Therapy For Hepatocellular Carcinoma Research Articles

Chitosan-enclosed SLN improved SV-induced hepatocellular cell carcinoma death by modulation of IQGAP gene expression, JNK, and HDAC activities.

Hepatocellular carcinoma (HCC) is a global life-threatening problem and therapeutic interventions are still encountered. IQGAP genes are involved in HCC oncogenesis. The modulatory effect of statins on the expression of IQGAP genes is still unclear. This study aims to study the effect of free SV and chitosan (CS) decorated simvastatin (SV) loaded solid lipid nanoparticles (C-SV-SLNs) on HCC mortality. Plain, SV-SLN, and C-SV- SLN were prepared and characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI). The biosafety of different SLN was investigated using fresh erythrocytes, moreover, cytotoxicity was investigated using HepG2 cell lines. The effect of SLNs on IQGAPs gene expression as well as JNK, HDAC6, and HDAC8 activity was investigated using PCR and MOE-docking. The current results displayed that SV-SLNs have nanosized, negative ZP and are homogenous, CS decoration shifts the ZP of SLN into cationic ZP. Furthermore, all SLNs exhibited desirable biosafety in terms of no deleterious effect on erythrocyte integrity. SV solution and SV-SLN significantly increase the mortality of HepG2 compared to undertreated cells, however, the effect of SV-SLN is more pronounced compared to free SV. Remarkably, C-SV-SLN elicits high HepG2 cell mortality compared to free SV and SV-SLN. The treatment of HepG2 cells with SV solution, SV-SLN, or C-SV-SLN significantly upregulates the IQGAP2 gene with repression of IQGAP1 and IQGAP3 genes. MOE-docking studies revealed both SV and tenivastatin exhibit interactions with the active sites of JNK, HDAC6, and HDAC8. Moreover, tenivastatin exhibited greater interactions with magnesium and zinc compared to SV. This research provides novel insights into the therapeutic potential of SV, SV-SLN and C-SV-SLNs in HCC treatment, modulating critical signaling cascades involving IQGAPs, JNK, and HDAC. The development of C-SV-SLNs presents a promising strategy for effective HCC therapy.

A Nanoreactor Based on Metal-Organic Frameworks With Triple Synergistic Therapy for Hepatocellular Carcinoma.

The transformation of monotherapy into multimodal combined targeted therapy to fully exploit synergistic efficacy is of increasing interest in tumor treatment. In this work, a novel nanodrug-carrying platform based on iron-based MOFs, which is loaded with doxorubicin hydrochloride (DOX), dihydroartemisinin (DHA), and glucose oxidase (GOx), and concurrently covalently linked to the photosensitizer 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) in polydopamine (PDA)-encapsulated MIL-101(Fe) (denoted as MIL-101(Fe)-DOX-DHA@TCPP/GOx@PDA, MDDTG@P), is successfully developed. Upon entering the tumor microenvironment, MDDTG@P catalyzes the hydrogen peroxide (H2O2) into hydroxyl radicals (·OH) and depletes glutathione (GSH); thus, exerting the role of chemodynamic therapy (CDT). The reduced Fe2+ can also activate DHA, further expanding CDT and promoting tumor cell apoptosis. The introduced GOx will rapidly consume glucose and oxygen (O2) in the tumor; while, replenishing H2O2 for Fenton reaction, starving the cancer cells; and thus, realizing starvation and chemodynamic therapy. In addition, the covalent linkage of TCPP endows MDDTG@P with good photodynamic therapeutic (PDT) properties. Therefore, this study develops a nanocarrier platform for triple synergistic chemodynamic/photodynamic/starvation therapy, which has promising applications in the efficient treatment of tumors.

Histone lactylation facilitates hepatocellular carcinoma progression by upregulating endothelial cell-specific molecule 1 expression.

