Search

Background: The most common loadable chemotherapeutic drugs in drug-eluting bead transarterial chemoembolization (DEB-TACE) include doxorubicin, epirubicin, etc. CalliSpheres® beads have exhibited efficient loadability and eluting characteristics for raltitrexed as well as in vitro and animal experiments. However, the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage hepatocellular carcinoma (HCC) remain unclear. Objectives: To assess the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage HCC. Design: The study was conducted as a single-arm prospective study. Methods: This study was a prospective, single-arm trial conducted between June 2019 and June 2022. CalliSpheres® beads loaded with raltitrexed were used in the DEB-TACE procedure. The follow-up lasted for at least 1 year or until death. The primary endpoint was overall survival (OS), and the secondary endpoints were time to progression (TTP), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Results: The 6-month ORR and disease control rates were 90.1% and 93.8%, respectively. The median OS was 33.0 months. The 1-, 2-, and 3-year survival rates were 95.1%, 82.1%, and 43.6%, respectively. Child–Pugh class and bilobar disease occurrence were identified as independent OS predictors. The median TTP and PFS were 22.7 and 19.8 months, respectively. Eleven (11.5%) patients experienced at least one grade 3 AE, and serious AEs were reported in five participants (5.2%). No patient experienced grade 4 or 5 AEs. Conclusion: Raltitrexed-loaded DEB-TACE is feasible, safe, and effective in patients with intermediate-stage HCC. Trial registration: This trial was registered at www.chictr.org.cn under the identifier: 1900024097 on 25 June 2019. Plain language summary: Efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage hepatocellular carcinoma The utility of raltitrexed-loaded CalliSphere® beads in drug-eluting bead transarterial chemoembolization (DEB-TACE) has been demonstrated in in vitro and animal experiments. However, its efficacy and safety in patients with intermediate-stage hepatocellular carcinoma (HCC) remain unclear. Hence, this study aimed to assess the efficacy and safety profiles of DEB-TACE for such patients. We discovered that raltitrexed-loaded DEB-TACE led to a 6-month ORR of 90.1%, a median OS of 33.0 months, a median TTP of 22.7 months, and a median PFS of 19.8 months. The 1-, 2-, and 3-year survival rates were 95.1%, 82.1%, and 43.6%, respectively. Factors such as Child-Pugh class and bilobar disease occurrence were identified as independent predictors of OS. The study also showed acceptable safety profiles, with a low incidence of grade 3 adverse events and no grade 4 or 5 adverse events. The results indicated that raltitrexed-eluting CalliSpheres® beads for TACE can be a viable option for treating patients with intermediate-stage HCC. [ABSTRACT FROM AUTHOR]

Although transcatheter arterial chemo-embolization (TACE) plays a key role on clinical treatment of hepatocellular carcinoma (HCC), it was greatly limited by the poor synergistic effect between chemotherapeutics and physical embolization to tumor-feeding arteries. In the present work, a temperature sensitive polymer poly(N-isopropylacrylamide-b-methacrylic acid) (PNA), which was modified with gold nanoparticles (AuNP@PNA), was successfully used to encapsulate doxorubicin (DOX) by electrostatic binding with their carboxyl groups. The resultant gold nanomedicines (AuNP@PNA/DOX) exhibited temperature responsive sol-gel phase transition, favorable shear thinning effect and X-ray angiography. By in vivo evaluation of vascular embolization on VX2-tumor-bearing rabbits, AuNP@PNA/DOX exhibited far better antitumor efficacy than Lipiodol/DOX, on either tumor growth inhibition, proliferation, apoptosis, necrosis or anti-metastasis. Owing to sufficient embolization to tumor vascular networks, AuNP@PNA/DOX down-regulated the expression levels of HIF-1α, VEGF and MMP-9, and prompted more efficient activation on CD3+/CD8+ T cells and the related cytokines, suggesting the synergistic effect between AuNP@PNA and DOX on the improvement of post-operative tumor immunosuppressive microenvironment. With their favorable pharmcokinetics and biocompatibility, AuNP@PNA/DOX is promising to be developed as a multi-functional artery-imaging/embolic agent with immune-chemo-embolization for enhancing TACE efficacy on HCC. [ABSTRACT FROM AUTHOR]

