Treatment Options For Hepatocellular Carcinoma Research Articles

Hepatocellular Carcinoma: Prevention, Diagnosis, and Treatment.

Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer globally, poses a substantial health burden. HCC development is influenced by multiple risk factors including hepatitis B and C infections, excessive alcohol consumption, nonalcoholic steatohepatitis (NASH), and demographic variables like gender, race, and age. Although the exact etiology of HCC is not fully understood, HCC formation is a multi-step process that is contributed by the interplays of viral infection, hepatocyte oncogenic mutations, and chronic liver diseases such as alcoholic cirrhosis and NASH. Disease stage significantly impacts HCC prognosis, with 5-year survival rates ranging from 36% in early-stage cases to 13% in late-stage metastatic cases. Therefore, there is significant potential for life-saving and socioeconomic benefits through the implementation of surveillance programs and the introduction of low-cost screening measures for high-risk groups, such as ultrasound imaging and blood tests. Treatment options for HCC encompass surgery, liver transplantation, radiation therapy, chemotherapy, targeted therapy, and immunotherapy. Despite therapeutic advances, the treatment of advanced HCC remains a challenge. The prognosis of advanced HCC could be greatly improved with continued efforts in prevention, early detection, and treatment development. These efforts will ultimately lead to improved patient outcomes and increased chances of long-term survival.

Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review).

Hepatocellular carcinoma (HCC), one of the leading causes of cancer‑related mortality worldwide, is challenging to identify in its early stages and prone to metastasis, and the prognosis of patients with this disease is poor. Treatment options for HCC are limited, with even radical treatments being associated with a risk of recurrence or transformation in the short term. Furthermore, the multi‑tyrosine kinase inhibitors approved for first‑line therapy have marked drawbacks, including drug resistance and side effects. The rise and breakthrough of immune checkpoint inhibitors (ICIs) have provided a novel direction for HCC immunotherapy but these have the drawback of low response rates. Since avoiding apoptosis is a universal feature of cancer, the induction of non‑apoptotic regulatory cell death (NARCD) is a novel strategy for HCC immunotherapy. At present, NARCD pathways, including ferroptosis, pyroptosis and necroptosis, are novel potential forms of immunogenic cell death, which have synergistic effects with antitumor immunity, transforming immune 'cold' tumors into immune 'hot' tumors and exerting antitumor effects. Therefore, these pathways may be targeted as a novel treatment strategy for HCC. In the present review, the roles of ferroptosis, pyroptosis and necroptosis in antitumor immunity in HCC are discussed, and the relevant targets and signaling pathways, and the current status of combined therapy with ICIs are summarized. The prospects of targeting ferroptosis, pyroptosis and necroptosis in HCC immunotherapy are also considered.

Current Roles of Ramucirumab in the Sequential Treatment of Unresectable Hepatocellular Carcinoma.

The treatment algorithm for systemic therapies for advanced hepatocellular carcinoma (HCC) has changed dramatically; however, the therapeutic landscape for sequential second-line or later-line treatments, including ramucirumab, remains controversial. This study aimed to investigate the role of ramucirumab for treating HCC. We retrospectively analyzed data from 17 patients with advanced HCC who received ramucirumab, and 8 of them who received lenvatinib re-administration after ramucirumab treatment failure. The median overall survival of 17 patients treated with ramucirumab was 11.5 months. The median ratios of the 1-month post-treatment α-fetoprotein (AFP) levels and albumin-bilirubin (ALBI) scores to the pre-treatment AFP levels and ALBI scores following ramucirumab treatment were 0.880 and 0.965, respectively. The median ratios of the 1-month post-treatment AFP and ALBI levels to the pre-treatment levels were 1.587 and 0.970 for mALBI grade 1/2a, and 1.313 and 0.936 for mALBI grade 2b/3, respectively. Six of the eight patients who received lenvatinib rechallenge treatment exhibited a decrease in AFP levels one month post-lenvatinib treatment. Deterioration of liver function 3 months post-lenvatinib treatment was noted in five of the eight patients who received lenvatinib rechallenge treatment after ramucirumab. Ramucirumab may be equally useful in patients with unresectable HCC who have poor liver function or whose liver function is aggravated by other therapies. Rechallenge treatment with lenvatinib after ramucirumab may be a valid treatment option for HCC.

