ions and Viscosity in a Mouse Model of Hepatocellular Carcinoma.

Abnormal ferrous ion (Fe2+) levels lead to an increase in reactive oxygen species (ROS) in cells, disrupting intracellular viscosity and the occurrence of hepatocellular carcinoma (HCC). Simultaneously visualizing Fe2+ and intracellular viscosity is essential for understanding the detailed pathophysiological processes of HCC. Herein, we report the first dual-responsive probe, QM-FV, capable of simultaneously monitoring Fe2+ and viscosity. QM-FV shows highly selective turn-on near-infrared fluorescence (∼30-fold enhancement at 740 nm) for Fe2+ with high sensitivity (LOD = 25 nM) and a significant Stokes shift (290 nm). Moreover, QM-FV shows a distinct orange-red fluorescence enhancement at 587 nm as the viscosity increases. Due to its lower cytotoxicity and high sensitivity, QM-FV can distinguish cancer cells from normal cells by detecting Fe2+ and viscosity in dual channels. More importantly, using QM-FV, we found that the levels of Fe2+ and viscosity elevated in the precancerous stage of HCC and gradually increased as the disease progressed. Overall, this work provides a new potential tool for investigating viscosity and Fe2+-related pathological processes underlying HCC.

Diagnostic Performance of PIVKA-II in Italian Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) represents the second leading cause of cancer deaths worldwide. Six-month imaging along with alpha-fetoprotein (AFP) serum levels detection are the current gold standard to exclude HCC. Protein induced by vitamin K absence (PIVKA-II) has been proposed as a potential screening biomarker for HCC. This study was designed to evaluate the role of PIVKA-II as diagnostic HCC marker, and the correlation between PIVKA-II levels and HCC stage. PIVKA-II levels were assessed on serum samples of Italian patients. The study population included 80 patients with HCC, 111 with liver cirrhosis (LC), and 111 with chronic hepatitis C (CHC). PIVKA-II serum levels progressively increase from patients with CHC to patients with HCC. In the HCC group, PIVKA-II values are higher in the more advanced stages of the disease, assessed by the Barcelona Clinic Liver Cancer (BCLC) staging system (BCLC-B vs. BCLC-A vs. BCLC-0). Youden's index analysis identified a value >37 mAU/mL as the optimal threshold for the best combination of sensitivity and specificity (80% and 76%, respectively) and, at the best cut-off of 5.2 ng/mL, AFP yielded 53% specificity and 78% sensitivity. The combination of PIVKA-II and AFP reached positive and negative predictive values of 73.9% and 94.2%, respectively. PIVKA-II levels are increased in the HCC patients, compared to control groups. The increase is more evident in patients with advanced HCC. The diagnostic performance of PIVKA-II seems more sensitive than AFP while the combination of PIVKA-II and AFP resulted in the best diagnostic accuracy, reaching 73.9% positive predictive value and 94.2% negative predictive value, thus improving the diagnostic capability of the single marker.

Development of a genetically tailored implantation hepatocellular carcinoma model in Oncopigs by somatic cell CRISPR editing.

Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis, necessitating preclinical models for evaluating novel therapies. Large-animal models are particularly valuable for assessing locoregional therapies, which are widely employed across HCC stages. This study aimed to develop a large-animal HCC model with tailored tumor mutations. The Oncopig, a genetically engineered pig with inducible TP53R167H and KRASG12D, was used in the study. Hepatocytes were isolated from Oncopigs and exposed to Cre recombinase in vitro to create HCC cells, and additional mutations were introduced by CRISPR/Cas9 knockout of PTEN and CDKN2A. These edits increased Oncopig HCC cell proliferation and migration. Autologous HCC cells with these CRISPR edits were implanted into Oncopigs using two approaches: ultrasound-guided percutaneous liver injections, which resulted in the development of localized intrahepatic masses, and portal vein injections, which led to multifocal tumors that regressed over time. Tumors developed by both approaches harbored PTEN and CDKN2A knockout mutations. This study demonstrates the feasibility of developing genetically tailored HCC tumors in Oncopigs using somatic cell CRISPR editing and autologous implantation, providing a valuable large-animal model for in vivo therapeutic assessment.

