Activation of AMPK pathway by low­dose donafenib and atorvastatin combination improves high­fat diet­induced metabolic dysfunction­associated steatotic liver disease.

Metabolic dysfunction­associated steatotic liver disease (MASLD) is an increasingly significant global health burden for which there is currently no effective treatment. The present study aimed to explore the underlying mechanisms and investigate the effects of donafenib and atorvastatin in MASLD. The effects of donafenib and atorvastatin on the activity and lipid metabolism of HepG2 cells were analyzed in vitro. A rat model of MASLD was established induced by a high­fat diet in vivo. H&E and Oil red O staining were used to observe the improvement in MASLD, western blotting analysis was used to detect the expression of proteins related to fat metabolism and immunofluorescence was used to detect reactive oxygen species (ROS) levels. In vitro, donafenib and atorvastatin inhibited lipid accumulation in HepG2 cells. In vivo, donafenib and atorvastatin activated the AMP­activated protein kinase (AMPK) pathway, downregulated the expressions of proteins related to fatty acid synthesis (sterol regulatory element­binding protein­1, 3­hydroxy­3­methylglutaryl­CoA reductase and fatty acid synthase) and upregulated the expression of proteins related to fatty acid ß­oxidation (carnitine palmitoyl­transferase 1C and acyl­CoA oxidase). The levels of free fatty acids, cholesterol and triglycerides in the liver and serum decreased in all three treatment groups. Additionally, donafenib and atorvastatin reduced oxidative stress in the liver tissue and decreased ROS levels. Low­dose donafenib combined with atorvastatin improved MASLD by regulating fatty acid metabolism and reducing oxidative stress through activation of the AMPK signaling pathway.

Ginkgetin exhibits antifibrotic effects by inducing hepatic stellate cell apoptosis via STAT1 activation.

Liver fibrosis affects approximately 800 million patients worldwide, with over 2 million deaths each year. Nevertheless, there are no approved medications for treating liver fibrosis. In this study, we investigated the impacts of ginkgetin on liver fibrosis and the underlying mechanisms. The impacts of ginkgetin on liver fibrosis were assessed in mouse models induced by thioacetamide or bile duct ligation. Experiments on human LX-2 cells and primary mouse hepatic stellate cells (HSCs) were performed to explore the underlying mechanisms, which were also validated in the mouse models. Ginkgetin significantly decreased hepatic extracellular matrix deposition and HSC activation in the fibrotic models induced by thioacetamide (TAA) and bile duct ligation (BDL). Beneficial effects also existed in inhibiting hepatic inflammation and improving liver function. In vitro experiments showed that ginkgetin markedly inhibited HSC viability and induced HSC apoptosis dose-dependently. Mechanistic studies revealed that the antifibrotic effects of ginkgetin depend on STAT1 activation, as the effects were abolished in vitro after STAT1 silencing and in vivo after inhibiting STAT1 activation by fludarabine. Moreover, we observed a meaningful cross-talk between HSCs and hepatocytes, in which IL-6, released by ginkgetin-induced apoptotic HSCs, enhanced hepatocyte proliferation by activating STAT3 signaling. Ginkgetin exhibits antifibrotic effects by inducing HSC apoptosis via STAT1 activation and enhances hepatocyte proliferation secondary to HSC apoptosis via the IL-6/STAT3 pathway.

Synergistic Effects of Nanoscale CaO2 Combined with PD-1 Inhibitors in the Treatment of Hepatocellular Carcinoma: A Promising Combination.