Enhancing HepG2 cell apoptosis with a combined nanoparticle delivery of miR-128–3p agomir and Oroxin B: A novel drug delivery approach based on PI3K-AKT and VEGF pathway crosstalk

Hepatocellular carcinoma (HCC) shows the highest morbidity among liver cancers and accounts for a major factor inducing cancer-associated mortality globally. It is characterized by genetic mutations in hepatocytes, leading to uncontrolled cell growth and proliferation. Treatment options for HCC include surgery, chemotherapy, and immunotherapy. But chemotherapeutics, which focus on single-targeted drug therapy, are still associated with certain limitations and may affect the treatment outcomes. Compared with chemotherapy drugs, natural products also show the anticancer effect of HCC and hypotoxicity, but overall low activity of natural products limits their further application. MiRNAs can modulate post-transcriptional functions of target genes. An increasing body of evidence has demonstrated that miRNAs are the key regulators in HCC by targeting different molecules in different signaling pathways. However, miRNAs are fragile and liable to catabolism by RNases in serum and other body fluids and small molecules separated from natural products may have limited bio-availability. According to this background, a chitosan based, targeted sustained-release nanoparticle delivery miR-128–3p agomir (NA-miR-128–3p) was developed in this work. This nanoparticle was prepared by pentasodium tripolyphosphate (TPP), chitosan hydrochloride, and miR-128–3p agomir with target aptamer which was loaded into the chitosan nanoparticle by self-assembly. It can intervene in HCC progress by affecting AKT1 expression. Based on this, a novel, efficient, long-acting, multi-mechanism, low-dosage combination drug delivery strategy was proposed in this work and showed a prominent anti-tumor effect. NA-miR-128–3p combined with natural product Oroxin B significantly affected HCC progression by the interference with VEGF and PI3K-AKT pathways, better than using NA-miR-128–3p and Oroxin B alone. Taken together, this nanoparticle and combinative administration compensate for the shortcomings of the fragile RNA drugs and the low activity of natural products, with high prospects in HCC treatment.

Clinical prediction of microvascular invasion in hepatocellular carcinoma using an MRI-based graph convolutional network model integrated with nomogram.

Based on enhanced MRI, a prediction model of microvascular invasion (MVI) for hepatocellular carcinoma (HCC) was developed using graph convolutional network (GCN) combined nomogram. We retrospectively collected 182 HCC patients confirmed histopathologically, all of them performed enhanced MRI before surgery. The patients were randomly divided into training and validation groups. Radiomics features were extracted from the arterial phase (AP), portal venous phase (PVP), and delayed phase (DP), respectively. After removing redundant features, the graph structure by constructing the distance matrix with the feature matrix was built. Screening the superior phases and acquired GCN Score (GS). Finally, combining clinical, radiological and GS established the predicting nomogram. 27.5% (50/182) patients were with MVI positive. In radiological analysis, intratumoural artery (P = 0.007) was an independent predictor of MVI. GCN model with grey-level cooccurrence matrix-grey-level run length matrix features exhibited area under the curves of the training group was 0.532, 0.690, and 0.885 and the validation group was 0.583, 0.580, and 0.854 for AP, PVP, and DP, respectively. DP was selected to develop final model and got GS. Combining GS with diameter, corona enhancement, mosaic architecture, and intratumoural artery constructed a nomogram which showed a C-index of 0.884 (95% CI: 0.829-0.927). The GCN model based on DP has a high predictive ability. A nomogram combining GS, clinical and radiological characteristics can be a simple and effective guiding tool for selecting HCC treatment options. GCN based on MRI could predict MVI on HCC.

Identification of a Novel Circadian Rhythm-Related Signature for Predicting Prognosis and Therapies in Hepatocellular Carcinoma Based on Bulk and Single-Cell RNA Sequencing