Identification and validation of an immune-related miRNA signature for predicting prognosis of hepatocellular carcinoma.

MicroRNAs play a significant role in the initiation and progression of hepatocellular carcinoma (HCC); however, their roles in immune regulation of HCC remain unclear. Our study aimed to identify an immune-related miRNA signature and explore its impact on the prognosis and tumor immune microenvironment HCC. Initially, we identified 48 differentially expressed immune-related miRNAs. Using the LASSO regression dimensionality reduction method, we constructed an immune-related miRNA signature from 12 of these miRNAs. This signature has emerged as an independent prognostic marker and is associated with the clinical stage of HCC. To elucidate the roles of the twelve-microRNA signature, we predicted their target genes. Enrichment analysis indicated that these target genes were involved in immune cell infiltration. Notably, the target genes regulated by hsa-miR-139-5p, hsa-miR-551a, and hsa-miR-7-5p showed a partial overlap. We further confirmed the differential expression of miR-7, miR-551a, miR-139-5p, and some of their overlapping target genes in tumor and non-tumor tissues derived from patients with HCC using RT-qPCR. Overall, we identified an immune-related miRNA signature that is strongly correlated with the prognosis and immune microenvironment of HCC; and confirmed the differential expression of the three most important microRNAs and their overlapping target genes in tumor and non-tumor tissues derived from HCC patients.

Expression and relationship of PD-L1, CD24, and CD47 in hepatitis B virus associated hepatocellular carcinoma

Immune checkpoint inhibitor (ICI) therapy is the new standard treatment for advanced or metastatic hepatocellular carcinoma (HCC); however, many patients still fail to respond. This study explored the expression and prognosis of programmed death ligand 1 (PD-L1), cluster of differentiation 24 (CD24), and cluster of differentiation 47 (CD47) in patients with hepatitis B virus-associated HCC (HBV-associated HCC). We analyzed sequencing data from the Cancer Genome Atlas (TCGA) and investigated the expression of PD-L1, CD24, and CD47 in HBV-associated HCC patients by immunohistochemistry and their relationship with prognosis and clinicopathological factors. HCC data from the TCGA database show that PD-L1 was substantially correlated with various immune cells. In 67 patients with HBV-associated HCC, high PD-L1 and CD24 expression levels were related to poor overall survival (OS) and progression-free survival (PFS). PD-L1 expression was significantly associated with the staging of HBV-associated HCC (p = 0.011) and Ki67 expression (p = 0.024). Correlation analysis between variables reveals that PD-L1 was significantly positively correlated with CD24 and CD47. High expression of PD-L1 and CD24 are risk factors for poor prognosis in HBV-associated HCC patients following curative resection. PD-L1 is significantly correlated with CD24 and CD47.

A Comprehensive Literature Review of Histopathology of Hepatocelullar Carcinoma

Background: The literature surrounding hepatocellular carcinoma (HCC) reveals a complex interplay of histopathological features, molecular genetics, and clinical implications that shape the understanding and management of this prevalent malignancy. Literature Review: The molecular and genetic markers associated with HCC are explored by (El-Nakeep, 2022), who address the high mortality rates associated with HCC and the complex relationship between cirrhosis and HCC development. This discussion emphasizes the necessity for further investigation into the molecular pathways underlying HCC progression. The role of imaging in diagnosis and management is reinforced by (Chartampilas et al., 2022), highlighting the importance of dynamic imaging techniques in accurately staging HCC and assessing treatment responses. Moreover, localized studies, such as that by (Sweed et al., 2022), contribute to the understanding of HCC's heterogeneous nature, emphasizing morpho-molecular classifications that guide diagnosis and treatment. The immune landscape, as discussed by (Gryziak et al., 2022), introduces the implications of immune cell interactions within the tumor microenvironment, suggesting that immune profiles should be considered alongside histopathological features in tailoring treatment strategies. The mutational landscape of HCC and the potential for precision medicine are examined by (Gorji et al., 2023), advocating for personalized therapeutic strategies that account for the genetic diversity of HCC. Finally, (Hyuk Choi & N. Thung, 2023) synthesize recent advancements in histological and molecular classification, emphasizing the importance of accurate pathological classification for effective management and prognostication. Conclusion: In conclusion, the literature collectively underscores the critical integration of histopathological analysis with molecular insights and clinical practices to enhance the understanding of HCC. This multifaceted approach is essential for improving diagnosis, treatment, and patient outcomes in the context of this complex malignancy.