Hepatocellular carcinoma (HCC) is a common malignant tumor. Histone lactylation, a novel epigenetic modification, plays a crucial role in various cancers. However, the functional role and underlying mechanism of histone lactylation in HCC progression have not yet been investigated. Histone lactylation levels in HCC tissues and cells were assessed using a densitometric kit and western blot analysis. The role of histone lactylation in cell malignant phenotypes was determined through functional assays in vitro, and a xenograft tumor model was established to verify the function of histone lactylation in vivo. ChIP assay was performed to explore the interaction between histone lactylation and endothelial cell-specific molecule 1 (ESM1). Additionally, gain-and-loss-of-function assays were conducted to investigate the regulatory role of ESM1 in HCC pathogenesis. Histone lactylation levels were increased in HCC tissues and cells, and H3K9 lactylation (H3K9la) and H3K56 lactylation (H3K56la) were identified as the histone modification sites. We observed that H3K9la and H3K56la caused abnormal histone lactylation and were associated with poor prognosis. Functionally, histone lactylation was found to promote HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in vitro. However, histone lactylation inhibition with 2-deoxy-d-glucose (2-DG) reduced the malignant phenotypes of HCC cells. In vivo, 2-DG treatment reduced tumor growth and metastasis in the HCC mouse model. Mechanistically, it was revealed that histone lactylation activated ESM1 transcription in HCC cells. ESM1 was expressed at a high level in HCC and exerted a carcinogenic role. Histone lactylation facilitates cell malignant phenotypes, tumor growth, and metastasis by upregulating ESM1 expression in HCC, which reveals the downstream molecular mechanism of histone lactylation and might provide a novel therapeutic target for HCC therapy.

Case report: Complete response after transcatheter arterial chemoembolization combined with donafenib plus tislelizumab therapy for hepatocellular carcinoma with main trunk portal vein tumor thrombus in a patient coinfected with HIV and HBV

BackgroundCoinfection with the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV) occurs in 5–67% of patients with HIV. HIV weakens the human immune system and leads to various tumors. Patients with unresectable hepatocellular carcinoma (HCC) and HIV experience poor treatment efficacy and have a short survival period. Approximately 70% of cases of HCC are diagnosed at advanced stages due to the subtle onset of the disease. As a result, most cases are not suits for curative therapy. Transcatheter arterial chemoembolization (TACE) is the first-line treatment for intermediate-stage HCC and is commonly used to treat unresectable HCC in China. Recent advancements in systemic treatments have significantly enhanced the effectiveness of unresectable HCC treatment. Several previous study showed that combination treatment combination therapy can enhance the efficacy. Notably, studies proposed that TACE combined targeted drugs with immune checkpoint inhibitors results in a high objective response rate and overall survival. However, the novelty of this study lies in its report of a complete response using a triple combination in patients with HIV and HCC with main trunk portal vein tumor thrombus.Case presentationA 57-year-old woman was diagnosed with HCC with a main trunk portal vein tumor thrombus combined with HIV infection, cirrhosis, and chronic viral hepatitis. She underwent TACE and was administered donafenib and tislelizumab. This triple therapy treatment regimen resulted in a clinical complete response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) based on contrast-enhanced computed tomography.ConclusionWe first used TACE combined with donafenib and tislelizumab for HCC patients with main trunk portal vein tumor thrombus and HIV-HBV coinfection and achieved complete response.

Sono-blasting Triggered Cascading-Amplification of Oxidative Stress for Enhanced Interventional Therapy of Hepatocellular Carcinoma.

Interventional therapy is widely regarded as a highly promising treatment approach for nonsurgical liver cancer. However, the development of drug resistance and tolerance to hypoxic environments after embolization can lead to increased angiogenesis, enhanced tumor cell stemness, and greater invasiveness, resulting in metastasis and recurrence. To address these challenges, a novel approach involving the use of lecithin and DSPE-PEG comodified Ca2+ loaded (NH4)2S2O8 (LDCNSO) drug in combination with transcatheter arterial embolization (TAE) has been proposed. The sono-blasting effect of LDCNSO under ultrasound triggers a cascading amplification of oxidative stress, by releasing sulfate radical (·SO4-), hydroxyl radical (·OH), and superoxide (·O2-), inducing Ca2+ overload, and reducing glutathione (GSH) levels, which eventually leads to apoptosis. LDCNSO alongside TAE has demonstrated remarkable therapeutic efficacy in the rabbit orthotopic cancer model, resulting in significant inhibition of tumor growth. This research provides valuable insights for the effective treatment of orthotopic tumors.

