HCC Patients Research Articles

Identifying disulfidptosis subtypes in hepatocellular carcinoma through machine learning and preliminary exploration of its connection with immunotherapy

BackgroundHepatocellular carcinoma (HCC) is a highly prevalent and deadly cancer, with limited treatment options for advanced-stage patients. Disulfidptosis is a recently identified mechanism of programmed cell death that occurs in SLC7A11 high-expressing cells due to glucose starvation-induced disintegration of the cellular disulfide skeleton. We aimed to explore the potential of disulfidptosis, as a prognostic and therapeutic marker in HCC.MethodsWe classified HCC patients into two disulfidptosis subtypes (C1 and C2) based on the transcriptional profiles of 31 disulfrgs using a non-negative matrix factorization (NMF) algorithm. Further, five genes (NEIL3, MMP1, STC2, ADH4 and CFHR3) were screened by Cox regression analysis and machine learning algorithm to construct a disulfidptosis scoring system (disulfS). Cell proliferation assay, F-actin staining and PBMC co-culture model were used to validate that disulfidptosis occurs in HCC and correlates with immunotherapy response.ResultsOur results suggests that the low disulfidptosis subtype (C2) demonstrated better overall survival (OS) and progression-free survival (PFS) prognosis, along with lower levels of immunosuppressive cell infiltration and activation of the glycine/serine/threonine metabolic pathway. Additionally, the low disulfidptosis group showed better responses to immunotherapy and potential antagonism with sorafenib treatment. As a total survival risk factor, disulfS demonstrated high predictive efficacy in multiple validation cohorts. We demonstrated the presence of disulfidptosis in HCC cells and its possible relevance to immunotherapeutic sensitization.ConclusionThe present study indicates that novel biomarkers related to disulfidptosis may serve as useful clinical diagnostic indicators for liver cancer, enabling the prediction of prognosis and identification of potential treatment targets.Graphical

Stereotactic body radiotherapy (SBRT) combined with transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) versus TACE and TKIs alone for unresectable hepatocellular carcinoma (uHCC) with portal vein tumor thrombus (PVTT): A randomized controlled trial.

4102 Background: TKIs-based systemic therapy is a primary treatment option for uHCC. Clinical studies have established the effectiveness and safety of radiotherapy (RT) in patients with PVTT, who typically have a poor prognosis. Previous research has shown that combining TACE and RT can extend survival in HCC patients with PVTT compared to sorafenib treatment. This study aimed to explore the efficacy and safety of combined local therapy (TACE plus SBRT) and TKIs in HCC patients with PVTT. Methods: This single-center, randomized controlled study enrolled patients aged ≥18 years with HCC and PVTT. Additional eligible criteria included ECOG PS 0-1, Child-Pugh score ≤B7, no extrahepatic metastasis on CT scan, and normal liver volume ≥700cc. Patients were randomly assigned to either the SBRT+TACE+TKIs group (Group A) or the TACE+TKIs group (Group B). SBRT was administered at 35-45 Gy in 5 fractions, 3 fractions per week. TKIs (sorafenib 0.4g bid; donafenib 0.2g bid; or lenvatinib 8mg/12mg qd, depending on body weight) were paused during the perioperative period of TACE (up to 4 times). The primary endpoint was the 6-month progression-free survival (PFS) rate, with secondary endpoints including objective response rate (ORR), overall survival (OS), disease control rate (DCR) and treatment-related adverse events (TRAEs). Treatment response was evaluated using mRECIST. Results: A total of 90 patients with uHCC were enrolled from June 2019 to October 2023 in this trial, with baseline characteristics presented in the Table. As of January 5th 2024, the median follow-up time was 14.5 months [IQR, 2.43-55]. The 6-month PFS rate was significantly higher in Group A (78%) compared to Group B (36%, P=0.0245). Group A also showed prolonged median PFS (9.75 vs. 4.89 months, HR=1.703 [95%CI, 1.045-2.777], P=0.0245) and OS (17.93 vs. 9.61 months, HR=1.869 [95%CI, 1.059-3.266], P=0.017). Improved ORR was observed in the SBRT group (74.4% vs. 40.5%, P=0.0015). DCR was 81.4% in Group A and 66.7% in Group B ( P=0.1211). The most common grade 3/4 TRAEs were hypertension (Group A: 17.8%, Group B: 13.3%, P=0.5608), ALT elevation (Group A: 26.7%, Group B: 22.2%, P=0.6237), and AST elevation (Group A: 22.2%, Group B: 15.6%, P=0.4191). There was one treatment-related death in Group B due to liver failure. Conclusions: In uHCC patients with PVTT, the combination of SBRT and TACE-TKIs showed significant survival benefit without the identification of any severe safety concerns. Clinical trial information: ChiCTR1900025300. [Table: see text]

A comprehensive analysis of portal vein thrombosis in malignancy.