Purpose: The present retrospective study aimed to evaluate the efficacy and safety of camrelizumab addition to transarterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC) with TACE-related untreatable progression (UP). Methods: Patients with HCC who received addition of camrelizumab due to UP after initial TACE treatment were enrolled at our institution between May 2019 and January 2021. Patients were assessed for tumor response, progression-free survival (PFS), and adverse events (AEs). Risk factors for PFS were evaluated with logistic regression analysis. Results: A total of 41 patients were included. The objective response rates (ORR) and disease control rates (DCR) were 24.4% and 61.0% at 2 to 3 months, and 12.2% and 58.5% at 6 months, respectively. The median PFS of the patients were 6 months (95% confidence interval [CI]: 3.8 months, 8.2 months). Of the 41 patients, 23 received camrelizumab combined with TACE (hereafter, camrelizumab–TACE) on whom 52 combined TACE procedures were performed, with a median of 2 procedures (range: 1-6) per patient. The remaining 18 patients received camrelizumab alone due to TACE contraindications. Multivariable analysis indicated that camrelizumab–TACE was an independent prognostic factor for PFS. Subgroup analysis showed a median PFS of 8 months in the camrelizumab–TACE group and 3 months in the camrelizumab monotherapy group (P <.001). No treatment-related mortalities occurred. Seventeen patients (41.5%) developed at least 1 type of AE after treatment with camrelizumab, with reactive cutaneous capillary endothelial proliferation (RCCEP) (n = 14, 34.1%) being the most common AE. Conclusion: Addition of camrelizumab to TACE offered an effective and safe treatment for HCC with UP. [ABSTRACT FROM AUTHOR]

Purpose: The aim was to investigate the association between microvascular invasion (MVI) and the peritumoral imaging features of gadolinium ethoxybenzyl DTPA-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) in hepatocellular carcinoma (HCC). Methods: Up until Feb 24, 2022, the PubMed, Embase, and Cochrane Library databases were carefully searched for relevant material. The software packages utilized for this meta-analysis were Review Manager 5.4.1, Meta-DiSc 1.4, and Stata16.0. Summary results are presented as sensitivity (SEN), specificity (SPE), diagnostic odds ratios (DORs), area under the receiver operating characteristic curve (AUC), and 95% confidence interval (CI). The sources of heterogeneity were investigated using subgroup analysis. Results: An aggregate of nineteen articles were remembered for this meta-analysis: peritumoral enhancement on the arterial phase (AP) was described in 13 of these studies and peritumoral hypointensity on the hepatobiliary phase (HBP) in all 19 studies. The SEN, SPE, DOR, and AUC of the 13 investigations on peritumoral enhancement on AP were 0.59 (95% CI, 0.41−0.58), 0.80 (95% CI, 0.75−0.85), 4 (95% CI, 3−6), and 0.73 (95% CI, 0.69−0.77), respectively. The SEN, SPE, DOR, and AUC of 19 studies on peritumoral hypointensity on HBP were 0.55 (95% CI, 0.45−0.64), 0.87 (95% CI, 0.81−0.91), 8 (95% CI, 5−12), and 0.80 (95% CI, 0.76−0.83), respectively. The subgroup analysis of two imaging features identified ten and seven potential factors for heterogeneity, respectively. Conclusion: The results of peritumoral enhancement on the AP and peritumoral hypointensity on HBP showed high SPE but low SEN. This indicates that the peritumoral imaging features on Gd-EOB-DTPA-enhanced MRI can be used as a noninvasive, excluded diagnosis for predicting hepatic MVI in HCC preoperatively. Moreover, the results of this analysis should be updated when additional data become available. Additionally, in the future, how to improve its SEN will be a new research direction. [ABSTRACT FROM AUTHOR]

