Untreated Hepatocellular Carcinoma Research Articles

Proton Beam Radiotherapy as a Curative Alternative to Radiofrequency Ablation for Newly Diagnosed Hepatocellular Carcinoma.

This study aimed to compare the oncological outcomes of proton beam radiotherapy (PBT) with those of radiofrequency ablation (RFA) for newly diagnosed hepatocellular carcinoma (HCC). This study included 323 patients who underwent PBT (n=40) or RFA (n=283) as a curative treatment for previously untreated HCC between October 2016 and June 2021. The primary endpoints were local progression and toxicity. The median follow-up was 3.4 years (range=1.1-5.7 years). In terms of portal vein tumor thrombosis, tumor size, alpha-fetoprotein, and prothrombin-induced by vitamin K absence-II, the PBT group had significantly more severe tumor burdens than those of the RFA group (p<0.0001, p<0.0001, p=0.0004, and p<0.0001, respectively). No significant difference was observed in cumulative local progression rate (10.4% in PBT vs. 7.8% in RFA at 3-years, p=0.895). Grade 3 or higher toxicity was reported in only one patient (0.4%) after RFA. Multivariable analysis demonstrated that treatment modality was not a significant prognostic factor for local progression (hazard ratio=1.05; 95% confidence interval=0.32-3.48; p=0.934). PBT demonstrated comparable local control with acceptable toxicity to RFA in newly diagnosed HCC. Therefore, PBT may be a valid alternative.

In Vitro Lactic Acid Bacteria Anti-Hepatitis B Virus (HBV) Effect and Modulation of the Intestinal Microbiota in Fecal Cultures from HBV-Associated Hepatocellular Carcinoma Patients.

Hepatocellular carcinoma (HCC), being ranked as the top fifth most prevalent cancer globally, poses a significant health challenge, with a considerable mortality rate. Hepatitis B virus (HBV) infection stands as the primary factor contributing to HCC, presenting substantial challenges in its treatment. This study aimed to identify lactic acid bacteria (LAB) with anti-HBV properties and evaluate their impact on the intestinal flora in HBV-associated HCC. Initially, two LAB strains, Levilactobacillus brevis SR52-2 (L. brevis SR52-2) and LeviLactobacillus delbrueckii subsp. bulgaicus Q80 (L. delbrueckii Q80), exhibiting anti-HBV effects, were screened in vitro from a pool of 498 LAB strains through cell experiments, with extracellular expression levels of 0.58 ± 0.05 and 0.65 ± 0.03, respectively. These strains exhibited the capability of inhibiting the expression of HBeAg and HBsAg. Subsequent in vitro fermentation, conducted under simulated anaerobic conditions mimicking the colon environment, revealed a decrease in pH levels in both the health control (HC) and HCC groups influenced by LAB, with a more pronounced effect observed in the HC group. Additionally, the density of total short-chain fatty acids (SCFAs) significantly increased (p < 0.05) in the HCC group. Analysis of 16S rRNA highlighted differences in the gut microbiota (GM) community structure in cultures treated with L. brevis SR52-2 and L. delbrueckii Q80. Fecal microflora in normal samples exhibited greater diversity compared to HBV-HCC samples. The HCC group treated with LAB showed a significant increase in the abundance of the phyla Firmicutes, Bacteroidetes and Actinobacteria, while Proteobacteria significantly decreased compared to the untreated HCC group after 48 h. In conclusion, the findings indicate that LAB, specifically L. brevis SR52-2 and L. delbrueckii Q80, possessing antiviral properties, contribute to an improvement in gastrointestinal health.

81 - Rapid progression of untreated hepatocellular carcinoma

81 - Rapid progression of untreated hepatocellular carcinoma

Ezetimibe Induces Paraptosis through Niemann-Pick C1-like 1 Inhibition of Mammalian-Target-of-Rapamycin Signaling in Hepatocellular Carcinoma Cells.