e24042 Background: Portal vein thrombosis (PVT) is a rare venous thromboembolism, is often linked to cirrhosis, infection, and malignancy. Advancements in imaging have noted an increasing incidence of PVT, particularly in solid cancers. Treating PVT with malignancy is challenging due to lack of data, poor recanalization, and substantial bleeding risk with anticoagulation. This study aims to enhance understanding of malignancy-related PVT, anticoagulation trends, and assess prognosis. Methods: We conducted a multicenter, observational retrospective analysis of patients diagnosed with PVT (ICD code 452,181) from 2013 to 2023. Inclusion criteria: age > 18 and acute portal vein thrombosis. Exclusion criteria: presence of tumor thrombosis, and thrombus in other splanchnic vessels (e.g., mesenteric vein). Data entry was performed on a study-specific REDCap database. Patients with concomitant malignancy were identified and further assessed for cancer type, anticoagulation use, bleeding outcomes, and prognosis. Proportion analysis using Z test was done to compare outcomes between groups. Results: In our study of 583 patients, 236 (40.48%) had concurrent malignancy, predominantly male (144, 61.01%),and female (92, 38.98%) mean age 65. Common malignancies included HCC (28.38%), pancreatic (24.15%), colo-rectal (11.86%), cholangiocarcinoma (8.47%), myeloproliferative neoplasm, prostate, and gynecological cancers each (2.96%), and other cancers (18.22%). 41% had metastasis to liver. Cirrhosis was present in 40%, particularly in HCC patients (89%). Of the total,163 (69%) received anticoagulation; 26.38% showed improvement or re-canalization within a year. The primary anticoagulants were Direct Oral Anticoagulants (DOACs) (57%), with an increasing trend in the last 5 years (69.44%), followed by Low-Molecular-Weight Heparin (LMWH) (19%) and warfarin (14%). Most patients initiated on heparin infusion (9.81%) transitioned to hospice care. Bleeding events in patients receiving DOAC versus LMWH + Warfarin were 36.55% and 33.33%, respectively (p = 0.69). Patients without anticoagulation demonstrated a higher one-year mortality compared to those with anticoagulation (83.56% vs. 63.19%, p value < 0.05). Overall,malignancy-associated PVT had a significantly higher case fatality rate than non-malignancy cases, regardless of anticoagulation (81.35% vs. 32.85%, p < 0.05). Conclusions: There is a significant association between malignancy and PVT, particularly in HCC and pancreatic cancer. The increased mortality in malignancy-related PVT emphasizes the critical role of anticoagulation, which has demonstrated efficacy in improving outcomes, including one-year mortality. Although DOACs have seen increased use in the last 5 years, bleeding events have remained comparable. Further research is warranted to explore patient selection for optimal anticoagulation strategies.

Utilization of personalized tumor-specific methylation haplotypes of circulating DNA to monitor minimal residual disease in patients with hepatocellular carcinoma undergoing curative resection.

e16245 Background: Minimal residual disease (MRD) is considered an essential factor leading to early relapse after radical surgery, which is challenging to be detected by conventional imaging. The majority of MRD studies in HCC are based on mutation detection. Simultaneously, in certain cancers such as lung and colorectal cancers, the use of methylation detection for MRD has been demonstrated to possess significant detection capabilities. In this study, we present a personalized methylation haplotype (MHP) method for MRD detection in HCC patients underwent curative resection. Methods: Tumor and paracancerous tissue samples were obtained from HCC patients undergoing surgical resections. WBC and plasma samples (T0) were collected before surgery, while plasma samples (T1) were collected in one month after surgery, and subsequent follow-up plasma samples were obtained every three months. All samples were tested using the GutSeer Panel. A personalized tumor-informed MRD detection approach, named TORNADO (Tumor-infORmed DNAm hAplotype DetectiOn), was then developed. Individual seed MHPs were pinpointed based on their presence in cancer tissue or plasma samples collected before surgery (T0 plasma), excluding those in para-cancer tissue and blood cells. The relapse risk score was determined by assessing the proportion of these MHPs detectable in follow-up evaluations. Results: We enrolled 39 early-stage HCC patients who have undergone surgical resections. All the patients have completed at least one year of regular clinical follow-up. Among them, 13 out of 39 patients (33.3%) were identified as MRD-positive based on predictions from T1. Of the MRD-positive patients, 6 experienced tumor relapse. In contrast, only 7.7% relapses were observed among the remaining 26 MRD-negative patients. When considering the T1 and T2 MRD cumulative risk score, 53.8% (21/39) of patients were classified as MRD-positive, and none of the MRD-negative patients experienced relapse. Regardless of whether based on T1 plasma alone or cumulative results, recurrence-free survival (RFS) was significantly correlated with MRD status. Kaplan-Meier analysis demonstrated that MRD-positive patients had significantly poorer RFS (p-value < 0.05). Cox regression analysis further revealed that MRD status was a significant variable for predicting recurrence-free survival (HR=16.00, 95% CI 2-130, P=0.009). Conclusions: The MRD status detected byTORNADOmethod emerged as a significant prognostic indicator for disease relapse in early-stage HCC patients undergoing curative resection, underscoring the clinical relevance of MHP-based MRD detection guided by tumor information. These discoveries pave the way for the development of effective postoperative cancer surveillance strategies specifically tailored for early-stage liver cancer.