Diagnostic Value of Serum Alpha-L-Fucosidase in Detecting Hepatocellular Carcinoma in Cirrhotic Patient

Background: Tumour markers are pivotal tools for the early diagnosis of tumours. Alpha Fetoprotein (AFP) is a major marker widely used for the detection of hepatocellular carcinoma (HCC). However, AFP shows poor sensitivity and specificity in the early stages of HCC. Moreover AFP levels are not elevated in some HCC patients, while they are elevated in other patients with benign liver disease. New biomarkers are urgently needed for specific early diagnosis of HCC patients. Alpha- L- Fucosidase (AFU), a lysosomal enzyme present in all mammalian cells, has been proposed as a tumour marker since many studies reported increased AFU serum levels in patients with cirrhosis with HCC patients. Objectives: This study aimed to evaluate the diagnostic value of AFU in detecting of HCC. Methods: This cross-sectional observational study was conducted in the Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka during the period from December 2019 to August 2020. Thirty three HCC patients with cirrhosis and 33 patients with liver cirrhosis were included. All HCC patients underwent FNA for cytopathological examination. Serum AFU levels were measured by enzyme-linked immunosorbent assay (ELISA) method and compared. Data were processed and analyzed with the help of computer program SPSS (Statistical Package for the Social Sciences) 25 version. Quantitative data were analyzed by mean and standard deviation; and comparison was done between two groups by unpaired t test or Mann-Whitney U test. Qualitative data were analyzed by frequency and percentage; and comparison was done between two groups by Chi- Square (χ2) test or Fisher' s Exact Test. A statistically significant result has been considered when p value less than 0.05. Results: The study revealed significant differences in serum Alpha-L-Fucosidase (AFU) and Alpha-Fetoprotein (AFP) levels between hepatocellular carcinoma (HCC) and cirrhosis groups. The median AFU levels were significantly ...

Design and evaluation of collagenase-loaded nanoparticles for mechanical intervention of orthotopic hepatocellular carcinoma in rat model

Altered tissue mechanics is vital for cancer development and malignancy, whether targeting the mechanical microenvironment could retard the initiation and progression of tumor is less explored. In this study, an orthotopic hepatocellular carcinoma (HCC) rat model was constructed to reproduce the mechanical and pathophysiological microenvironment of HCC development. LpMSN@CLG, a liver-targeted (L) and pH-sensitive (p) mesoporous silica nanoparticle (MSN) encapsulated with collagenase type-I (CLG), and DOX-LpMSN@CLG, on the basis of LpMSN@CLG, encapsulated with CLG and doxorubicin (DOX), were prepared to reduce matrix stiffness by degrading collagen in liver and HCC tumor. LpMSN@CLG, and DOX-LpMSN@CLG were respectively injected (i.v.) into rats at the stage of fibrosis and HCC, resulting in decreased collagen content in liver and HCC tissue, as well as reduced matrix stiffness. In addition, LpMSN@CLG treatment at the fibrosis stage retarded HCC initiation, and DOX-LpMSN@CLG treatment inhibited the growth of HCC tumor when compared with that of the rats treated by DOX alone, suggesting that reducing matrix stiffness in HCC tumor can improve the therapeutic efficacy of DOX. Taken together, our study demonstrated that mechanical intervention of tissue stiffness by CLG-loaded nanoparticles could retard the initiation and progression of HCC, suggesting the promising of mechanical intervention of hepatocellular carcinoma.

Zbtb7b defines a compensatory mechanism in MASLD-related HCC progression by suppressing H19-mediated hepatic lipid deposition.