Background: Patients with different primary tumor oligometastases can obtain survival benefits from external radiotherapy. The study was conducted to explore the efficacy and safety of transarterial chemoembolization (TACE) plus iodine 125 seed (TACE-I) implantation for hepatocellular carcinoma (HCC) oligometastases. Methods: 187 patients who received TACE-I in our institution were retrospectively reviewed from January 2014 to December 2018. Thirty-two patients were included in the analysis. The primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). The secondary endpoints of the study were tumor response and PFS of the metastatic sites. Results: The median OS (mOS) of patients was 18 months, and the median PFS (mPFS) was 7 months. The objective response rate (ORR) and disease control rate (DCR) of patients three months after receiving TACE-I were 34.4% and 71.9%, respectively. The ORR and DCR of patients for metastatic sites were 50% and 81.3%, respectively. The mPFS of patients for metastatic sites was 14 months. The univariable and multivariable regression analyses indicated that the ECOG score was an independent predictor for mOS and mPFS. The number of iodine seeds and ECOG scores were independent predictors for mPFS for metastatic sites. After patients received TACE-I, the most common adverse events were abdominal pain, fever, and appetite. The adverse events of patients were relieved after receiving symptomatic treatments. Conclusion: Iodine 125 seed implantation may be an effective and safe treatment for patients with hepatocellular carcinoma with oligometastasis, thereby providing a new selective option for these patients. [ABSTRACT FROM AUTHOR]

Background. Recently, radiotherapy has been used in the treatment of hepatocellular carcinoma (HCC). However, there is no study analyzing the efficacy of radiotherapy in cases of advanced HCC. The objective of this investigation was to determine the efficacy of radiotherapy in patients with HCC invading distant organs. Methods. The data of 2342 patients diagnosed between 2010 and 2015 with HCC invading distant organs were extracted from the SEER database. Propensity score matching (PSM) was used to reduce selection bias. Results. Before PSM, the median overall survival (mOS) and median cancer-specific survival (mCSS) in the radiotherapy group (mOS = 5 months, 95% CI: 4.5–5.5; mCSS = 5 months, 95% CI: 4.4–5.6) were longer than those in the nonradiotherapy group (mOS = 3 months, 95% CI: 2.8–3.2; mCSS = 3 months, 95% CI: 2.8–3.2; both P < 0.001). After PSM, mOS in the radiotherapy group (5 months, 95% CI: 4.5–5.5) was longer than that in the nonradiotherapy group (3 months, 95% CI: 2.6–3.4; P < 0.001), and the mCSS in the radiotherapy group (5 months, 95% CI: 4.4–5.6) was longer than that in the nonradiotherapy group (3 months, 95% CI: 2.6–3.4; P < 0.001). Before PSM, the multivariate analysis showed that all-cause and cancer-specific mortality rates were higher in the nonradiotherapy group than in the radiotherapy group. The adjusted Cox regression analysis for subgroups showed that, in the nonradiotherapy group, patients with bone metastases and multiorgan metastases had a worse survival than those in the radiotherapy group. Conclusion. HCC patients with metastases to distant organs obtain survival benefit from radiotherapy, particularly patients with bone metastases and multiorgan metastases. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to evaluate the efficacy and safety of transarterial chemoembolization (TACE) in the treatment of patients with treatment-naïve hepatocellular carcinoma (TN-HCC) and recurrent HCC (R-HCC). In addition, risk signature analysis was performed to accurately assess patients' recurrence and survival. Methods: This retrospective study assessed the consecutive medical records of TN-HCC and R-HCC patients from January 2014 to December 2018. In order to reduce the patient selection bias, propensity score matching (PSM) analysis was applied. Conditional inference tree was used to establish a risk signature. Results: A total of 401 eligible patients were included in our study, including 346 patients in the TN-HCC group and 55 patients in the R-HCC group. Forty-seven pairs of patients were chosen after the PSM analysis. Before the PSM analysis, the objective tumor regression (ORR) and