Study on the mechanism of quercetin in Sini Decoction Plus Ginseng Soup to inhibit liver cancer and HBV virus replication through CDK1.

To explore the anti-tumor and anti-virus key active ingredients of Sini Decoction Plus Ginseng Soup (SNRS) and their mechanisms. The main ingredients of SNRS were analyzed by network pharmacology, and quercetin was identified as the key active ingredient. Then, we obtained the targets of quercetin by using Drugbank, PharmMapper, and SwissTargetPrediction databases. Then, the targets of HBV-related hepatocellular carcinoma (HBV-related HCC) were obtained by using Genecards database. In addition, using the gene expression profiles of HBV-related HCC patients in GEO database and the genes with the greatest survival difference in GEPIA 2 database identified the potential targets of quercetin. In addition, the mechanism of potential genes was studied through GO, KEGG analysis, and PPI network. Using AUC and survival analysis to evaluate the diagnostic and prognostic value of cyclin-dependent kinase 1 (CDK1) and CCNB1. Finally, the effects of quercetin on proliferation of Hep3B and HepG2215 cells and the level of CDK1 and CCNB1 were verified invitro. ELISA was used to measure the expression levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) after the intervention by quercetin for 24 h and 48 h in HepG2215 cell. The first 10 key ingredients of SNRS were identified, and quercetin was the most key ingredient. The 101 potential quercetin targets were identified for the treatment of HBV-related HCC. GO and KEGG showed that 101 potential target enrichment in cancer and cell cycle regulation. By Venn analysis, CDK1 and CCNB1 were intersection targets, which could be used as potential targets for the action of quercetin on HBV-related HCC. Moreover, the expression of CDK1 and CCNB1 was highly expressed in the high-risk group, while the OS rate was low. The 1-year, 3-year and 5-year area under the curve (AUC) curves of CDK1 and CCNB1 were 0.724, 0.676, 0.622 and 0.745, 0.678, 0.634, respectively. Moreover, experimental results also showed that quercetin inhibited cell proliferation and reduced CDK1 expression in Hep3B and HepG2215 cells. The expressions of HBsAg and HBeAg in HepG2215 cell supernatant and cell gradually decreased with the increase of intervention time of quercetin and CDK1 inhibitor. Quercetin is a key ingredient of anti-HBV-related HCC activity and inhibits HBV replication in SNRS by inhibiting CDK1.

189P The synergic effect of metformin and atezolizumab/bevacizumab in diabetic HCC patients: A retrospective study from ARTE multicentric Italian dataset

189P The synergic effect of metformin and atezolizumab/bevacizumab in diabetic HCC patients: A retrospective study from ARTE multicentric Italian dataset

Analysis of proteomics based on LC-MS detection on the efficacy of immunocombined therapy for hepatocellular carcinoma.

e14549 Background: Combined immunotherapy has become the preferred treatment for HCC. However, it faces challenges: possible serious adverse reactions, the low objective response rate, and the median overall survival is about 20 months, which is far from meeting the clinical treatment needs. There is still a lack of effective predictive biomarkers in clinical practice to screen the dominant population of combined immunotherapy. The purpose of this study is to use LC-MS to screen and identify differential metabolites between patients with different efficacy to help screen the dominant population of clinical immunotherapy. Methods: 38 HCC patients were included who were treated in the Tumor Center of the First Hospital of Jilin University from June 2020 to March 2022 and received combined immunotherapy. Sample collection and follow· -up, and collect basic clinical data. The enrolled patients underwent enhanced CT examination every 3 treatment cycles, and the efficacy of the patients was evaluated according to the solid tumor efficacy evaluation standard 1.1 (RECIST V1.1). The serum of patients before treatment was detected by LC-MS, and the difference of mass spectrometry data between patients with different curative effects was compared, and the differential metabolites were explored by proteomics analysis. Results: The best of response was partial response in 7 patients (22.6 %), stable disease in 6 patients, and progressive disease in 18 patients (58.1 %). Based on LC-MS proteomics analysis, differential metabolites between patients with different therapeutic effects were screened and identified, namely Q9Y275, Q56UQ5, P13611, and P30530 (P < 0.05). The relative abundance of Q9Y275, Q56UQ5, P13611 and P30530 in the disease control rate group was higher than that in the PD group. Conclusions: Based on LC-MS proteomics analysis, four types of differential metabolites between different populations of PLC patients receiving combined immunotherapy were screened and identified, namely Q9Y275, Q56UQ5, P13611 and P30530.