Hepatocellular carcinoma (HCC) is a widely prevalent type of primary liver cancer. However, strategies for pretumor intervention are still limited. In this study, a liver-specific Zbtb7b knockout mouse model was used to evaluate the role of Zbtb7b in metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC development. We revealed that Zbtb7b was compensatively increased and restricted lipid deposition in the liver during MASLD progression, which protects against MASLD-related HCC initiation. Mechanistically, Zbtb7b suppresses the expression of the long noncoding RNA H19 to attenuate hepatic de novo lipogenesis and increase fatty acid oxidation, thereby preventing lipid accumulation in hepatocytes. As a result, the proliferation and migration abilities of HCC cells are reduced. Overall, we demonstrated that Zbtb7b serves as a tumor suppressor at an early stage of HCC, thus providing a promising target for the treatment of HCC at a premalignant stage.

Comparison of various liver cancer staging systems in predicting prognosis after initial transcatheter arterial chemoembolization: a retrospective study from China.

Hepatocellular carcinoma (HCC) constitutes approximately 75-85% of primary liver cancers and is a heavy burden on public health. Many innovative prediction systems have integrated radiomics, artificial intelligence, pathological information, or even genetic information for the stratification and prognosis prediction of patients with HCC. However, these systems still lack practical and clinical applications. Classical HCC staging systems remain the mainstream tool for stratification and prediction of treatment efficacy to date; although, variable characteristics and emphases between different classical HCC staging systems render its clinical selection inconsistent and therefore may be unreliable. In this study, we aimed to compare the predictive performance of classical liver cancer staging systems, including China Liver Cancer (CNLC), Barcelona Clinic Liver Cancer (BCLC), Hong Kong Liver Cancer (HKLC), modified Japanese Integrated Staging (mJIS), modified Cancer of the Liver Italian Program (mCLIP), and Tumor-Node-Metastasis (TNM) staging system, for the efficacy and prognosis of transcatheter arterial chemoembolization (TACE) in HCC patients. A total of 148 patients with HCC who received TACE as the initial therapy between 02/01/2019 and 08/31/2022 were retrospectively included. Patients' clinical information, laboratory and imaging data, were collected. Cox regression analysis was applied to identify independent risk factors for progression-free survival (PFS) and overall survival (OS). Six liver cancer staging systems, including the CNLC, BCLC, HKLC, mJIS, mCLIP, and TNM staging system, were applied for the staging of every enrolled patient. The PFS and OS of patients with HCC following initial TACE in different staging systems were assessed, and the predictive performance of different systems was evaluated using the concordance index. The presence of portal vein tumor thrombus (PVT), alpha fetoprotein (AFP) ≥400 ng/mL, and ineffective initial TACE treatment were independent risk factors for overall disease progression, while the presence of PVT and ineffective initial TACE treatment were independent risk factors for death. In the prediction of PFS and OS, CNLC, BCLC, HKLC, mJIS, and mCLIP all showed good predictive ability, but the predictive ability of the TNM staging system was relatively poor. The CNLC, BCLC, HKLC, mJIS, and mCLIP staging systems provide comparable predictive value for the prognosis after the initial TACE, while the TNM staging system has poor predictive ability due to its exclusion of hepatic function.

Prostate-Specific Membrane Antigen (PSMA) PET/CT in the Detection and Diagnosis of Hepatocellular Carcinoma (HCC): A Systematic Review and Meta-Analysis.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is widely used in prostate cancer. Recent studies indicate hepatocellular carcinoma (HCC) demonstrates PSMA PET uptake. The diagnostic accuracy of PSMA PET for HCC is not known. We conducted a systematic review and meta-analysis of studies assessing 68Ga-PSMA-11 in HCC. Nine studies were included, with 196 patients and a total of 491 HCC lesions. Per-patient analysis yielded a pooled sensitivity of 89.8% (95% CI 78.5-95.5). Specificity was poorly reported, with insufficient data. When per-lesion level analysis was performed on seven studies, the pooled sensitivity was 94.5% (95% CI 82.9-98.4), and specificity was again poorly reported with insufficient data. Among the three studies with adequate data for full per-lesion meta-analysis, 115 lesions in 41 patients demonstrated sensitivity of 97.1% (95% CI 87.8-99.4), while specificity was 42.2% (95% CI 0.3-99.4). Two studies provided sufficient data for meta-analysis on a per-patient level (n = 50 patients), demonstrating a sensitivity of 92.5% (95% CI 64.0-98.9) and specificity of 72.4% (95% CI 1.3-99.8). PSMA PET demonstrates a high sensitivity for HCC and shows promise as an imaging modality for diagnosis and staging of HCC. However, the existing literature does not provide enough data to confidently evaluate its specificity and, therefore, accuracy. Further prospective studies are necessary, with a focus on the accurate reporting of benign lesions and inclusion of patients with an intermediate probability of HCC.