Currently, hepatocellular carcinoma (HCC) is characterized by its unfavorable prognosis and resistance to conventional chemotherapy and radiotherapy. Drug repositioning, an approach aimed at identifying novel therapeutic applications for existing drugs, presents a cost-effective strategy for developing new anticancer agents. We explored the anticancer properties of Ezetimibe, a widely used oral lipid-lowering drug, in the context of HCC. Our findings demonstrate that Ezetimibe effectively suppresses HCC cell proliferation through paraptosis, an apoptotic-independent cell death pathway. The examination of HCC cells lines treated with Ezetimibe using light microscopy and transmission electron microscopy (TEM) showed cytoplasmic vacuolation in the perinuclear region. Notably, the nuclear membrane remained intact in both Ezetimibe-treated and untreated HCC cell lines. Probe staining assays confirmed that the cytoplasmic vacuoles originated from dilated endoplasmic reticulum (ER) compartments rather than mitochondria. Furthermore, a dose-dependent accumulation of reactive oxygen species (ROS) was observed in Ezetimibe-treated HCC cell lines. Co-treatment with the general antioxidant NAC attenuated vacuolation and improved cell viability in Ezetimibe-treated HCC cells. Moreover, Ezetimibe induced paraptosis through proteasome activity inhibition and initiation of the unfolded protein response (UPR) in HCC cell lines. In our in vivo experiment, Ezetimibe significantly impeded the growth of HCC tumors. Furthermore, when combined with Sorafenib, Ezetimibe exhibited a synergistic antitumor effect on HCC cell lines. Mechanistically, Ezetimibe induced paraptosis by targeting NPC1L1 to inhibit the PI3K/AKT/mTOR signaling pathway. In conclusion, our study highlights the potential of Ezetimibe as an anticancer agent by triggering paraptosis in HCC cells.

Rictor mediates p53 deactivation to facilitate the malignant transformation of hepatocytes and promote hepatocarcinogenesis

BackgroundMutations in TP53 gene is considered a main driver of hepatocellular carcinoma (HCC). While TP53 mutations are the leading cause of p53 dysfunction, their occurrence rates may drop to approximately 10% in cohorts without hepatitis B virus and aflatoxin exposure. This observation suggests that the deactivation of wild-type p53 (p53wt) may be a critical factor in the majority of HCC cases. However, the mechanism undermining p53wt activity in the liver remains unclear.MethodsMicroarray analysis and luciferase assay were utilized to confirm target associations. Gain- and/or loss-of-function methods were employed to assess alterations in signaling pathways. Protein interactions were analyzed by molecular immunological methods and further visualized by confocal microscopy. Bioinformatic analysis was performed to analyze clinical significance. Tumor xenograft nude mice were used to validate the findings in vivo.ResultsOur study highlights the oncogenic role of Rictor, a key component of the mammalian target of rapamycin complex 2 (mTORC2), in hepatocytes. Rictor exerts its oncogenic function by binding to p53wt and subsequently blocking p53wt activity based on p53 status, requiring the involvement of mTOR. Moreover, we observed a dynamic nucleocytoplasmic distribution pattern of Rictor, characterized by its translocation from the nucleus (in precancerous lesions) to the cytoplasm (in HCCs) during malignant transformation. Notably, Rictor is directly targeted by the liver-enriched microRNA miR-192, and the disruption of the miR-192-Rictor-p53-miR-192 signaling axis was consistently observed in both human and rat HCC models. Clinical analysis associated lower miR-192/higher Rictor with shorter overall survival and more advanced clinical stages (P < 0.05). In mice, xenograft tumors overexpressing miR-192 exhibited lower Rictor expression levels, leading to higher p53 activity, and these tumors displayed slower growth compared to untreated HCC cells.ConclusionsRictor dynamically shuttles between the nucleus and cytoplasm during HCC development. Its pivotal oncogenic role involves binding and inhibiting p53wt activity within the nucleus in early hepatocarcinogenesis. Targeting Rictor presents a promising strategy for HCC based on p53 status.

Multicenter Retrospective Study of Stereotactic Body Radiotherapy for Patients with Previously Untreated Initial Small Hepatocellular Carcinoma.