Background. Circadian rhythm disruption involves tumorigenesis and tumor progression. However, the influences of circadian rhythm on the tumor microenvironment (TME) and the prognosis of hepatocellular carcinoma (HCC) are unknown. Methods. Bulk RNA-seq and single-cell RNA-seq from TCGA, ICGC, and GEO were used to comprehensively identify prognostic circadian control cells and circadian rhythm associated genes (CRRGs) using R and Python packages. Besides, the circadian rhythm-related prognostic signature was identified and validated. The biological function, immune infiltration, and therapeutic response associated with circadian rhythm-related (CR) risk were detected. Results. A total of 252 differentially expressed CRRGs in HCC were identified, and HCC with a high CR score revealed poor survival. We annotated 11 major cell types in TME; immune cells (B cells, myeloid, CD4+ cells, CD8+ cells, NK cells, Tregs) with high CR score, and hepatocyte, bio-potent cells, fibroblasts, and endothelial cells with low CR score were identified. Moreover, five CRRGs (RPL29, PFKFB3, RPS7, SLC6A6, and RPLP2) were selected and validated as the prognostic signature in HCC. The risk score was calculated based on the prognostic signature, and patients then were divided into high-risk and low-risk groups according to the median value of the risk score. High risk is linked to several metabolism-related pathways and canonical cancer-related pathways and is negatively associated with immunotherapeutic responses and positively associated with some chemotherapeutic drugs. Conclusion. Our finding provides the novel circadian rhythm-related prognostic signature and represents a novel viable “time-dependent” therapeutic option for HCC treatment.

Abstract 5729: ADCK1 inhibition alters cell proliferation and cell cycle progression in liver cancer cells

Abstract In 2020, there were over 830,000 reported liver cancer deaths. Incidence rates of liver cancer have tripled, and death rates have doubled since the 1980s; giving this disease one of the highest mortality rates when compared to its incidence rate. Hepatocellular carcinoma (HCC) is derived from hepatocytes and is the main type of liver cancer in adults, accounting for 75-85% of all primary liver cancers. Current treatment options for HCC like radiation therapy and chemotherapy are imperfect and cause significant side effects. Tumorigenesis is dependent on an organism’s cellular metabolism. Metabolic reprogramming is a promising area of focus for cancer therapeutics. Cancer cells thrive in nutrient-deficient environments by hijacking and reprogramming the cells existing cellular metabolism. Metabolic reprogramming is driven by genetic alterations and environmental cues. AarF Domain Containing Kinase 1 (ADCK1) is a protein-coding gene that acts as a mitochondrial protein with putative kinase activity. The role of ADCK1 has not been well studied, particularly in liver cancer. Our group has sought to study how ADCK1 impacts the metabolism and cellular environment of HCC cells to help establish a more effective drug target. Bioinformatics performed by our lab report that ADCK1 was highly expressed in HCC tumor cells. The expression levels of ADCK1 were also correlated with a decrease in patient survival. ADCK1 knockout clones were generated; these knockout cells showed decreased proliferation and altered cell cycle progression. Proteomics analysis demonstrated that loss of ADCK1 was also seen to alter the expression of proteins involved in several cellular processes related to the cell cycle and cellular metabolism. How ADCK1 regulates these processes will be studied in the future. Citation Format: Noel A. Jacquet, Yunfeng Zhao. ADCK1 inhibition alters cell proliferation and cell cycle progression in liver cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5729.

Surgical resection for hepatocellular carcinoma: a single-centre's one decade of experience.

Liver cancer is the third leading cause of global cancer deaths, and hepatocellular carcinoma is its most common type. Liver resection is one of the treatment options for hepatocellular carcinoma (HCC). This study aims to explore our hospital's more than a decade of experience in liver resection for HCC patients. This is a retrospective cohort study on HCC patients undergoing resection from 2010 to 2021 in a tertiary-level hospital in Jakarta, Indonesia. Mortality rates were explored as the primary outcome of this study. Statistical analysis was done on possible predictive factors using Pearson's χ2. Survival analysis was done using the Log-Rank test and Cox Regression. Ninety-one patients were included in this study. The authors found that the postoperative mortality rates were 8.8% (in hospital), 11.5% (30 days), and 24.1% (90 days). Excluding postoperative mortalities, the long-term mortality rates were 44.4% (first year), 58.7% (3 years), and 69.7% (5 years). Cumulatively, the mortality rates were 46.4% (1 year), 68.9% (3 years), 77.8% (5 years), and 67.0% (all time). Significant predictive factors for cumulative 1-year mortality include large tumour diameter [odds ratio (OR) 14.06; 95% CI: 2.59-76.35; comparing <3cm and >10cm tumours; P<0.01], positive resection margin (OR 2.86; 1.17-77.0; P=0.02), and tumour differentiation (P=0.01). Multivariate analysis found hazard ratios of 6.35 (2.13-18.93; P<0.01) and 1.81 (1.04-3.14; P=0.04) for tumour diameter and resection margin, respectively. The mortality rate of HCC patients undergoing resection is still very high. Significant predictive factors for mortality found in this study benefit from earlier diagnosis and treatment; thus, highlighting the importance of HCC surveillance programs.