Gadoxetic Acid-Enhanced Magnetic Resonance Imaging Features Can Predict Immune-Excluded Phenotype of Hepatocellular Carcinoma

Introduction: Immunotherapy is the first-line treatment for intermediate-advanced stage hepatocellular carcinoma (HCC), although its outcomes vary. This study aimed to identify imaging biomarkers of immunotherapy susceptibility linked to gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) and immune phenotypes, particularly immune-excluded phenotypes, with a tumor immune barrier. Methods: We performed immunohistochemical staining with a CD8+ antibody, and samples were classified into immune-inflamed, -intermediate, -excluded, and -ignored phenotypes. We assessed EOB-MRI findings obtained from 104 patients who underwent hepatectomy for HCC and evaluated the relationship between MRI findings and immune phenotype. Spatial transcriptome analysis of tumor tissues in each immune phenotype was performed to characterize the MRI findings. For validation, we analyzed the treatment effect on 60 nodules in another cohort of 27 patients who received combined immunotherapy using anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies. Results: HCCs with rim arterial phase hyperenhancement (APHE) (odds ratio [OR] 17.3, p = 0.009), peritumoral enhancement in the arterial phase (OR: 8.6, p < 0.004), and intermediate intensity on the hepatobiliary phase (HBP) measured with a visual 3-point scale (OR: 28.2, p = 0.002) were associated with immune-excluded phenotype, where tumors tended to be larger and of the single nodular type with extranodular growth and confluent multinodular rather than the simple nodular type. Spatial transcriptome analysis revealed a spatial relationship among cytotoxic T lymphocytes, VEGF signals, and cancer-associated fibroblasts at the tumor-invasive margins in this phenotype. From the validation study, nodules with any one of these three imaging findings had a significantly prolonged time to-nodular progression (p = 0.007, median not reached vs. 226 days). Conclusion: HCCs with rim APHE, peritumoral enhancement in arterial phase, and intermediate intensity on HBP with visual 3-point scale could be non-invasive biomarkers to predict the immune-excluded phenotype with the tumor immune barrier. These HCCs were most likely to respond to combined immunotherapy.

Comparison of stereotactic body radiotherapy and transcatheter arterial chemoembolization for hepatocellular carcinoma: Systematic review and meta‐analysis

Stereotactic body radiation therapy (SBRT) is an emerging treatment for hepatocellular carcinoma (HCC), which provides excellent local control (LC) and prolongs overall survival (OS). However, in current guidelines, transcatheter arterial chemoembolization (TACE) has been proposed as a key treatment option for patients with early- and intermediate-stage HCC, whereas SBRT is not. Therefore, we performed a systematic review and meta-analysis of randomized controlled trials and retrospective studies using the propensity score (PS) to compare the outcomes of SBRT and TACE for HCC in a balanced manner. We systematically searched the PubMed, Cochrane, EMBASE, and Web of Science databases to identify randomized controlled trials and studies comparing SBRT and TACE using PS analysis. The hazard ratios (HRs) for OS and LC were pooled. The heterogeneity between the data collected from these studies was also assessed. SBRT led to a comparable OS (HR: 0.83; 95 % confidence interval (CI): 0.52–1.34; p = 0.44) to TACE, and significantly improved LC (HR: 0.25; 95 % CI: 0.09–0.67; p = 0.006). Considerable heterogeneity was observed in the HR of OS and LC. Although there was no significant difference in the rate of grade 3 or higher toxicities between TACE and SBRT, or between studies, liver toxicity was identified as a common adverse event associated with both SBRT and TACE. Compared to TACE, SBRT showed a comparable OS and improved LC without serious toxicity. Therefore, SBRT should be considered an effective treatment option for various stages of HCC, depending on the tumor factors and pretreatment liver function.