The effectiveness of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has been shown in many studies and its therapeutic effect is similar to radiofrequency ablation (RFA). However, many of these studies were done in combination with transcatheter chemoembolization (TACE), for recurrent HCC, or on a small scale. To better understand the specific outcomes of SBRT for HCC, we conducted a multicenter retrospective analysis of SBRT for previously untreated initial HCC at Japanese Society of Clinical Oncology (JCOG) member hospitals. Patientswho underwent SBRT for HCC at JCOG member hospitals between July 2013 and December 2017 and met the following eligibility criteria were included: (1) initial HCC; (2) ≤ 3 nodules, ≤ 5 cm in diameter; (3) a Child-Pugh (CP) score of A or B; and (4) unsuitability for or refusal of standard treatment, such as surgery, transplantation, RFA and TACE. We evaluated the overall survival (OS), recurrence-free survival (RFS) which was defined as the first instance of intra-hepatic recurrence after SBRT, disease-specific survival (DSS) using Kaplan-Meier analysis. Using Grey's test, patients who died of other diseases were analyzed as competing risks to estimate the cumulative incidence of local recurrence (CLR). Adverse events directly related to SBRT also analyzed using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Seventy-three patients with 79 lesions from 14 hospitals were analyzed. The median age was 77 years (range; 50-89 years), and the median tumor size was 23 mm (range; 6-50 mm). The median radiation dose was 40 Gy (range; 35-60 Gy) in five fractions (range; 4-8). The median follow-up period was 45 months (range; 0-103 months). There were three cases where follow-up was not possible due to unexpected events unrelated to SBRT, while the remaining 70 patients were successfully followed for at least six months. The 2 and 3year OS, RFS, DSS, and CLR rates were 84.3% (95% CI: 75.8-92.8%) and 69.9% (95% CI: 58.7-81%), 67.5% (95% CI: 56.0-79.0%) and 57.9% (95% CI: 45.2-70.5%), 95.1% (95% CI:89.7-100%)/87.6% (95% CI:78.8-96.3%), and 11.4% (95% CI: 5.3-20.0%) and 20.0% (95% CI: 11.2-30.5%), respectively. Four cases (5.5%) of adverse events of grade 3 or higher were reported: one case of grade 3 laboratory toxicities, one case of grade 3 liver failure, one case of grade 3 portal tumor thrombosis, and one case of grade 4 duodenal ulcer. No grade 5 toxicities were observed. The results of our study demonstrate that SBRT for HCC is highly effective in achieving local control and is safe to administer. In addition, survival outcomes are favorable. SBRT is a promising treatment modality, especially for small HCCs for that is not suitable for standard treatment.

A nationwide study on the current treatment status and natural prognosis of hepatocellular carcinoma in elderly

The aim of this study was to identify the treatment status and natural prognosis of hepatocellular carcinoma (HCC) patients aged 65 years or older in Korea. We analyzed 3,492 patients’ data from the liver cancer stage of the Central Cancer Registry of National Cancer Center. The most common etiology of HCC was hepatitis B (32.7%), followed by hepatitis C. 2624 patients (69.2%) received first-line active treatment for HCC. The most frequently selected treatment was transarterial chemoembolization (TACE), followed by surgical resection and radiofrequency ablation (RFA). The proportion of patients receiving supportive care increased with age. Second-line treatment was performed in only 36.7% of cases, with all others choosing supportive care. Among the various treatments, liver transplantation was found to have the greatest effect in reducing the risk of death (HR [hazard ratio] 0.164, 95% CI [confidence interval] 0.061–0.444), followed by resection, RFA, radioembolization, and TACE. A similar pattern was observed when sub-analyzing the age group over 75 years old. The median survival for untreated HCC in Barcelona Clinic Liver Cancer stage 0/A/B/C/D was 3.7 years, 2.3 years, 7.9 months, 3.9 months, and 2.9 months, respectively. This study highlights the current status of elderly patients with HCC in Korea. While the proportion of patients receiving supportive care is high among the elderly, effective treatment can improve their survival rate.

External validation of subclassification system and progression pattern analysis in hepatocelluar carcinoma with macroscopic vascular invasion

Background and purposeThe present study aimed to validate the performance of a previously proposed subclassification model to predict prognosis after combined transarterial chemoembolization (TACE) and external beam radiotherapy (RT) for hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) in an independent cohort that received the same first-line treatment for the patients with the similar disease extent characteristics, and analyzed the progression patterns as well as progression-free survival (PFS). Materials and methodsThis study was conducted using prospectively collected data from the XXXXX HCC registry for newly diagnosed, previously untreated HCC between 2005 and 2018. Finally, 417 patients who satisfied the eligibility criteria were included and analyzed. ResultsThe median PFS and overall survival (OS) were 5.2 and 13.9 months, respectively. Similar to a previous study, subclassification of patients into very low-, low-, intermediate-, and high-risk groups showed a median OS of 98.4, 18.3, 9.7, and 5.8 months, respectively (P < 0.001). Additionally, subclassification of patients into the very low-, low-, intermediate-, and high-risk groups showed median PFS of 18.7, 6.7, 3.3, and 2.3 months, respectively (p < 0.001). Overall, intrahepatic progression was the most common pattern of progression; however, extrahepatic progression was more common in the intermediate- and high-risk groups. ConclusionThe previously proposed subclassification model was successfully validated in an independent cohort. Treatment modification should be considered in the intermediate- and high-risk patient groups because of their frequent extrahepatic as well as intrahepatic progressions after combined TACE and RT.

Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial.

This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT). Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n=36) or TACE (n=40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost. Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54-0.86, and 65%, 95% CI, 0.52-0.83 (p=.80), however, median PFS was improved for PBT versus TACE (not reached vs. 12months, p=.002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78-17.9, p=.003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p<.001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT. PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria.

Factors associated with the survival outcomes of patients with untreated hepatocellular carcinoma: An analysis of nationwide data.

In this study, we examined the natural course of untreated hepatocellular carcinoma (HCC) and identified predictors of survival in an area where hepatitis B is the predominant cause of HCC. We identified 1,045 patients with HCC who did not receive HCC treatment and were registered in the Korean Primary Liver Cancer Registry between 2008 and 2014, and were followed-up up to December 2018. Thereafter, we analyzed the clinical characteristics of patients who survived for <12 or ≥12 months. A Cox proportional regression model was used to identify the variables associated with patient survival. The mean age of the untreated patients at HCC diagnosis was 59.6 years, and 52.1% of patients had hepatitis B. Most untreated patients (94.2%) died during the observation period. The median survival times for each Barcelona Clinic Liver Cancer (BCLC) stage were as follows: 31.0 months for stage 0/A (n = 123), 10.0 months for stage B (n = 96), 3.0 months for stage C (n = 599), and 1.0 month for stage D (n = 227). Multivariate Cox regression analysis demonstrated that BCLC stage D (hazard ratio, 4.282; P < 0.001), model for end-stage liver disease (MELD) score ≥10 (HR, 1.484; P < 0.001), and serum alpha-fetoprotein (AFP) level ≥1,000 ng/mL (HR, 1.506; P < 0.001) were associated with poor survival outcomes in patients with untreated HCC. In untreated patients with HCC, advanced stage BCLC, serum AFP level ≥1,000 ng/mL, and MELD score ≥10 were significantly associated with overall survival.

Treatment with a Cholecystokinin Receptor Antagonist, Proglumide, Improves Efficacy of Immune Checkpoint Antibodies in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated deaths worldwide. Treatment with immune checkpoint antibodies has shown promise in advanced HCC, but the response is only 15-20%. We discovered a potential target for the treatment of HCC, the cholecystokinin-B receptor (CCK-BR). This receptor is overexpressed in murine and human HCC and not in normal liver tissue. Mice bearing syngeneic RIL-175 HCC tumors were treated with phosphate buffer saline (PBS; control), proglumide (a CCK-receptor antagonist), an antibody to programmed cell death protein 1 (PD-1Ab), or the combination of proglumide and the PD-1Ab. In vitro, RNA was extracted from untreated or proglumide-treated murine Dt81Hepa1-6 HCC cells and analyzed for expression of fibrosis-associated genes. RNA was also extracted from human HepG2 HCC cells or HepG2 cells treated with proglumide and subjected to RNA sequencing. Results showed that proglumide decreased fibrosis in the tumor microenvironment and increased the number of intratumoral CD8+ T cells in RIL-175 tumors. When proglumide was given in combination with the PD-1Ab, there was a further significant increase in intratumoral CD8+ T cells, improved survival, and alterations in genes regulating tumoral fibrosis and epithelial-to-mesenchymal transition. RNAseq results from human HepG2 HCC cells treated with proglumide showed significant changes in differentially expressed genes involved in tumorigenesis, fibrosis, and the tumor microenvironment. The use of the CCK receptor antagonist may improve efficacy of immune checkpoint antibodies and survival in those with advanced HCC.

Evaluation of Amino Acids Profile as Non-Invasive Biomarkers of Hepatocellular Carcinoma in Egyptians.