Treatment Options for Hepatocellular Carcinoma Using Immunotherapy: Present and Future.

Hepatocellular carcinoma (HCC) is a common cancer, and the body's immune responses greatly affect its progression and the prognosis of patients. Immunological suppression and the maintenance of self-tolerance in the tumor microenvironment are essential responses, and these form part of the theoretical foundations of immunotherapy. In this review, we first discuss the tumor microenvironment of HCC, describe immunosuppression in HCC, and review the major biomarkers used to track HCC progression and response to treatment. We then examine antibody-based therapies, with a focus on immune checkpoint inhibitors (ICIs), monoclonal antibodies that target key proteins in the immune response (programmed cell death protein 1, anti-cytotoxic T-lymphocyte associated protein 4, and programmed death-ligand 1) which have transformed the treatment of HCC and other cancers. ICIs may be used alone or in conjunction with various targeted therapies for patients with advanced HCC who are receiving first-line treatments or subsequent treatments. We also discuss the use of different cellular immunotherapies, including T cell receptor (TCR) T cell therapy and chimeric antigen receptor (CAR) T cell therapy. We then review the use of HCC vaccines, adjuvant immunotherapy, and oncolytic virotherapy, and describe the goals of future research in the development of treatments for HCC.

The Role of Anti-PD 1 (Programmed Cell Death-1) (Pembrolizumab) in Hepatocellular Carcinoma: A Narrative Literature Review

Hepatocellular carcinoma (HCC) is a malignant tumor originating from liver cells, HCC occurs in around 85% of patients diagnosed with cirrhosis. Treatment options for HCC consider liver function, extrahepatic spread, invasiveness, and the number and size of nodules. HCC therapy options include surgical resection, liver transplantation, tumor ablation, transarterial therapy and systemic chemotherapy. Pembrolizumab is a second-line systemic therapy option for the treatment of HCC after sorafenib therapy. Pembrolizumab is a class of immune checkpoint inhibitors (ICIs) and more specifically works as a programmed cell death-1 (PD-1) inhibitor.

A novel nomogram for prediction of intrahepatic recurrence-free survival in patients with HCC followed by radiofrequency ablation.

Although radiofrequency ablation (RFA) has been considered as the favourable treatment option for hepatocellular carcinoma (HCC), there still exist some challenges for new recurrence after RFA. The present study aims to determine the factors affecting recurrence and develop an effective model to predict intrahepatic recurrence-free survival (RFS). Patients with HCC followed by RFA between 2000 and 2021 were included in this study. Multivariable Cox regression analysis was used to determine the independent prognostic factors and establish the nomogram predicting intrahepatic RFS after RFA. The predictive performance of the nomogram was assessed according to the C-index, calibration plots, and Kaplan-Meier curves stratified by the tertiles. A total of 801 sessions in 660 patients (including 1155 lesions) were enrolled into this study. Intrahepatic new recurrence was observed in all patients during the follow-up, and the mean intrahepatic RFS was 21.9 months in the present cohort. According to multivariate COX regression analysis, five independent prognostic factors affecting intrahepatic RFS were determined, including age, Child-Pugh class, tumour distribution, number of tumours, and a-fetoprotein (AFP). Based on all independent prognostic factors, the nomogram model was developed and evaluated, which achieved favourable discrimination and calibration. This study established five independent prognostic factors and constructed a nomogram model to predict intrahepatic RFS for HCC patients followed by RFA. It could better help clinicians select RFA candidates, as well as offering the important information about whether patients need receive comprehensive treatment to prevent new recurrence after RFA. (1) In this study, 5 preoperative clinic-pathological variables were determined as the independent prognostic factors affecting RFS after RFA in the current largest sample size. (2) Based on these independent prognostic factors, a prognostic nomogram predicting RFS after RFA was established, which may be used to select patients who benefit from RFA and could help both surgeons and patients provide useful information for choosing the personalized treatment.

Prognostic Biomarkers for Hepatocellular Carcinoma Based on Serine and Glycine Metabolism-related Genes.