The efficacy and safety of donafenib combined with transcatheter arterial chemoembolization and anti-PD-1 antibodies as first-line therapy for hepatocellular carcinoma: A retrospective study.

e16178 Background: In Phase III study (ZGDH3), donafenib showed the survival benefit and better safety compared with sorafenib as the first-line treatment for uHCC. Recently, combination therapies have shown favorable results in patients with HCC. Some studies have shown that molecular targeted drugs combined with anti-PD1 antibodies and TACE exhibit improved anti-tumor efficacy compared with monotherapy. This study aimed to evaluate the efficacy and safety of the combination therapy of donafenib,anti-PD-1 antibodies and TACE as first-line treatments for HCC patients in the real world. Methods: This single-center retrospective study involved patients with histopathologically/cytologically or clinically confirmed HCC at Zhejiang Cancer Hospital between July 2021 and June 2023. Eligible patients were treated with donafenib (100 mg po bid) combined with TACE and anti-PD-1 antibodies until the point of disease progression, death, or intolerable toxicity. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) datas of patients were collected and analyzed according to the mRECIST, and the incidence of adverse events (AEs) was evaluated using CTCAE 5.0. Results: There were 34 patients in this study (Table). The median age was 64 years (IQR: 57, 69) at the data cut-off in January 2024, with 94.1% of the population being male and 82.4% having HBV infection. Of these patients, 5(14.7%) were classed as BCLC stage A, 11(32.3%) were classed as BCLC stage B, and 18 (52.9%) were BCLC stage C. The median PFS was 7.9 months (95%CI, 5.6–NA), and median OS was not reached, respectively, the 12-month PFS and OS rates were 46.9% (95%CI: 16.8%-72.5%) and 96.9% (95%CI: 79.8%-99.6%). The ORR and DCR for all patients were 73.5% and 97.1%, respectively, based on both mRECIST (CR 3 [8.8%], PR 22 [64.7%], SD 8 [23.5%]). The surgical conversion rate was 26.5%. Treatment-related adverse events (TRAE) of any grade were observed by 18 patients (52.9%), of which 4 patients (11.8%) had grade 3 TRAE. No grade 4 or 5 TRAE was observed. Conclusions: The study indicated that donafenib combined with TACE and anti PD-1 antibodies exhibited encouraging efficacy and favorable safety profile in patients with HCC. [Table: see text]

Precision medicine for papillary thyroid carcinoma (PTC) variants: A machine learning approach to prognosis and treatment guidance.

e18072 Background: PTC is a common endocrine cancer with a good prognosis, but aggressive subtypes, such as Hürthle cell (HCC) and columnar cell variants (CCV), pose challenges due to their higher recurrence and metastasis rates. To provide personalized care, we applied machine learning to evaluate the treatment effectiveness and develop precise prognostic models for PTC variants. Methods: The Surveillance, Epidemiology, and End Results (SEER) database provided the data used for this study’s analysis (2000–2019). Patients who met any of the following criteria were excluded: diagnosis not confirmed by histology, previous history of cancer or with other concurrent malignancies, and unknown data. To identify prognostic variables, we conducted Cox regression analysis and constructed prognostic models using machine learning (ML) algorithms to predict the 5-year survival. Patient records were randomly divided into training (70 %) and validation (30 %) sets. A validation method incorporating the area under the curve (AUC) of the receiver operating characteristic curve was used to validate the accuracy and reliability of the ML models. Results: The study population comprised 3690 patients. Among them 3180 patients with CCV and 510 patients with HCC, respectively. Most patients (62.8%) were 45 years or older, with a median age of 52 years. A total of 56.9% of patients had a tumor size greater than 2 cm, with a median tumor size of 3.1 cm. The largest racial group was white, comprising 83.8% of the cases, and 11.8% of the cases were Asian. Most cases were regional (53.4%, n=1969), followed by localized (38.3%, n= 1413). Multivariate Cox regression analysis revealed that N1 negatively affected the survival of HCC patients. CCV has a favorable prognosis after surgery, radiotherapy, or total thyroidectomy. Poor prognosis in CCV is associated with black race, large tumor size, and T4 stage. Improved survival in the localized/regional stage and decreased survival with male sex, older age, distant metastasis, and advanced AJCC stage in both PTC subtypes. ML models revealed that the random forest classifier (RFC) and K-Nearest Neighbors (KNN) accurately predicted outcomes, followed by Logistic Regression (LR) models. The highest contributing factors were AJCC staging, tumor size, and T aspect of TNM staging. Conclusions: Our study offers a method for evaluating and treating patients with PTC variants. The machine learning model that we created serves as a useful and personalized resource to aid in clinical decision-making processes.[Table: see text]

Plasma growth hormone as a prognostic biomarker to durvalumab and tremelimumab in patients with advanced hepatocellular carcinoma.