Combined neurokinin-1 receptor antagonist and sorafenib is a promising approach for hepatocellular carcinoma therapy

BackgroundHCC (Hepatocellular carcinoma) is the most common primary malignant cancer in the liver. Treatment options to incurable HCC such as sorafenib, an oral multikinase inhibitor, had numerous side effects and questionable effectiveness. Neurokinin-1 receptor (NK1R) have a major role in inflammation and tumour environment including the resistance to cell death, the induction of angiogenesis and the promotion of cell migration and proliferation. Additionally, NK-1R is over-expressed in human tumour cells including HCC. Moreover, Aprepitant, one of the NK-1R antagonists exerts multiple antitumor activities (antiproliferative, apoptotic, antimigration, and antiangiogenesis) in vivo and in vitro.Study aimTo analyze the effectiveness of combining sorafenib with aprepitant in the management of HCC (experimental).Patients and methodsIn this retrospective experimental study, the human HCC cell line, HepG2, cells were exposed to increasing concentrations of sorafenib alone, aprepitant alone and combination of both sorafenib and aprepitant evaluation of cytotoxicity, apoptosis, MMP-9, VEGF, NF-kB p-65, p-AKT and p-ERK were done. Moreover, The extent of the NK-1 receptor expression was assessed by immunocytochemistry on 50 HCC paraffin blocks of Egyptian HCC patients and another 50 paraffin blocks of liver cirrhosis only as a control.ResultsDecreased levels of MMP-9, VEGF, NF-kB p-65, p-AKT and p-ERK was more substantial in the combination therapy compared to sorafenib alone and aprepitant alone. Moreover, the rate of apoptosis and cytotoxicity were significantly higher in the combination treatment group than the monotherapy groups with more anti inflammatory, anti angiogentic and anti metastatic effects. Also, among the 50 HCC paraffin blocks, the majority (60%) showed a strong NK-1 expression; which significantly (p < 0.05) correlated with the progression free survival (PFS) but not the overall survival (OS) of the patients when applying multivariate analysis.ConclusionHCC had strong expression and immunostaining for NK1R.Therefore, combined aprepitant and sorafenib may be a promising approach in HCC treatment compared to each one alone.

Targeted redox-responsive peptide for arterial chemoembolization therapy of orthotropic hepatocellular carcinoma.

Transcatheter Arterial Chemoembolization (TACE) is the first choice for the treatment of advanced-stage hepatocellular carcinoma (HCC). However, TACE suffers from a lack of specificity and rapid drug release. Herein, a targeted redox-responsive peptide (TRRP) was synthesized and used as a carrier of doxorubicin (DOX) to enhance the efficacy of TACE through tumor cells targeting and controlled drug release. TRRP has a high loading capacity of DOX and a sensitive drug release behavior at high glutathione (GSH) concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models. TRRP has a high loading capacity of DOX and a sensitive drug release behavior at GSH concentration. Moreover, TRRP could bind to the transferrin receptor on the surface of tumor cells, which enhanced the efficacy of TACE and reduced side effects of TACE. TACE with TRRP@DOX dispersed in lipiodol shows an enhanced therapeutic outcome compared to the treatment with DOX + lipiodol emulsion in orthotopic rat HCC models. This study demonstrated that TRRP was a promising therapeutic agent for enhancing TACE therapy for HCC treatment.

Epigallocatechin Gallate Derivative Y6 Reverses Oxaliplatin Resistance in Hepatocellular Carcinoma via Targeting the MiR-338-3p/HIF-1α/TWIST Axis to Inhibit EMT.