Targeted therapy and immunotherapy have emerged as treatment options for hepatocellular carcinoma (HCC) in recent years. The significance of serine and glycine metabolism in various cancers is widely acknowledged. This study aims to investigate their correlation with the prognosis and tumor immune microenvironment (TIME) of HCC. Based on the public database, different subtypes were identified by cluster analysis, and the prognostic model was constructed through regression analysis. The gene expression omnibus (GEO) data set was used as the validation set to verify the performance of the model. The survival curve evaluated prognostic ability. CIBERSORT was used to evaluate the level of immune cell infiltration, and maftools analyzed the mutations. DsigDB screened small molecule compounds related to prognostic genes. HCC was found to have two distinct subtypes. Subsequently, we constructed a risk score prognostic model through regression analysis based on serine and glycine metabolism-related genes (SGMGs). A nomogram was constructed based on risk scores and other clinical factors. HCC patients with a higher risk score showed a poor prognosis, and there were significant differences in immune cell infiltration between the high- and low-risk groups. In addition, three potential drugs associated with prognostic genes, streptozocin, norfloxacin, and hydrocotarnine, were identified. This study investigated the expression patterns of SGMGs and their relationship with tumor characteristics, resulting in the development of a novel model for predicting the prognosis of HCC patients. The study provides a reference for clinical prognosis prediction and treatment of HCC patients.

BCG as an Innovative Option for HCC Treatment: Repurposing and Mechanistic Insights.

This study investigates Bacillus Calmette-Guérin (BCG) as a potential treatment for hepatocellular carcinoma (HCC), a condition often associated with unfavorable treatment outcomes. Exploiting BCG's recognized immune-boosting properties, preclinical trials are conducted using HCC mice, with a single subcutaneous dose of BCG administered post-tumor formation. Results indicate that BCG treatment effectively diminishes tumor burden and extends survival in both male and female HCC mice. Positive influences on hepatic fibrosis and metabolism are observed, leading to a reduction in lipid levels. Spatial analysis underscores BCG's tumor-specific effects, inducing the enrichment of metabolic pathways and inhibiting various cancer-related pathways. Furthermore, BCG promotes immune cell infiltration, including CD4+, CD8+ T cells, and M1 macrophages, in both v-akt murine thymoma viral oncogene homolog 1(AKT)/neutoblastoma RAS viral oncogene homolog (RAS) and β-catenin positive HCC models. Interestingly, blocking T cells, trained immunity, and Interferon-γ (IFN-γ) function reverses BCG's anti-HCC effects. In conclusion, BCG emerges as a promising treatment option for HCC, characterized by a favorable safety profile and efficacy in inhibiting fibrosis, improving metabolism, and engaging both trained immunity and T cells in therapeutic mechanisms.

Bulk and single-cell transcriptome reveal the immuno-prognostic subtypes and tumour microenvironment heterogeneity in HCC.

Accumulating evidences suggest tumour microenvironment (TME) profoundly influence clinical outcome in hepatocellular carcinoma (HCC). Existing immune subtypes are susceptible to batch effects, and integrative analysis of bulk and single-cell transcriptome is helpful to recognize immune subtypes and TME in HCC. Based on the relative expression ordering (REO) of 1259 immune-related genes, an immuno-prognostic signature was developed and validated in 907 HCC samples from five bulk transcriptomic cohorts, including 72 in-house samples. The machine learning models based on subtype-specific gene pairs with stable REOs were constructed to jointly predict immuno-prognostic subtypes in single-cell RNA-seq data and validated in another single-cell data. Then, cancer characteristics, immune landscape, underlying mechanism and therapeutic benefits between subtypes were analysed. An immune-related signature with 29 gene pairs stratified HCC samples individually into two risk subgroups (C1 and C2), which was an independent prognostic factor for overall survival. The machine learning models verified the immune subtypes from five bulk cohorts to two single-cell transcriptomic data. Integrative analysis revealed that C1 had poorer outcomes, higher CNV burden and malignant scores, higher sensitivity to sorafenib, and exhibited an immunosuppressive phenotype with more regulators, e.g., myeloid-derived suppressor cells (MDSCs), Mø_SPP1, while C2 was characterized with better outcomes, higher metabolism, more benefit from immunotherapy, and displayed active immune with more effectors, e.g., tumour infiltrating lymphocyte and dendritic cell. Moreover, both two single-cell data revealed the crosstalk of SPP1-related L-R pairs between cancer and immune cells, especially SPP1-CD44, might lead to immunosuppression in C1. The REO-based immuno-prognostic subtypes were conducive to individualized prognosis prediction and treatment options for HCC. This study paved the way for understanding TME heterogeneity between immuno-prognostic subtypes of HCC.