e16161 Background: In this study, we explored the potential of plasma growth hormone (GH) as a prognostic biomarker in patients with advanced HCC treated with durvalumab plus tremelimumab (D+T). Methods: In this study, we included 24 patients with advanced HCC who received D+T at MD Anderson Cancer Center between 2022 and 2023. Plasma GH levels were measured from prospectively collected blood samples from 16 of the 24 patients and were correlated with progression-free survival (PFS) and overall survival (OS). The cutoff for normal GH levels in women and men was defined as ≤3.7 μg/L and ≤0.9 μg/L, respectively. The Kaplan-Meier method was employed to compute the median OS and PFS, while the Log-rank test was applied to compare the survival outcomes between the GH-high and GH-low groups. Results: Twenty-four patients were included in this analysis, four female and twenty male, with a median age of 66.5 years. Of these 24 patients, 16 had GH levels available for analysis. At the time of the analysis, the 6-month OS rate was 100% among GH-low patients (6 patients) and 30% among GH-high patients (10 patients). OS was significantly longer in GH-low patients (not evaluable) compared to GH-high patients (3.94 months) (p = 0.030). PFS was also significantly longer in GH-low patients (not evaluable) compared to the GH-high patients (1.87 months) (p = 0.036). Conclusions: Plasma GH is a prognostic biomarker in patients with advanced HCC treated with D+T. Given the relatively small patient cohort size, this finding should be further validated in larger randomized clinical trials in advanced HCC patients.

Low protein expression of LZTR1 in hepatocellular carcinoma triggers tumorigenesis via activating the RAS/RAF/MEK/ERK signaling

LZTR1 is a substrate specific adaptor for E3 ligase involved in the ubiquitination and degradation of RAS GTPases, which inhibits the RAS/RAF/MEK/ERK signaling to suppress the pathogenesis of Noonan syndrome and glioblastoma. However, it's still unknown whether LZTR1 destabilizes RAS GTPases to suppress HCC progression by inhibiting these signaling pathway. Lenvatinib is the first-line drug for the treatment of advanced HCC, however, it has high drug resistance. To explore the roles of LZTR1 in HCC progression and the underlying mechanisms of lenvatinib resistance, techniques such as bioinformatics analysis, immunohistochemical staining, RT-qPCR, Western blot, cell functional experiments, small interfering RNA transfection and cycloheximide chase assay were applied in our study. Among these, bioinformatics analysis and immunohistochemical staining results indicated that LZTR1 protein was aberrantly expressed at low levels in HCC tissues, and low protein expression of LZTR1 was associated with poor prognosis of HCC patients. In vitro functional experiments confirmed that low expression of LZTR1 promoted HCC cell proliferation and migration via the aberrant activation of the RAS/RAF/MEK/ERK signaling due to the dysregulation of LZTR1-induced KRAS ubiquitination and degradation. Transwell assays revealed that blocking of LZTR1-mediated KRAS degradation could induce lenvatinib resistance in HCC cells. In conclusion, our study revealed that LZTR1 knockdown promoted HCC cell proliferation and migration, and induced lenvatinib resistance via activating the RAS/RAF/MEK/ERK signaling, which may provide new ideas for HCC treatment.

Neoadjuvant tislelizumab combined with lenvatinib plus transcatheter arterial chemoembolization in resectable hepatocellular carcinoma with high-risk of recurrence: A prospective, single-arm, phase II trial.

e16242 Background: Currently, more than 55% of liver cancer patients have recurrence within 1 years after radical surgery. However,there is no standard treatment of neoadjuvant therapy for resectable HCC patients. This study aimed to explore the efficacy and safety of the triple therapy [Tislelizumab combined with lenvatinib plus transcatheter arterial chemoembolization (TACE)] as neoadjuvant therapy in patients with resectable HCC with high-risk of recurrence. Methods: This prospective, single-arm, phase II trial (ChiCTR2200059574) enrolled patients with primary resectable HCC who had not received prior anti-tumor therapy. The recurrence rate was predicted to be > 50% according to the risk predictor ( http://www.asapcalculate.top/Cal2_ch.html ) of early recurrence before surgery. TACE will be performed once on Day 1. Tislelizumab (an anti-PD-1 antibody, 200 mg) intravenously once every 3 weeks and lenvatinib (body weight ≥ 60 kg, 12 mg;< 60 kg, 8 mg) orally daily was initiated 3 days after TACE treatment. Surgery was performed after two cycles of neoadjuvant treatment. After 4-6 weeks of surgery, patients continued to receive tislelizumab and lenvatinib for 6 months to 1 year. Primary endpoint was adverse events (AE) and major pathological reactions. Secondary endpoints were objective response rate (ORR) by mRECIST, relapse-free survival (RFS) and overall survival (OS). Results: From April 2022 to August 2023, 19 patients (median age, 55 years) were enrolled, all Child-Pugh A and ECOG PS 0, mostly males (89.5%) and HBV infection (94.7%). According to mRECIST, the ORR was 94.7% (18/19, CR 2, PR 16), and the DCR was 94.7% too (18/19, CR 2, PR 16, SD 0). In 19 patients, 14 patients had received surgical treatment (R0 resection rates were 100%), 12 patients (12/14, 85.7%) achieved major pathological reaction (necrosis≥90%), and 2 patients (2/14, 14.3%) achieved complete pathological response. For those patients who did not undergo surgery, 3 of them refused surgery, and 2 patients lost the chance of surgery because of disease progression and high ICG R-15, respectively. At the end of the last follow-up (January 20, 2024), tumor recurrence was detected in 2 patients after surgery. The 12-month RFS rate and OS rate were 80.2%(95% CI: 40.4%-94.8%)and 94.7%(95% CI: 68.1%-99.2%), respectively. Median RFS and OS were not reached. No grade 3 or above AE were observed. Conclusions: Tislelizumab, lenvatinib, and TACE were safe and showed promising efficacy as a neoadjuvant therapy for resectable HCC with high risk of recurrence. Clinical trial information: ChiCTR2200059574.