The emergence of drug resistance to oxaliplatin (OXA) is one of the critical obstacles in the therapy of advanced Hepatocellular Carcinoma (HCC). As an ethyl derivative of the natural compound epigallocatechin gallate (epigallocatechin-3-gallate, EGCG), Y6 was found to be able to enhance the sensitivity of HCC cells to doxorubicin. This study aimed to investigate the effect of Y6 on oxaliplatin resistance in HCC. MTT was used to determine the reversal effect of Y6 on OXA resistance. To further explore the reversal mechanism, we treated OXA alone or in combination with Y6 or EGCG in drugresistant cells and observed the morphological changes of the cells. At the same time, transwell assay was used to detect the invasion and migration ability of cells. Moreover, Real-time PCR and Western blot analysis were performed to determine the expression levels of the miR-338-3p gene, HIF-1α/Twist proteins, and EMT-related proteins. We found that Y6 could inhibit the proliferation of HCC cells and effectively reverse the drug resistance of oxaliplatin-resistant human liver cancer cells (SMMC-7721/OXA) to OXA, and the reversal effect was more significant than that of its lead drug EGCG. Most of the cells in the control group and OXA group showed typical mesenchymal-like cell morphology, while most of the cells in co-administration groups showed typical epithelioid cell morphology, and the ability of the cells to invade and migrate decreased dramatically, particularly in Y6 plus OXA group. At the same time, Y6 could up-regulate the EMT epithelial marker protein E-cadherin and down-regulate the interstitial marker protein Vimentin. In addition, in co-administration groups, the expression of miR-338-3p was up-regulated, while the expression of HIF-1α and Twist was down-regulated. Y6 significantly enhanced the susceptibility of drug-resistant cells to OXA, and the process may be related to the regulation of miR-338-3p/HIF-1α / TWIST pathway to inhibit EMT. Therefore, Y6 could be considered an effective medication resistance reversal agent, which could improve the therapeutic effect for hepatocellular cancer patients.

3D-CEUS/MRI-CEUS fusion imaging vs 2D-CEUS after locoregional therapies for hepatocellular carcinoma: a multicenter prospective study of therapeutic responseevaluation.

To compare the diagnostic accuracy of 3D contrast-enhanced ultrasound (CEUS)/MRI-CEUS fusion imaging with 2D-CEUS in assessing the response of hepatocellular carcinoma (HCC) to locoregional therapies in a multicenter prospective study. A consecutive series of patients with HCC scheduled for locoregional treatment were enrolled between April 2021 and March 2023. Patients were randomly divided into 3D-CEUS/MRI-CEUS fusion imaging group (3D/fusion group) or 2D-CEUS group (2D group). CEUS was performed 1 week before and 4-6 weeks after locoregional treatment. Contrast-enhanced MRI (CE-MRI) 4-6 weeks after treatment was set as the reference standard. CEUS images were evaluated for the presence or absence of viable tumors. Diagnostic performance criteria, including sensitivity, specificity, accuracy, and area under the curve (AUC), were determined for each modality. A total of 140 patients were included, 70 patients in the 2D group (mean age, 60.2 ± 10.4 years) and 70 patients in the 3D/fusion group (mean age, 59.8 ± 10.6 years). The sensitivity of the 3D/fusion group was 100.0% (95% CI: 75.9, 100.0), higher than that of the 2D group (55.6%, 95% CI: 22.7, 84.7; p = 0.019). The specificity of the 3D/fusion group was 96.3% (95% CI: 86.2, 99.4), which was comparable to that of the 2D group (98.4%, 95% CI: 90.0, 99.9; p = 0.915). The AUC of the 3D/fusion group was 0.98 (95% CI: 0.95, 1.00), higher than that of the 2D group (0.77, 95% CI: 0.56, 0.98; p = 0.020). 3D-CEUS/MRI-CEUS fusion imaging exhibits superior diagnostic accuracy in evaluating the treatment response to locoregional therapies for HCC. 3D-CEUS/MRI-CEUS fusion imaging can be applied for post-treatment assessment of residual tumors in HCC undergoing locoregional treatment, offering potential benefits in terms of accurate diagnosis and clinical management. Evaluating for HCC recurrence following locoregional therapy is important. 3D-CEUS/MRI-CEUS fusion imaging achieved a higher sensitivity than 2D-CEUS in assessing residual tumors after locoregional therapies. 3D-CEUS/MRI-CEUS fusion imaging can help clinicians intervene early in residual HCC lesions after locoregional treatment.