Left radial vs right femoral: comparison between arterial accesses in c-TACE procedures in terms of operator radiations exposure and patient comfort.

This multicenter prospective study aims to compare transradial access versus transfemoral access in conventional transarterial chemoembolization (c-TACE) procedures, focusing on operators radiations exposure, patients comfort, technical success and vascular access complications. Patients were affected by hepatocellularcarcinoma (HCC) in intermediate stage or previous stages unfit for ablation and/or surgery; they were randomized into two groups according to arterial access site (Group F: right femoral access in standard position; Group R: radial access with left arm abduced 90°). Overall fluoroscopy time was recorded. Eight thermoluminescence dosimeters were positioned immediately before each procedure to monitor radiation doses. Technical success was intended as complete HCC nodules lipiodolization at final plain cone-beam CT. Group F included 23 patients, while group R 19. Mean fluoroscopy time was lower in group F but difference was not statistically significant (p-value > 0.05). In terms of operators radiations exposure, no significant differences were found (p-value > 0.05). Technical success was obtained in 81.5% in group F and 84.8% in group R, without significant differences (p-value > 0.05). Patients discomfort was significantly (p-value < 0.05) higher in group F. Concerning minor complications, no statistical differences were appreciated (p-value > 0.05); no major complications occurred. In this study, no statistical differences were observed in terms of operators radiations exposure, fluoroscopy time and technical success during c-TACE performed with left radial access compared to right femoral access; patients comfort was significantly better with radial access. These data should lead interventional radiologists to favor radial access in c-TACE interventions.

Real-World Effectiveness of All-Oral Direct-Acting Antivirals in Patients With Hepatitis C Virus-Related HCC.

The association between direct-acting antiviral (DAA) treatment and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is currently unclear. Hence, we aim to assess the association between DAA treatment and mortality rate among Medicare beneficiaries with HCV-related HCC. This retrospective cohort study screened 19,813 adults in 2013-2019 Surveillance, Epidemiology, and End Results data linked with Medicare data. Patients with HCV-related HCC initiating DAA therapy after their first HCC diagnosis were compared with patients with HCV-related HCC who received no HCV treatment. After inverse probability treatment weighting, multivariable Cox proportional hazards models compared mortality rates between the groups. Subgroup and sensitivity analyses were based on HCC stage (early vs. advanced), type of HCC treatment (curative, palliative, none), and DAA treatment duration. In total 3,777 patients with HCV-related HCC were identified (mean age: 68.2 years, 75.2% male, 61.8% White), of whom 19% initiated DAA therapy. Crude incidence mortality rates were 17.9 and 90.7 deaths per 100 person-years in the DAA and HCV-untreated groups, respectively. Cox regression models indicated that DAA therapy was associated with decreased risk of all-cause mortality (adjusted hazard ratio, 0.33; 95% CI 0.31-0.36). Median survival time was 45.7 (95% CI 40.9-57.9) months in the DAA group and 7.7 (95% CI 7.3-8.2) months in the HCV-untreated group (P < 0.001). All subgroup and sensitivity analyses were consistent with the main analyses. DAA therapy was associated with survival benefits for patients with HCV-related HCC regardless of the stage or type of HCC treatment and should not be withheld from this population of Medicare beneficiaries.

Interventional Oncology Meets Immuno-oncology: Combination Therapies for Hepatocellular Carcinoma.

The management of hepatocellular carcinoma (HCC) is undergoing transformational changes due to the emergence of various novel immunotherapies and their combination with image-guided locoregional therapies. In this setting, immunotherapy is expected to become one of the standards of care in both neoadjuvant and adjuvant settings across all disease stages of HCC. Currently, more than 50 ongoing prospective clinical trials are investigating various end points for the combination of immunotherapy with both percutaneous and catheter-directed therapies. This review will outline essential tumor microenvironment mechanisms responsible for disease evolution and therapy resistance, discuss the rationale for combining locoregional therapy with immunotherapy, summarize ongoing clinical trials, and report on developing imaging end points and novel biomarkers that are relevant to both diagnostic and interventional radiologists participating in the management of HCC.