Hepatocellular carcinoma (HCC) is the most dangerous complication of chronic liver disease. It is a multifactorial complicated disease. Hepatitis C and hepatitis B viruses (HCV and HBV, respectively) represent the main causes of HCC in Egypt. Early diagnosis is very important to aid in early intervention. The goal of this research is to evaluate the metabolic role of different amino acids as non-invasive biomarkers over the course of HCC. This study included 302 participants with 97 diagnosed, untreated HCC patients, 81 chronic HCV patients, 56 chronic HBV patients, 18 co-infected patients, and a control group of 50 normal age and gender-matched individuals. All participants provided complete medical histories and underwent complete clinical examinations, abdominal ultrasonography and/or computed tomography, routine laboratory investigations, estimation of serum α-fetoprotein, and determination of amino acid levels using ultra-performance liquid chromatography (UPLC MS/MS). This work revealed a decline in branched chain amino acids (BCAA) and increase in aromatic amino acids (AAA) among infected groups (HCC, HBV, HCV, and co-infected patients) compared to control subjects and a marked change in Fisher's and the BCAAs/tyrosine molar concentration ratios (BTR) between controls and infected groups. Different amino acids could be used as non-invasive markers to discriminate and follow chronic hepatitis patients to predict the course of HCC.

Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients

ObjectiveImmune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed...

Attenuation of diethylnitrosamine-induced hepatocellular carcinoma in a rat model by combination therapy of diacerein and gold nanoparticles: a histopathological and immunohistochemical study

ABSTRACT The purpose of this study was to investigate the effect of combined therapy of diacerein and gold nanoparticles (AuNP) on diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in a rat model. Normal healthy and DEN-induced (HCC) rats were divided into five groups. Group I healthy rats served as normal control, Group II untreated HCC rats, Group III HCC rats administered diacerein, Group IV HCC rats administered AuNP, and Group V HCC rats administered diacerein and AuNP. All treatments were given once daily for 4 weeks. Liver morphology and necroinflammation in all groups were evaluated using hematoxylin and eosin (H&E), Masson’s trichrome for fibrosis, and immunohistochemistry assays for expression of TNF-α, IL-6, β-catenin, and caspase-3. Liver sections from Group II HCC rats showed loss of lobular architecture, thick fibrous tissue deposition, leukocyte infiltration, degenerated hepatocytes and HCC neoplastic nodules surrounded by extensive fibrosis. Group II had high expression of TNF-α, IL-6, and β-catenin, and low caspase-3 expression as compared to Group I. HCC rats treated with the combined therapy of diacerein and AuNP (Group V) showed markedly decreased HCC lesions, significant necroinflammation reduction (p ˂ 0.05) and 90% reduction in fibrosis as compared to Group II HCC + diacerein. This combined therapy also reduced (p ˂ 0.05) TNF-α, IL-6, β-catenin expression and increased caspase-3 expression. In conclusion, diacerein combined with AuNP synergistically attenuated the severity of HCC lesions by reducing necroinflammation and fibrosis, decreased TNF-α, IL-6, β-catenin expression, and increased caspase-3 expression for apoptosis.

Antitumor Effect of Zinc Acetate in Hepatocellular Carcinoma Cell Lines via the Induction of Apoptosis.

We aimed to verify antitumor effects of zinc acetate on hepatocellular carcinoma (HCC) in vitro. Five HCC cell lines (HepG2, Hep3B, Huh7, HLE and Alex) were used to evaluate the antitumor effects of zinc acetate. Cell viability was determined by the Cell Counting Kit-8 assay. The cell-cycle alteration was evaluated by a flow cytometric analysis and the detection of cell cycle-related proteins. Apoptosis was determined based on the caspase-cleaved cytokeratin 18 (cCK18) levels. The microRNAs (miRNAs) related to an antitumor effect of zinc acetate were identified using microarrays. Zinc acetate significantly inhibited the proliferation of HCC cells in a dose-dependent manner. The treatment with zinc acetate resulted in significantly increased cCK18 levels in the supernatant and enhanced the expression of heme oxygenase-1 (HO-1) in HCC cells. The flow cytometric analysis revealed an increase of HCC cells in the S and G2/M phases by the administration of zinc acetate, and the expressions of Cdk2 and cyclin E were increased. The miRNA expression profile of the HCC cells treated with zinc acetate was extremely different from that of the untreated HCC cells. These results suggest that the zinc acetate supplementation induces the apoptosis of HCC cells, but does not affect the cell cycle progression. Upregulation of HO-1 and the alteration of miRNAs' profile may be involved in antitumor effects of zinc acetate in HCC cells.

ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation

Endoplasmic reticulum (ER) stress is widely involved in the drug resistance of hepatocellular carcinoma (HCC), but the mechanism of ER stress-induced drug resistance involves multiple signaling pathways that cannot be fully explained. Exploring genes associated with ER stress could yield a novel therapeutic target for ER stress-induced drug resistance. By analyzing RNA-sequencing, ATAC-sequencing, and Chip-sequencing data of Tunicamycin (TM)-treated or untreated HCC cells, we found that Rho guanine nucleotide exchange factor 2 (ARHGEF2) is upregulated in HCC cells with ER stress. ARHGEF2 plays an active role in tumor malignant progression. Notwithstanding, no research has been done on the link between ER stress and ARHGEF2. The function of ARHGEF2 as a novel downstream effector of ER stress in the angiogenesis and treatment resistance of HCC was revealed in this work. ARHGEF2 overexpression was linked to malignant development and a poor prognosis in HCC. ER stress stimulates the expression of ARHGEF2 through upregulation of ZNF263. Elevated ARHGEF2 accelerates HCC angiogenesis via the EDN1 pathway, enhances HCC cell proliferation and tumor growth both in vitro and in vivo, and contributes to ER stress-related treatment resistance. HCC cell growth was more inhibited when ARHGEF2 knockdown was paired with targeted medicines. Collectively, we uncovered a previously hidden mechanism where ARHGEF2/EDN1 pathway promotes angiogenesis and participates in ER stress-related drug resistance in HCC.

AdvanTIG-206: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (BGB-A1217; OCI) plus anti-programmed cell death protein-1 (PD-1) mAb tislelizumab (TIS) plus BAT1706 versus TIS plus BAT1706 as first-line (1L) treatment for advanced hepatocellular carcinoma (HCC).

TPS4172 Background: Treatment with PD-1/programmed death ligand 1 (PD-L1) inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated HCC. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T cells and natural killer cells in multiple solid tumors. OCI is a novel, humanized mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells. TIS is an anti-PD-1 mAb that has demonstrated clinical activity in patients with previously treated, unresectable HCC (NCT03419897). BAT1706 is a similar biological product to the anti-angiogenic agent bevacizumab. OCI combined with TIS and BAT1706 could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC. Methods: AdvanTIG-206 is a Phase 2, randomized, open-label clinical study (NCT04948697). Patients aged ≥ 18 years with histologically confirmed advanced HCC that is not amenable to a curative treatment approach are eligible. Patients must have a Child-Pugh A score, ECOG PS ≤ 1, and have received no prior systemic therapy for HCC. Approximately 90 patients will be randomized 2:1 to OCI 900 mg combined with TIS 200 mg plus BAT1706 15 mg/kg (Arm A) or TIS 200 mg plus BAT1706 15 mg/kg (Arm B), all administered intravenously (once every 3 weeks [Q3W]). The primary endpoint is objective response rate as assessed by the investigator (RECIST v1.1). Radiological assessment of tumor response status will be performed Q6W for the first 48 weeks and Q12W thereafter. Secondary endpoints include duration of response, time to response, disease control rate, clinical benefit rate, and progression-free survival (all by investigator’s assessment), overall survival, safety, pharmacokinetics, and immunogenicity. Study enrollment is ongoing. Clinical trial information: NCT04948697.

Pembrolizumab monotherapy for previously untreated advanced hepatocellular carcinoma (aHCC): 3-year follow-up of the phase 2 KEYNOTE-224 study.