disease control rate (DCR) of R-HCC patients were better than that of TN-HCC patients; however, after the PSM analysis, there was no significant difference in the ORR and DCR between the two groups (P>0.05). Before the PSM analysis, the median overall survival (OS) and progression-free survival (PFS) in the R-HCC group were significantly greater than those of the TN-HCC group (OS: 24 months vs. 18 months, P =0.004; PFS: 9 months vs. 6 months, P =0.012). However, after the PSM analysis, the median OS and PFS in the R-HCC group were inferior to those in the TN-HCC group (OS: 24 months vs. 33 months, P = 0.0035; PFS: 10 months vs. 12 months, P = 0.01). The conditional inference tree divided patients into different subgroups according to tumor size, BCLC stage, and TACE sessions and shared different hazards ratio to recurrence or survival. Conclusion: Patients with R-HCC treated with TACE achieved satisfactory results, although survival after the PSM analysis was not as good as in the TN-HCC group. In addition, risk signature based on conditional inference tree analysis can more accurately predict the recurrence and survival in both groups of patients. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common type of malignant neoplasm of the liver with high morbidity and mortality. Extensive research into the pathology of HCC has been performed; however, the molecular mechanisms underlying the development of hepatitis B virus-associated HCC have remained elusive. Thus, the present study aimed to identify critical genes and pathways associated with the development and progression of HCC. The expression profiles of the GSE121248 dataset were downloaded from the Gene Expression Omnibus database and the differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) analyses were performed by using the Database for Annotation, Visualization and Integrated Discovery. Subsequently, protein-protein interaction (PPI) networks were constructed for detecting hub genes. In the present study, 1,153 DEGs (777 upregulated and 376 downregulated genes) were identified and the PPI network yielded 15 hub genes. GO analysis revealed that the DEGs were primarily enriched in 'protein binding', 'cytoplasm' and 'extracellular exosome'. KEGG analysis indicated that DEGs were accumulated in 'metabolic pathways', 'chemical carcinogenesis' and 'fatty acid degradation'. After constructing the PPI network, cyclin-dependent kinase 1, cyclin B1, cyclin A2, mitotic arrest deficient 2 like 1, cyclin B2, DNA topoisomerase IIα, budding uninhibited by benzimidazoles (BUB)1, TTK protein kinase, non-SMC condensin I complex subunit G, NDC80 kinetochore complex component, aurora kinase A, kinesin family member 11, cell division cycle 20, BUB1B and abnormal spindle microtubule assembly were identified as hub genes based on the high degree of connectivity by using Cytoscape software. In addition, overall survival (OS) and disease-free survival (DFS) analyses were performed using the Gene Expression Profiling Interactive Analysis online database, which revealed that the increased expression of all hub genes were associated with poorer OS and DFS outcomes. Receiver operating characteristic curves were constructed using GraphPad prism 7.0 software. The results confirmed that 15 hub genes were able to distinguish HCC form normal tissues. Furthermore, the expression levels of three key genes were analyzed in tumor and normal samples of the Human Protein Atlas database. The present results may provide further insight into the underlying mechanisms of HCC and potential therapeutic targets for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Golgi phosphoprotein 73 (GP73) has been regarded as a novel serum biomarker for the diagnosis of hepatocellular carcinoma (HCC) in recent years. It has been reported that the upregulation of GP73 may promote the carcinogenesis and metastasis of HCC; however, the mechanisms remain poorly understood. In this study, GP73 correlates positively with matrix metalloproteinase‐2 (MMP‐2) in HCC‐related cells and tissues. Further studies indicate that the knockdown of GP73 blocks MMP‐2 trafficking and secretion, resulting in cell invasion inhibition. Additionally, the knockdown of GP73 induces the accumulation of intracellular MMP‐2, which inhibits the phosphorylation of Src at Y416 and triggers the inhibition of SAPK/JNK and p53‐p21 signalling pathways through a negative feedback loop. Finally, the transactivation of MMP2 was inhibited by the reduction in E2F1. This study reveals that GP73 plays functional roles in the trafficking and equilibrium of epithelial‐mesenchymal transition (EMT)‐related secretory proteins and that GP73 serves as a new potential target for combating the metastasis of HCC. [ABSTRACT FROM AUTHOR]