Recent Advances in RNA Interference-Based Therapy for Hepatocellular Carcinoma: Emphasis on siRNA.

Even though RNA treatments were first proposed as a way to change aberrant signaling in cancer, research in this field is currently ongoing. The term "RNAi" refers to the use of several RNAi technologies, including ribozymes, riboswitches, Aptamers, small interfering RNA (siRNA), antisense oligonucleotides (ASOs), and CRISPR/Cas9 technology. The siRNA therapy has already achieved a remarkable feat by revolutionizing the treatment arena of cancers. Unlike small molecules and antibodies, which need administration every three months or even every two years, RNAi may be given every quarter to attain therapeutic results. In order to overcome complex challenges, delivering siRNAs to the targeted tissues and cells effectively and safely and improving the effectiveness of siRNAs in terms of their action, stability, specificity, and potential adverse consequences are required. In this context, the three primary techniques of siRNA therapies for hepatocellular carcinoma (HCC) are accomplished for inhibiting angiogenesis, decreasing cell proliferation, and promoting apoptosis, are discussed in this review. We also deliberate targeting issues, immunogenic reactions to siRNA therapy, and the difficulties with their intrinsic chemistry and transportation.

Atezolizumab plus bevacizumab as first-line systemic therapy for hepatocellular carcinoma: a multi-institutional cohort study.

Atezolizumab plus bevacizumab is the standard of care for advanced hepatocellular carcinoma (HCC) in the first-line setting, although was only evaluated in patients with Child-Pugh (CP) A liver function in the IMbrave150 trial. We sought to determine the outcomes of these patients based on CP score and ALBI grade in the US population. This multicenter cohort study included patients with HCC who received atezolizumab with bevacizumab as first-line systemic therapy between March 2018 and November 2023. Overall survival (OS) was determined using the Kaplan-Meier method and multivariate analyses were performed using Cox proportional hazard regression method. Among 322 patients, 226, 86, and 10 patients had CP-A, CP-B, and CP-C liver function, respectively. Median age was 66.5 years, 78.6% were male, and 82.6% were White. Median OS (mOS) was 21.6 months for those with CP-A, 9.1 months for those with CP-B7, and 4.7 months for those with CP-B8-C12 (P < .0001). Among patients with CP-A, those with ALBI grade 1 had an mOS of 34.9 months versus 14.2 months in those with grade 2. In multivariate analyses, CP score, ALBI grade, hepatitis B, performance status, and macrovascular invasion were significantly associated with survival. CP score is an important prognostic tool for patients with HCC receiving atezolizumab plus bevacizumab, and this regimen remains a viable option for patients with CP-B7 with no additional safety concern, although the benefit is significantly less than those with CP-A. ALBI score has independent predictive value in patients with CP-A liver function.

Machine learning-based decision support model for selecting intra-arterial therapies for unresectable hepatocellular carcinoma: A national real-world evidence-based study.

Intra-arterial therapies(IATs) are promising options for unresectable hepatocellular carcinoma(HCC). Stratifying the prognostic risk before administering IAT is important for clinical decision-making and for designing future clinical trials. To develop and validate a machine learning(ML)-based decision support model(MLDSM) for recommending IAT modalities for unresectable HCC. Between October 2014 and October 2022, a total of 2,959 patients with HCC who underwent initial IATs were enroled retrospectively from 13 tertiary hospitals. These patients were divided into the training cohort (n = 1700), validation cohort (n = 428), and test cohort (n = 200). Thirty-two clinical variables were input, and five supervised ML algorithms, including eXtreme Gradient Boosting (XGBoost), Categorical Gradient Boosting (CatBoost), Gradient Boosting Decision Tree (GBDT), Light Gradient Boosting Machine (LGBM) and Random Forest (RF), were compared using the areas under the receiver operating characteristic curve (AUC) with the DeLong test. A total of 1856 patients were assigned to the IAT alone Group(I-A), and 1103 patients were assigned to the IAT combination Group(I-C). The 12-month death rates were 31.9% (352/1103) in the I-A group and 50.4% (936/1856) in the I-C group. For the test cohort, in the I-C group, the CatBoost model achieved the best discrimination when 30 variables were input, with an AUC of 0.776 (95% confidence intervals [CI], 0.833-0.868). In the I-A group, the LGBM model achieved the best discrimination when 24 variables were input, with an AUC of 0.776 (95% CI, 0.833-0.868). According to the decision trees, BCLC grade, local therapy, and diameter as top three variables were used to guide clinical decisions between IAT modalities. The MLDSM can accurately stratify prognostic risk for HCC patients who received IATs, thus helping physicians to make decisions about IAT and providing guidance for surveillance strategies in clinical practice.

Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma.

The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1pg/ml) and LAG-3 (cut-off value: 3736.3pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.

Recent update of proton beam therapy for hepatocellular carcinoma: A systematic review and meta-analysis.

Although access to proton beam therapy (PBT) is limited worldwide, its use for the treatment of hepatocellular carcinoma (HCC) is gradually increasing with the expansion of new facilities. Therefore, we conducted a systematic review and meta-analysis to investigate the updated evidence of PBT for HCC. The MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were systematically searched for studies that enrolled patients with liver-confined HCC that were treated with PBT for a cure up to February 2024. A total of 1858 HCC patients receiving PBT from 22 studies between 2004 and 2023 were selected for this meta-analysis. The median proportion of Child-Pugh class A was 86% (range: 41-100%), and the median tumor size was 3.6 cm (range: 1.2-9 cm). The median total dose ranged from 55 GyE to 76 GyE (median, 69 GyE). The pooled rates of 3- and 5-year local progression-free survival after PBT were 88% (95% confidence interval [CI], 85-91%) and 86% (95% CI, 82-90%), respectively. The pooled 3- and 5-year overall rates were 60% (95% CI, 54-66%) and 46% (95% CI, 38-54%), respectively. The pooled rates of grade 3 hepatic toxicity, classic radiation-induced liver disease (RILD), and non-classic RILD were 1%, 2%, and 1%, respectively. The current study supports PBT for HCC and demonstrates favorable long-term survival and low hepatic toxicities compared with other published studies on other radiotherapy modalities. However, further studies are needed to identify the subgroups that will benefit from PBT.

Microwave Ablation Therapy for Hepatocellular Carcinoma: The Effect of Metabolic Heat on Temperature Distribution

Hepatocellular carcinoma is the main cause of liver cancer and one of the most occurring cancers worldwide. Microwave Ablation (MWA) is a method to destroy cancer cells by heating tumors above 50°C. Cancerous tissues can have high metabolic heat rates and affect temperature gain and distribution in thermal therapies. This research clarifies the metabolic heat effects in MWA therapy of liver cancer. Using Pennes Bioheat transfer equation with finite element numerical method, this research simulates temperature distribution with metabolic heat value ranging from 368,1 W/m3 to 29000 W/m3. The heat generated by metabolic heat is lower than the MWA heat source. However, the temperature increase should be considered as it can increase healthy surrounding tissue temperature to dangerous levels.

Development of an Optimized Promoter System for Exosomal and Naked AAV Vector-Based Suicide Gene Therapy in Hepatocellular Carcinoma

Development of an Optimized Promoter System for Exosomal and Naked AAV Vector-Based Suicide Gene Therapy in Hepatocellular Carcinoma

Hepatic arterial infusion chemotherapy plus camrelizumab and apatinib for advanced hepatocellular carcinoma.