Purpose: To explore the effect of calcium peroxide nanoparticles (CaO2 NPs) combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of liver cancer and its related mechanism. Methods: Hepa1-6 cells were cultured to construct the Hepa1-6 mouse liver cancer model. In vivo mechanism study, a unilateral tumor model was established. Eighteen tumor-bearing mice were randomly divided into the control group (intra-tumoral injection of PBS solution) and the experimental group (intra-tumoral injection of CaO2 NPs). A hypoxic probe, pH probe, and micro-CT were used to evaluate the effect of CaO2 NPs on improving hypoxia, neutralizing acidity, and inducing calcium overload within the tumor. To study the effect of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors, the bilateral tumor model was established. Forty tumor-bearing mice were randomly divided into the control group (intra-tumoral/intra-peritoneal injection of PBS solution), CaO2 NPs group (intra-tumoral injection of CaO2 NPs), PD-1 group (intra-peritoneal injection of PD-1 inhibitor), and the combination group (intra-tumoral injection of CaO2 NPs and intra-peritoneal injection of PD-1 inhibitors). The administered side was recorded as the proximal tumor. Tumor volume and body weight were measured every 2 days after treatment. On day 8, serum and tumor samples were collected. The immune factors in serum (Interferon-γ (IFN-γ), Tumour necrosis factor-α (TNF-α), Interleukin-2 (IL-2), and Interleukin-10 (IL-10)) and tumor tissue (IFN-γ and TNF-α) were detected by ELISA. H&E staining was used to detect tumor necrosis. Immunohistochemical staining was used to detect the amount of CD4+ and CD8+ T cells within the tumor. By analyzing the tumor volume, pathological indexes, and immune-related indexes, the effects of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors were evaluated, and they mediated immunomodulatory effects (including local and systemic immunity), and their effects on tumor burden were studied. In addition, a unilateral tumor model was established to study the effect of CaO2 NPs combined with PD-1 inhibitors on survival time. Results: The results of in vivo mechanism study showed that CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors. The results of the study on the effect of CaO2 NPs combined with PD-1 inhibitor on proximal and distal tumors showed that, compared with the other three groups, the bilateral tumor burden of the combination group was significantly reduced, the intra-tumoral infiltration of CD8+ and CD4+ T cells were significantly increased, the secretion of anti-tumor immune factors in tumor and serum was increased, and the secretion of pro-tumor immune factors was decreased. Mice in the combination group showed the longest survival compared with the other groups. Conclusion: CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors, so as to reduce tumor burden and realize an immunosuppressive tumor transformation to a hot tumor, and play a synergistic role with PD-1 inhibitors in anti-liver cancer.

Reversion of liver cirrhosis after endovascular treatment in Chinese patients with Budd-Chiari syndrome.

AIMS: To investigate the impact of endovascular (EV) treatment on liver cirrhosis in Chinese patients with Budd-Chiari syndrome (BCS). METHODS: From September 2011 to March 2022, 97 patients from four hospitals in China who were diagnosed with primary BCS complicated with liver cirrhosis and received EV treatment were retrospectively enrolled in this study for clinical analysis. In addition, liver tissues for basic research were acquired from 25 patients between June 2022 and March 2023, including six with benign liver tumors, 11 with BCS before EV treatment, and eight with EV-treated BCS. Liver cirrhosis was assessed by clinical outcomes, histological studies, and the expression of related genes at the mRNA and protein levels. RESULTS: The patients with BCS had better liver function after EV treatment, evidenced by an increased albumin level and reduced total bilirubin, ALT, and AST. The imaging findings suggested an amelioration of liver cirrhosis and portal hypertension, including increased portal vein velocity (13.52 ± 8.89 cm/s vs. 17.51 ± 6.67 cm/s, p < 0.001) and decreased liver stiffness (30.37 ± 6.39 kPa vs. 23.70 ± 7.99 kPa, p < 0.001), portal vein diameter (14.97 ± 3.42 mm vs. 13.36 ± 2.89 mm, p < 0.001), and spleen volume (870.00 ± 355.61 cm3 vs. 771.36 ± 277.45 cm3 , p < 0.001). Furthermore, histological studies revealed that EV treatment resulted in a restoration of liver architecture with reduced extracellular matrix deposition. Meanwhile, hepatic angiogenesis and inflammation, which have a close relationship with cirrhosis, were also inhibited. In addition, the state of hepatocytes switches from apoptosis to proliferation after EV treatment. CONCLUSIONS: BCS-induced liver cirrhosis could be reversed by EV treatment from macroscopic to microscopic dimensions. Our study may provide further insights into understanding BCS and treating cirrhosis.

Changes and influencing factors of liver volume after transjugular intrahepatic portosystemic shunt: a retrospective cohort study.