4109 Background: Pembrolizumab monotherapy showed durable antitumor activity and a manageable safety profile in patients with sorafenib-treated (cohort 1) and treatment-naive (cohort 2) aHCC in the open-label, phase 2 KEYNOTE-224 (NCT02702414) study. Longer term data from KEYNOTE-224 after ̃3 years of follow-up for patients with treatment-naive aHCC are reported. Methods: Eligible patients in cohort 2 had histologically, cytologically, or radiologically confirmed aHCC, Barcelona Clinic Liver Cancer stage C or B not amenable or refractory to locoregional therapy and not amenable to curative treatment, Child-Pugh A liver function, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and ECOG PS 0 or 1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (̃2 years). Primary end point was ORR assessed per RECIST v1.1 by BICR. Secondary end points included DOR, DCR, TTP, and PFS, all assessed per RECIST v1.1 by BICR, OS, and safety/tolerability. Results: All 51 patients enrolled in cohort 2 received ≥1 dose of pembrolizumab. Median follow-up, defined as the time from first dose to the data cutoff (October 1, 2021), was 35 months (range, 31-37). ORR was 16% (95% CI, 7-29). Median DOR was not reached (NR; range, 3 to 24+ months); 58% of responders were estimated to have a response duration ≥18 months. Best overall response was 8 (16%) PRs, 21 (41%) SDs, and 17 (33%) PDs; no CRs were observed and response was not evaluable for 2 patients (4%) and not assessed for 3 patients (6%). DCR was 57% (95% CI, 42-71). ORR was generally consistent among patients with a viral and nonviral etiology for HCC, although sample sizes were small. The median TTP was 4 months (95% CI, 3-9). Median PFS was 4 months (95% CI, 2-8). Estimated PFS rate at 24 months was 15%. Median OS was 17 months (95% CI, 8-23). Estimated OS rate at 24 months was 34%. No new or unexpected adverse events (AEs) occurred. Treatment-related AEs were reported in 28 patients (55%; grade 3-5, 8 [16%]). Conclusions: Updated results from cohort 2 of the KEYNOTE-224 study continued to demonstrate durable antitumor activity, promising OS, and manageable safety for pembrolizumab monotherapy in patients with aHCC and no prior systemic therapy. These data, together with recent positive results from KEYNOTE-394, underscore the broad applicability of pembrolizumab in patients with aHCC both as monotherapy and in combination with other therapies. Clinical trial information: NCT02702414.

Prognostic impact of serum soluble PD-1 and ADV score for living donor liver transplantation in patients with previously untreated hepatocellular carcinoma

Shin HWANG*, Deok-Bog MOON, Gi-Won SONG, Dong-Hwan JUNG, Kyung Jin LEE, Yun Kyu KIM, Hunji YANG, Da Eun AN, Sion LEE. Ann Hepatobiliary Pancreat Surg 2022;26:S298. https://doi.org/10.14701/ahbps.2022S1.EP-16

The Significance of Systemic Inflammation Markers in Intrahepatic Recurrence of Early-Stage Hepatocellular Carcinoma after Curative Treatment.

Simple SummaryThis retrospective study using the prospectively collected registry data of newly diagnosed, previously untreated hepatocellular carcinoma (HCC) evaluates the significance of systemic inflammatory markers (SIMs) to intrahepatic recurrence (IHR) after curative treatment. Out of 4076 patients who met the inclusion criteria, 52.6% experienced IHR. SIMs, including pre-treatment platelet-to-lymphocyte ratio (PLR), post-treatment changes of neutrophil-to-lymphocyte ratio PLR, and lymphocyte-to-monocyte ratio were significantly associated with the prognosis of early-stage HCC patients who received initial curative treatment. The prognostic significances of SIMs were consistent for IHR-free survival, early and late IHR, and overall survival.Systemic inflammatory markers (SIMs) are known to be associated with carcinogenesis and prognosis of hepatocellular carcinoma (HCC). We evaluated the significance of SIMs in intrahepatic recurrence (IHR) of early-stage HCC after curative treatment. This study was performed using prospectively collected registry data of newly diagnosed, previously untreated HCC between 2005 and 2017 at a single institution. Inclusion criteria were patients with Barcelona Clinic Liver Cancer stage 0 or A, who underwent curative treatment. Pre-treatment and post-treatment values of platelet, neutrophil, lymphocyte, monocyte, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR) were analyzed with previously well-known risk factors of HCC to identify factors associated with IHR-free survival (IHRFS), early IHR, and late IHR. Of 4076 patients, 2142 patients (52.6%) experienced IHR, with early IHR in 1018 patients (25.0%) and late IHR in 1124 patients (27.6%). Pre-treatment platelet count and PLR and post-treatment worsening of NLR, PLR, and LMR were independently associated with IHRFS. Pre-treatment platelet count and post-treatment worsening of NLR, PLR, and LMR were significantly related to both early and late IHR. Pre-treatment values and post-treatment changes in SIMs were significant factors of IHR in early-stage HCC, independent of previously well-known risk factors of HCC.