There is limited information on combination of hepatic arterial infusion chemotherapy (HAIC) and systemic therapy for advanced hepatocellular carcinoma (Ad-HCC). We aim to compare the efficacy and safety of HAIC plus camrelizumab (a PD-1 inhibitor) and apatinib (an VEGFR-2 inhibitor) versus camrelizumab and apatinib for Ad-HCC. From April 2019 to October 2022, 416 patients with Ad-HCC who received either HAIC plus camrelizumab and apatinib (TRIPLET protocol, n = 207) or camrelizumab and apatinib (C-A protocol, n = 209) were reviewed retrospectively. The propensity score matching (PSM) was used to reduce selective bias. Overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan-Meier method with the log-rank test. Cox regression analyses of independent prognostic factors were evaluated. After PSM 1:1, 109 patients were assigned to two groups. The median OS of not reached in the TRIPLET group was significantly longer than that of 19.9months in the C-A group (p < 0.001), while in the TRIPLET group, the median PFS of 11.5months was significantly longer than that of 9.6months in the C-A group (p < 0.001). Multivariate analyses showed that the factors significantly affected the OS were CTP grade, tumor number > 3, and TRIPLET treatment (p < 0.001). Grade 3/4 adverse events occurred at a rate of 82.1% vs. 71.3% in TRIPLET and C-A groups, respectively. The TRIPLET protocol has promising survival benefits in the management of patients with Ad-HCC, with acceptable safety. The study has been retrospectively registered at Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ , ChiCTR2300075828).

Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π-πinteraction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model.

Validation of LI-RADS Treatment Response Algorithm after Loco-Regional Therapy of Hepatocellular Carcinoma

Abstract Background Hepatocellular carcinoma (HCC) is the third cause of cancer related death worldwide and liver cirrhosis is the most common predisposing factor for HCC. Loco-regional therapy as radiofrequency ablation (RFA) or trans-arterial chemoembolization (TACE) have very important role as potentially curative or palliative methods for treatment of HCC. Objective To investigate the potential application of LI-RADS Treatment Response [LRTR] algorithm in terminology and diagnostic performance after local- regional treatment of hepatic lesions. Methods During the period from September 2021 to March 2022, the present study included 31 patients: 26 were males and 5 were females with hepatocellular carcinoma treated by loco-regional therapy including 21 conventional TACE and 10 RF. Their ages ranged between 51 - 80 years with mean age of 70 years old. Results There were excellent inter-observer agreements between both reader radiologists regarding the classification of treated HCC: LR-TR viable, LR-TR non- viable and LR-TR equivocal according to major features of LIRADS. DWI and ADC as well as T1 and T2 pre-contrast signal are considered good ancillary features in evaluating post treatment response of treated HCC. Conclusion Our study demonstrates that LIRADS treatment response algorithm is a good reporting system for explaining the outcome of the treated HCC with loco-regional therapy as it doesn’t depend only on APHE and mentions that there is expected post-treatment enhancement pattern that does not denote viability. This isn’t found in modified RECIST criteria.

Anti-hepatoma immunotherapy of Pholiota adiposa polysaccharide-coated selenium nanoparticles by reversing M2-like tumor-associated macrophage polarization

Targeting macrophages to regulate the tumor microenvironment is a promising strategy for treating cancer. This study developed a stable nano drug (PAP-SeNPs) using Se nanoparticles (SeNPs) and the Pholiota adiposa polysaccharide component (PAP-1a) and reported their physical stability, M2-like macrophages targeting efficacy and anti-hepatoma immunotherapy potential, as well as their molecular mechanisms. Furthermore, the zero-valent and well-dispersed spherical PAP-SeNPs were also successfully synthesized with an average size of 55.84 nm and a negative ζ-potential of −51.45 mV. Moreover, it was observed that the prepared PAP-SeNPs were stable for 28 days at 4 °C. Intravital imaging highlighted that PAP-SeNPs had the dual effect of targeting desirable immune organs and tumors. In vitro analyses showed that the PAP-SeNPs polarized M2-like macrophages towards the M1 phenotype to induce hepatoma cell death, triggered by the time-dependent lysosomal endocytosis in macrophages. Mechanistically, PAP-SeNPs significantly activated the Tlr4/Myd88/NF-κB axis to transform tumor-promoting macrophages into tumor-inhibiting macrophages and successfully initiated antitumor immunotherapy. Furthermore, PAP-SeNPs also enhanced CD3+CD4+ T cells and CD3+CD8+ T cells, thereby further stimulating anti-hepatoma immune responses. These results suggest that the developed PAP-SeNPs is a promising immunostimulant that can assist hepatoma therapy.