Background: Liver volume is an important measure of liver reserve and helps to determine the course of liver disease. This study aimed to observe the dynamic changes of liver volume after transjugular intrahepatic portosystemic shunt (TIPS) and analyze the related factors. Methods: Clinical data of 168 patients who underwent TIPS procedures between February 2016 and December 2021 were collected and analyzed retrospectively. The changes in liver volume after TIPS in the patients were observed, and the independent predictors affecting increases in liver volume were analyzed using a multivariable logistic regression model. Results: The mean liver volume was decreased by 12.9% at 2±1 months post TIPS and rebounded at 9±3 months post TIPS, but did not recover to its pre-TIPS level completely. Most patients (78.6%) had decreased liver volume at 2±1 months post TIPS, and in multivariable logistic regression, a lower albumin (ALB) level, a lower subcutaneous fat area at L3 (L3-SFA), and a higher degree of ascites were identified as independent factors predicting increased liver volume. The risk score model for predicting increased liver volume was Logit(P)=1.683-0.078 (ALB) -0.01 (pre TIPS L3-SFA) +0.996 (grade 3 ascites =1; non-grade 3 ascites =0). The area under the curve of the receiver operating characteristic curve was 0.729, and the cut-off value was 0.375. The rate of liver volume change at 2±1 months post TIPS was significantly correlated with that of spleen volume change (R2=0.378, P<0.001). The rate of subcutaneous fat change at 9±3 months post TIPS was significantly correlated with that of liver volume change (R2=0.782, P<0.001). In patients with a liver volume increase, the mean computed tomography value (Hounsfield units) decreased significantly after TIPS placement (65.9±17.7 vs. 57.8±18.2, P=0.009). Conclusions: Liver volume was decreased at 2±1 months post TIPS and slightly increased at 9±3 months post TIPS; however, it did not recover to its pre-TIPS level completely. A lower ALB level, a lower L3-SFA, and a higher degree of ascites were all predictors for increased liver volume post TIPS.

Management of traumatic peripheral artery pseudoaneurysm: A 10-year experience at a single center.

Purpose: This study aimed to report our 10-year experience with the management of iatrogenic (penetrating trauma) and traumatic (blunt or penetrating trauma) peripheral artery pseudoaneurysms, based on data from a tertiary referral center. Methods: From January 2012 to December 2021, the medical records of consecutive patients with iatrogenic and traumatic peripheral artery pseudoaneurysms were retrospectively reviewed. Patient demographics, clinical features, imaging data, treatment details, and follow-up results were analyzed. Results: Sixty-one consecutive patients were included in this study; 48 (79%) were men and 13 (21%) women, with a mean age of 49.4 â€‹± â€‹13.4 years (range 24-73 years). There were 42 patients (69%) who underwent open surgery, 18 (29%) undergoing endovascular embolization or stent implantation, and one (2%) undergoing ultrasound-guided thrombin injection. All patients successfully underwent open or interventional treatment. The median follow-up was 46.8 months (2.5-117.9 months), and the overall reintervention rate was 10%. Of these, one (5%) patient in the interventional treatment group and five (12%) patients in the open surgery group underwent reintervention. The overall complication rate was 8%, with complications occurring only in the open surgery group. No deaths occurred in the peri-operative period. No late complications, such as thrombosis or pseudoaneurysm recurrence, were observed. Conclusion: Peripheral artery pseudoaneurysms arising from iatrogenic or traumatic causes can be effectively treated by both open surgery and interventional procedures in selected patients with acceptable mid- and long-term outcomes.

Nanoscale CaO2 materials for synergistic transarterial chemoembolization in a VX2 orthotopic rabbit liver cancer model.

Transcatheter arterial chemoembolization (TACE) is extensively used in the treatment of hepatocellular carcinoma (HCC), but its efficacy is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). Herein, we synthesized polyvinyl pyrrolidone (PVP)-coated CaO2 nanoparticles (CaO2 NPs) and applied them as a synergistic agent to improve the antitumor efficacy of TACE. After injection into the tumor, CaO2 NPs reacted with water to generate abundant oxygen, hydroxyl ions (OH-), and calcium ions (Ca2+), thereby relieving tumor hypoxia, neutralizing acid, and overloading Ca2+ to mediate antitumor effects. Moreover, the effect of chemotherapeutic drugs within the TACE was improved due to the modulated TME. CaO2 NPs efficiently regulated the TME and improved the antitumor effect of doxorubicin under hypoxia conditions in vitro. Compared to other groups, the TACE+CaO2 NPs group achieved the lowest tumor growth rate, highest tumor necrosis rate, lowest expression of histological markers associated with hypoxia and angiogenesis (HIF-α, VEGF, and CD31), and highest CD8+ T cell recruitment in vivo. Thus, these findings demonstrated that CaO2 NPs provide synergy for TACE therapy in the VX2 orthotopic rabbit liver cancer model, suggesting that they have a potential broad clinical application. STATEMENT OF SIGNIFICANCE: The efficacy of transcatheter arterial chemoembolization (TACE) for treatment of hepatocellular carcinoma is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). To address this issue, we synthesized CaO2 nanoparticles (CaO2 NPS) which would react with water to generate abundant oxygen, hydroxyl ions (OH-), and calcium ions (Ca2+), thereby relieving tumor hypoxia, neutralizing the acidic TME, and inducing Ca2+ overloading. The efficacy of CaO2 NPs in combination with TACE was investigated in an orthotopic rabbit liver cancer model, and the results showed the great synergetic antitumor effect of TACE and CaO2 NPs.