Sorafenib plus transarterial chemoembolization vs sorafenib alone for patients with advanced hepatocellular carcinoma: A systematic review and meta-analysis.

Although the past decade has seen remarkable advances in treatment options for hepatocellular carcinoma (HCC), the dismal overall prognosis still envelops HCC patients. Several comparative trials have been conducted to study whether transarterial chemoembolization (TACE) could improve clinical outcomes in patients receiving sorafenib for advanced HCC; however, the findings have been inconsistent. To study the potential synergies and safety of sorafenib plus TACE vs sorafenib alone for treating advanced HCC, by performing a systematic review and meta-analysis. This study was conducted following the PRISMA statement. A systematic literature search was conducted using the Cochrane Library, Embase, PubMed, and Web of Science databases. Data included in the present work were collected from patients diagnosed with advanced HCC receiving sorafenib plus TACE or sorafenib alone. Data synthesis and meta-analysis were conducted using Review Manager software. The present study included 2780 patients from five comparative clinical trials (1 was randomized control trial and 4 were retrospective studies). It was found that patients receiving sorafenib plus TACE had better prognoses in terms of overall survival (OS), with a combined hazard ratio (HR) of 0.65 [95% confidence interval (95%CI): 0.46-0.93, P = 0.02, n = 2780]. Consistently, progression free survival (PFS) and time to progression (TTP) differed significantly between the sorafenib plus TACE arm and sorafenib arm (PFS: HR = 0.62, 95%CI: 0.40-0.96, P = 0.03, n = 443; TTP: HR = 0.73, 95%CI: 0.64-0.83, P < 0.00001, n = 2451). Disease control rate (DCR) was also significantly increased by combination therapy (risk ratio = 1.36, 95%CI: 1.02-1.81, P = 0.04, n = 641). Regarding safety, the incidence of any adverse event (AE) was increased due to the addition of TACE; however, no significant difference was found in grade ≥ 3 AEs. The combination of sorafenib with TACE has superior efficacy to sorafenib monotherapy, as evidenced by prolonged OS, PFS, and TTP, as well as increased DCR. Additional high-quality trials are essential to further validate the clinical benefit of this combination in the treatment of advanced HCC.

Lenvatinib in recurrent hepatocellular carcinoma after liver transplantation.

TPS578 Background: Liver transplantation is a curative treatment option in hepatocellular carcinoma (HCC) however; up to 20% of patients develop recurrent disease. HCC recurrence post-transplant is usually extrahepatic (up to 67%) hence requires effective systemic therapy options. Available data are limited and restricted to small non-randomized studies and case series. Lack of prospective clinical trial data and limited data indicates an area of unmet need in treatment of recurrent HCC after liver transplantation. This phase II study aims evaluate the safety and efficacy of lenvatinib in patients with recurrent HCC after liver transplantation. Methods: This is a multi-institutional phase II trial with lenvatinib in patients with recurrent HCC after transplantation. Lenvatinib is administered 12 mg daily orally in patients ≥60 kg, and 8 mg daily orally in patients &lt;60 kg. Each cycle is 28 days. Restaging scans will be performed every 8 weeks. Eligible patients must have histologically proven HCC that has recurred after liver transplantation and not amenable for surgical resection, age ≥18 years, ECOG PS 0-1, Child Pugh Class A, measurable disease per RECIST version 1.1, adequate organ function, no prior systemic therapy with lenvatinib or another systemic therapy in the post-transplant setting. Prior liver directed therapy is allowed, should be at least &gt;28 days prior to the study enrollment, and should have at least one measurable untreated lesion by RECIST 1.1 Primary endpoint is overall response rate (ORR). Secondary endpoints are safety/tolerability, progression free survival, and overall survival. Pre-treatment and on-treatment peripheral blood samples will be collected for correlative research. A Simon`s two stage Minimax design is employed (H0: ORR = 5%; H1: ORR = 24%; Type I error = 0.05; power = 80%). In the first stage, 11 patients will be accrued, and if there is no objective response among them, the study will be stopped for futility. Otherwise, additional 6 patients will be accrued for a total of 17 patients. This study is currently enrolling patients. Clinical trial information: NCT05103904 .