Efficacy and safety analysis of donafenib combined with transarterial chemoembolization in the treatment of unresectable hepatocellular carcinoma: A prospective, single-arm, single center, phase II clinical study.

e16134 Background: To observe and assess the efficacy of donafenib combined with TACE in the treatment of unresectable hepatocellular carcinoma. Methods: It was a prospective, single-arm, single center, and phase II clinical study. A total of 34 initial unresectable HCC patients who had not received any systemic treatment were enrolled. The patients received donafenib ( 100mg po bid), TACE and or not and camrelizumab (200mg iv Q3W). The primary endpoint was short-term efficacy based on mRECIST criteria, with secondary endpoints including PFS, TTR, DCR and adverse events (AEs).The diameter of tumor feeding artery was measured. Results: A total of 36 patients were included in the study, including 26 who received donafenib and TACE and 10 who received donafenib and TACE plus PD-1 inhibitors. A total of 34 subjects were eligible for efficacy evaluation, and among them, there were 4 cases of CR, 17 cases of PR, 10 cases of SD and 3 cases of PD; Four patients (11.8%) successfully underwent conversion therapy and all achieved R0 resection. Two patients achieved a complete pathological response. The ORR was 61.8% and the DCR was 91.2% based on mRECIST criteria. The mPFS was 10.7 months (95%CI: 8.37-NA months), median OS was not reached, median TTR was 1.4 months ( 95% CI: 0.8-6.9 months). The 6 moths and 12 moths progression-free survival rate were 73.4% and 47.9% respectively. Treatment related adverse events (TRAEs) occurred in all 25 subjects, and grade 3 TRAE occurred in 4 subjects (11.3%), and no grade 4 or 5 TRAE occurred. The tumor feeding artery diameter was (4.5±1.4)mm pre-treatment, and reduced to (3.2±1.1)mm post-treatment (P = 0.036). The multivariable analysis indicated that the sum of baseline target lesion diameters、best tumor response and post-treatment tumor artery diameter were independent predictor for PFS. Conclusions: TACE combined with donafenib could reduce the tumor feeding artery diameter, which had a good safety profile and a high objective response rate in patients with unresectable HCC. Clinical trial information: ChiCTR2100054041.

Comparing clinical outcomes between PD-1 and PD-L1 inhibitors plus bevacizumab combined with hepatic arterial interventional therapies in unresectable hepatocellular carcinoma: A single-center real-world study.

e16229 Background: Systemic therapies combined with locoregional therapies were considered a potent therapeutic strategy in treating patients with unresectable hepatocellular carcinoma (uHCC). Given the A+T strategy became the first-line treatment for advanced HCC patients, the roles of programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors in the combination therapies for treating patients with uHCC needed to be further discussed. The current study compared the clinical outcomes between PD-1 and PD-L1 inhibitors plus bevacizumab combined with hepatic arterial interventional therapies (HAIT) among patients with uHCC. Methods: From October 2019 to May 2023, 142 uHCC patients were retrospectively analyzed in Sun Yat-sen University Cancer Center, including 73 or 69 patients treated with either PD-1 (PD-1 group) or PD-L1 (PD-L1 group) inhibitors, respectively, combined with HAIT plus bevacizumab. The progression-free survival (PFS) and tumor responses were analyzed per mRECIST. Results: At the data cut-off, the median PFS was 5.5 months (95% CI 5.3-7.1 months) in the PD-1 group and 7.5 months (95% CI 7.0-9.6 months) in the PD-L1 group, respectively ( P=0.280; HR=0.74; 95%CI 0.43-1.28). The PD-L1 group showed a significantly better median intrahepatic PFS (8.1 months, 95%CI 7.6-10.2 months) than the PD-1 group (6.5 months, 95%CI 6.2-9.0 months; P=0.014; HR=0.35; 95%CI 0.16-0.81). The overall response rate (ORR; 49.3% vs. 66.7%, P=0.054), intrahepatic control rates (53.4% vs. 69.6%, P=0.070) and overall disease control rate (DCR; 68.5% vs. 78.3%, P=0.261) showed no significant difference in both groups, while the PD-L1 group demonstrated significantly higher intrahepatic disease control rate than the PD-1 group (76.7% vs. 92.6%, P=0.016). Conclusions: PD-1 and PD-L1 plus bevacizumab combined HAIT shared similar PFS, DCRs, and ORRs in treating uHCC patients. The PD-L1 plus bevacizumab combined with HAIT demonstrated a better intrahepatic control than those of PD-1, which needed further validation at a higher evidence level.