The biological behaviors of residual hepatoma cells after transarterial embolization therapy, which exist in a hypoxic or even anaerobic tumor microenvironment, differ from the tumor cells under normoxic conditions. This study aimed to use a phage display peptide library for in vivo and in vitro screening to obtain a peptide which could specifically bind to hypoxic hepatoma cells, allowing further targeted diagnosis and treatment for liver cancer. In this study, hypoxic hepatoma cells HepG2 (targeted cells), and normal liver cells HL-7702 (control cells), were utilized to perform three rounds of in vitro screening using a phage-displayed 7-mer peptide library. In addition, hypoxic HepG2 were subcutaneously injected into nude mice to establish a hepatocarcinoma model, followed by performing three rounds of in vivo screening on the phages identified from the in vitro screening. The products from the screening were further identified using ELISA and immunofluorescence staining on cells and tissues. The results indicated that the P11 positive clone had the highest binding effect with hypoxic hepatoma cells. The sequence of the exogenous insert fragment of P11 positive clone was obtained by sequencing: GSTSFSK. The binding assay indicated that GSTSFSK could specifically bind to hypoxic hepatoma cells and hepatocarcinoma tissues. This 7-mer peptide has the potential to be developed as an useful molecular to the targeting diagnosis and treatment of residual hepatoma cells after transarterial chemoembolization. [ABSTRACT FROM AUTHOR]

Tirapazamine (TPZ) is a promising hypoxia-selective cytotoxic agent that may exert synergistic tumor-killing activity with transcatheter arterial embolization (TAE) for liver cancer. To investigated whether TPZ-loaded microspheres enhance the synergy between TPZ and TAE in liver cancer, we prepared TPZ-loaded CalliSpheres microspheres (CSMTPZs) and characterized their properties as a chemoembolization agent in vitro. Tumor hypoxia after TAE was detected in the rabbit VX2 model of liver cancer using a modified Clark-type microelectrode research system. CSMTPZ therapy was performed in the animal model. The plasma and tumor concentrations of TPZ and its metabolites were measured, and the efficacy and safety of CSMTPZ therapy were evaluated and compared with those of the conventional combination of intraarterial TPZ injection and embolization. The results showed that CSMTPZs displayed favorable in vitro properties including drug loading and release and microsphere size, shape, and surface profiles. TAE induced acute tumor hypoxia, but residual tumor cells responded to hypoxia through hypoxia-inducible factor 1α. CSMTPZ therapy improved TPZ delivery into tumor tissue with minimal systemic exposure. Accordingly, CSMTPZ therapy exhibited advantages in terms of hypoxia-selected cytotoxicity, tumor apoptosis and necrosis, animal survival, and safety over the conventional combination of TPZ and TAE. We revealed the improved synergistic anti-tumor effects of CSMTPZ therapy in the rabbit VX2 liver cancer model. Our data support the clinical evaluation of CSMTPZs in the treatment of hepatocellular carcinoma, and CSMTPZ administration might serve as a successful therapeutic strategy for this malignancy. [Display omitted] • TPZ can be loaded into CSMs as a chemoembolization agent targeting hypoxic tumor. • TAE induces acute hypoxia, but residual viable tumor responds to hypoxia by HIF-1α. • CSMTPZs improve TPZ delivery into liver cancer. • CSMTPZs enhance the synergy between TPZ and embolization against liver cancer. [ABSTRACT FROM AUTHOR]