Ischemic Stroke Post-Transradial Chemoembolization

AbstractTransarterial chemoembolization is one of the approved locoregional treatment options for hepatocellular carcinoma. The procedure is safe; however, stroke may happen as one of the rarest complications. Our patient is a 68-year-old male who underwent transradial chemoembolization to treat hepatocellular carcinoma, who then developed ischemic stroke on postoperative day 1. The possible causes of stroke in our patient will be presented with review of the literature. Although rare, stroke post-chemoembolization can happen. The presence of intratumoral shunt or inadvertent injection of air bubbles in a coexisting right-to-left shun or the use of transradial approach can increase the risk of stroke.

SPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma

Tumor lineage plasticity, considered a hallmark of cancer, denotes the phenomenon in which tumor cells co-opt developmental pathways to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the underlying molecular events remain largely elusive. Our recent study identified CD133/Prom1 in hepatocellular carcinoma (HCC) tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. Here we show SPINK1 to strongly associate with CD133 + HCC, and tumor dedifferentiation. Enhanced transcriptional activity of SPINK1 is mediated by promoter binding of ELF3, which like CD133, is found to increase following 5-FU and cisplatin treatment; while targeted depletion of CD133 will reduce both ELF3 and SPINK1. Functionally, SPINK1 overexpression promotes tumor initiation, self-renewal, and chemoresistance by driving a deregulated EGFR-ERK-CDK4/6-E2F2 signaling axis to induce dedifferentiation of HCC cells into their ancestral lineages. Depleting SPINK1 function by neutralizing antibody treatment or in vivo lentivirus-mediated Spink1 knockdown dampens HCC cancer growth and their ability to resist chemotherapy. Targeting oncofetal SPINK1 may represent a promising therapeutic option for HCC treatment.

Folic/lactobionic acid dual-targeted polymeric nanocapsules for potential treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor that affects many patients diagnosed with hepatic cell inflammation and liver cirrhosis. Targeted polymeric nanocapsules could facilitate the internalization and accumulation of anticancer drugs. Dual-targeted folic acid/lactobionic acid-poly lactic co-glycolic acid nanocapsules (NCs) were prepared and loaded with pterostilbene (PTN) and characterized for their physicochemical properties, as well as in vitro and in vivo anticancer activity. NCs displayed a size of 222nm, zeta potential of - 16.5mV, and sustained release for 48h. The IC50 of PTN NCs (5.87 ± 0.8µg/mL) was 20 times lower than unencapsulated PTN (121.26 ± 9.42µg/mL) on HepG2 liver cancer cells owing to the enhanced cellular uptake of the former, as delineated by flow cytometry. In vivo study on HCC-induced animals delineated the superiority of the dual-targeted NCs over the unencapsulated PTN, which significantly reduced the liver markers ALT, AST, and ALP, as well as the tumor-related markers AFP and Bcl2, and elevated the anti-apoptotic marker caspase 3. Furthermore, the NCs significantly reduced the oxidative stress and exhibited almost comparable histological features to the normal group. Therefore, it can be concluded that the dual-ligated folic acid/lactobionic acid nanocapsules can be considered a promising potential treatment option for hepatocellular carcinoma.

Targeting stroma and tumor, silencing galectin 1 treats orthotopic mouse hepatocellular carcinoma

This study examines inhibiting galectin 1 (Gal1) as a treatment option for hepatocellular carcinoma (HCC). Gal1 has immunosuppressive and cancer-promoting roles. Our data showed that Gal1 was highly expressed in human and mouse HCC. The levels of Gal1 positively correlated with the stages of human HCC and negatively with survival. The roles of Gal1 in HCC were studied using overexpression (OE) or silencing using Igals1 siRNA delivered by AAV9. Prior to HCC initiation induced by RAS and AKT mutations, lgals1-OE and silencing had opposite impacts on tumor load. The treatment effect of lgals1 siRNA was further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9% or even 42% of the body weight. Comparing spatial transcriptomic profiles of Gal1 silenced and OE HCC, inhibiting matrix formation and recognition of foreign antigen in CD45+ cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 silencing. Within the tumors, silencing Gal1 inhibited translational initiation, elongation, and termination. Furthermore, Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor, and the anti-HCC effect of lgals1 siRNA was CD8-dependent. Overall, Gal1 silencing has a promising potential for HCC treatment.