Efficacy and safety in advanced hepatocellular carcinoma between patients with negative and positive APF treated with targeted and immunotherapy.

e16162 Background: Serum alpha-fetoprotein (AFP) is widely accepted as a crucial tool for clinical diagnosis and screening of HCC. However, there are cases where patients test negative for AFP but are confirmed to have Hepatocellular Carcinoma through imaging or pathological examinations. Despite these findings, there is limited research focusing on the medicine selection for AFP-negative patients. Methods: This retrospective cohort study, involving 223 untreated advanced HCC patients, and the first-line regimen consisted of targeted therapy and TKI+ICIs therapy. Patients are categorized into negative and positive AFP groups based on initial serum levels. Main efficacy endpoint was progression free survival (PFS), evaluated in accordance with RECIST v1.1. Adverse events (AEs) were recorded according to CTCAE v5.0. Results: According to the level of serum AFP, they were divided into negative group(100) and positive group(123). The two groups showed no statistically significant differences in age, gender, Child-Pugh score and other baseline clinical characteristics( P> 0.05). At data cut-off at February 2023, median OS was not matured and mPFS in negative group was higher than positive group(8.2 vs 5.3months, P< 0.0001). In the ICIs+TKI therapy cohort, mPFS in the negative AFP group(52) was significantly higher than in the positive AFP group(70) (10 vs. 5.8 months, P = 0.0021). Considering all patients in the negative AFP group as a subgroup, an analysis of survival benefits between those receiving targeted therapy and those receiving TKI+ICIs therapy revealed no significant difference in PFS( P> 0.05). Moreover, AEs were compared between the negative and positive group, with no significant differences observed in Any Grade or Grade 3/4( P> 0.05). Conclusions: Patients with negative AFP exhibited superior survival benefits compared to those with positive AFP in first-line therapy. Regarding PFS, the TKI+ICIS therapy did not demonstrate a better benefit over targeted therapy in the negative AFP subgroup.

Comprehensively analysis of IL33 in hepatocellular carcinoma prognosis, immune microenvironment and biological role.

IL33 plays an important role in cancer. However, the role of liver cancer remains unclear. Open-accessed data was obtained from the Cancer Genome Atlas, Xena, and TISCH databases. Different algorithms and R packages are used to perform various analyses. Here, in our comprehensive study on IL33 in HCC, we observed its differential expression across cancers, implicating its role in cancer development. The single-cell analysis highlighted its primary expression in endothelial cells, unveiling correlations within the HCC microenvironment. Also, the expression level of IL33 was correlated with patients survival, emphasizing its potential prognostic value. Biological enrichment analyses revealed associations with stem cell division, angiogenesis, and inflammatory response. IL33's impact on the immune microenvironment showcased correlations with diverse immune cells. Genomic features and drug sensitivity analyses provided insights into IL33's broader implications. In a pan-cancer context, IL33 emerged as a potential tumour-inhibitor, influencing immune-related molecules. This study significantly advances our understanding of IL33 in cancer biology. IL33 exhibited differential expression across cancers, particularly in endothelial cells within the HCC microenvironment. IL33 is correlated with the survival of HCC patients, indicating potential prognostic value and highlighting its broader implications in cancer biology.

Clinical application of dual-layer spectral CT multi-parameter feature to predict microvascular invasion in hepatocellular carcinoma.

This study aimed to investigate the feasibility of using dual-layer spectral CT multi-parameter feature to predict microvascular invasion of hepatocellular carcinoma. This retrospective study enrolled 50 HCC patients who underwent multiphase contrast-enhanced spectral CT studies preoperatively. Combined clinical data, radiological features with spectral CT quantitative parameter were constructed to predict MVI. ROC was applied to identify potential predictors of MVI. The CT values obtained by simulating the conventional CT scans with 70 keV images were compared with those obtained with 40 keV images. 50 hepatocellular carcinomas were detected with 30 lesions (Group A) with microvascular invasion and 20 (Group B) without. There were significant differences in AFP,tumer size, IC, NIC,slope and effective atomic number in AP and ICrr in VP between Group A ((1000(10.875,1000),4.360±0.3105, 1.7750 (1.5350,1.8825) mg/ml, 0.1785 (0.1621,0.2124), 2.0362±0.2108,8.0960±0.1043,0.2830±0.0777) and Group B (4.750(3.325,20.425),3.190±0.2979,1.4700 (1.4500,1.5775) mg/ml, 0.1441 (0.1373,0.1490),1.8601±0.1595, 7.8105±0.7830 and 0.2228±0.0612) (all p < 0.05). Using 0.1586 as the threshold for NIC, one could obtain an area-under-curve (AUC) of 0.875 in ROC to differentiate between tumours with and without microvascular invasion. AUC was 0.625 with CT value at 70 keV and improved to 0.843 at 40 keV. Dual-layer spectral CT provides additional quantitative parameters than conventional CT to enhance the differentiation between hepatocellular carcinoma with and without microvascular invasion. Especially, the normalized iodine concentration (NIC) in arterial phase has the greatest potential application value in determining whether microvascular invasion exists, and can offer an important reference for clinical treatment plan and prognosis assessment.

MiRNA Expression and HCC Occurrence in HCV Cirrhotic Patients Treated with Direct Acting Antivirals

Background: The risk of hepatocarcinoma in HCV cirrhotic patient responders after treatment with DAAs decrease, but HCC still occurs. A correlation between specific miRNAs and the development of hepatocarcinoma have been highlighted. Aim: To investigate miRNA expression in HCV-infected cirrhotic patients treated with DAAs, regarding whether or not they developed HCC at follow-up. Methods: A total of 73 outpatients with HCV-related cirrhosis treated with DAAs were enrolled, 28 of which had HCC. Samples were collected at the start and at the end of treatment. In the screening phase, 172 miRNAs were analyzed at baseline. Differentially expressed miRNAs were validated in the entire cohort. Results: In the validation phase, at baseline and in patients treated for 12 weeks, miR-28-5p was confirmed to be more highly expressed in the HCC group compared to the non-HCC group. In all of the patients treated for 12 weeks, at end of the treatment we found a significant downregulation in miR-132-3p, miR-133b-3p, miR-221-3p and miR-324-3p. In the HCC group, miR-28-5p was significantly downregulated after DAA therapy as well as in HCC patients treated for 24 weeks. Conclusion: In the HCC group, miR28-5p was differently expressed both at baseline and at the end of therapy with DAAs. This difference in expression should suggest its involvement in HCC development.

Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting.

Hepatitis B virus (HBV)-DNA integration in HBV-related hepatocellular carcinoma (HBV-HCC) can be targeted by HBV-specific T cells. SCG101 is an autologous, HBV-specific T-cell product expressing a T-cell receptor (TCR) after lentiviral transduction recognizing the envelope-derived peptide (S20-28) on HLA-A2. We here validated its safety and efficacy preclinically and applied it to an HBV-related HCC patient (NCT05339321). Good Manufacturing Practice-grade manufactured cells were assessed for off-target reactivity and functionality against hepatoma cells. Subsequently, a patient with advanced HBV-HCC (Child-Pugh class A, Barcelona Clinic Liver Cancer stage B, Eastern Cooperative Oncology Group performance status 0, hepatitis B e antigen-, serum hepatitis B surface antigen [HBsAg]+, HBsAg+ hepatocytes 10%) received 7.9×107 cells/kg after lymphodepletion. Safety, T-cell persistence, and antiviral and antitumor efficacy were evaluated. SCG101, produced at high numbers in a closed-bag system, showed HBV-specific functionality against HBV-HCC cells in vitro and in vivo. Clinically, treatment was well tolerated, and all adverse events, including transient hepatic damage, were reversible. On day 3, ALT levels increased to 1,404 U/L, and concurrently, serum HBsAg started decreasing by 3.84 log10 and remained <1 IU/mL for over six months. HBsAg-expressing hepatocytes in liver biopsies were undetectable after 73 days. The patient achieved a partial response according to modified RECIST with a >70% reduction in target lesion size. Transferred T cells expanded, developed a stem cell-like memory phenotype, and were still detectable after six months in the patient's blood. SCG101 T-cell therapy showed encouraging efficacy and safety in preclinical models and in a patient with primary HBV-HCC and concomitant chronic hepatitis B with the capability to eliminate HBsAg+ cells and achieve sustained tumor control after single dosing.

The potential diagnostic value of serum pentraxin-3 in hepatocellular carcinoma in Egyptian patients

Background and aimHepatocellular carcinoma (HCC) is considered one of the most common cancers in the world and one of the principal causes of cancer-linked deaths. Therefore, identification of new biomarkers for diagnosis, especially early diagnosis of HCC, is very important. Pentraxin 3 (PTX3) is possibly involved in cancer development, and as regard to liver diseases, plasma PTX3 was implicated to be associated with HCC occurrence. Therefore, this study will determine the serum PTX3 levels in patients with cirrhosis and HCC and to assess the potential diagnostic value in HCC in Egyptian patients.ResultsPentraxin 3 was significantly higher in HCC patients than in cirrhotic patients (p < 0.001); also, serum PTX3 was significantly correlated with number, size of focal lesions, the presence of portal vein thrombosis, and BCLC staging (p < 0.001).ConclusionThe significant increased levels of serum pentraxin 3 in HCC may support its use as an early marker for HCC, either alone or in combination with serum alpha-fetoprotein (AFP), allowing early diagnosis and prompt intervention.