A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy.

Transcatheter arterial chemoembolization (TACE) has become the preferred therapy for unresectable advanced hepatocellular carcinoma (HCC). However, the embolization of tumor-feeding arteries by TACE always leads to hypoxia-related tumor angiogenesis, which limited the therapeutic effect for HCC. In this paper, we used a VEGFR targeting peptide VEGF125 - 136 (QKRKRKKSRYKS) to conjugate with a lytic peptide (KLUKLUKKLUKLUK) to form a peptide-drug conjugate (PDC). We used cell affinity assay to detect the peptide binding ability to VEGFR highly expressed cell lines, and CCK8, cell apoptosis to confirm the cellular toxicity for different cell lines. Meanwhile, we created a VX2 tumor-bearing rabbit model to assess the in vivo anti-tumor effect of the peptide conjugate in combination with TAE. HE staining was used to verify the in vivo safety of the peptide conjugate. IHC was used to assess the anti-angiogenesis and cell toxicity of the peptide conjugate in tumor tissues. The peptide conjugate could not only target VEGFR in cell surface and inhibit VEGFR function, but also have potent anti-cancer effect. We luckily found the peptide conjugate showed potent cytotoxicity for liver cancer cell Huh7 (IC50 7.3 ± 0.74 µM) and endothelial cell HUVEC (IC50 10.7 ± 0.292 µM) and induced cell apoptosis of these two cell lines. We also found the peptide conjugate inhibited cell migration of HUVEC through wound healing assay. Besides, these peptides also showed better in vivo anti-tumor effect than traditional drug DOX through TACE in VX2 rabbit tumor model, and efficiently inhibit angiogenesis in tumor tissues with good safety. In conclusion, our work may provide an alternative option for clinical HCC therapy via TACE combination.

Late combination of transarterial chemoembolization with apatinib and camrelizumab for unresectable hepatocellular carcinoma is superior to early combination.

OBJECTIVE: The purpose of this study was to explore the efficacy and safety of transarterial chemoembolization (TACE) combined with apatinib and camrelizumab (TACE + AC) for unresectable hepatocellular carcinoma (HCC), and the impact of the timing of the combination on it. METHODS: In this single-arm retrospective study, consecutive data of patients with unresectable HCC treated to our hospital from March 2017 to September 2021 were collected. These patients were treated with TACE and started on camrelizumab and apatinib within one week of TACE. Camrelizumab 200 mg intravenously once every three weeks and apatinib 250 mg orally once daily. Repeat TACE treatment was available on an on-demand basis. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. The univariate and multivariate Cox regression analyses were used to assess the effect of early and late combination on OS and PFS. RESULTS: A total of 80 patients were enrolled in this study. The median OS was 22.1 months (95% confidence interval [CI]: 13.8-30.5 months) and the median PFS was 15.7 months (95% CI: 14.7-16.6 months). The ORR was 58.8% (95% CI: 47.2-69.6) and DCR reached 81.2% (95% CI: 71.0-89.1). Multivariable Cox proportional hazard regression analyses showed that TACE late combined with apatinib and camrelizumab provided better OS than early combination (HR = 0.175, 95% CI:0.060-0.509, P = 0.001), as did PFS (HR = 0.422, 95% CI:0.184-0.967, P = 0.041). All treatment-related adverse events were tolerable, and no serious adverse events were observed. CONCLUSION: TACE combined with apatinib plus camrelizumab for patients with unresectable HCC has promising antitumor activity and a manageable safety profile. For unresectable HCC with large tumor burden, late combination provides better OS and PFS compared to early combination.

Microwave ablation combined with anti-PD-1 therapy enhances systemic antitumor immunity in a multitumor murine model of Hepa1-6.

BACKGROUND: To evaluate the changes of immune environment of distant tumors after combined microwave ablation (MWA) and anti- programmed death receptor - 1 (anti-PD-1) therapy, and assess the changes of systemic immune response. METHODS: Bilateral hepatocellular carcinoma model was established in mice, which were then subsequently treated with MWA, or anti-PD-1, or no treatment, or MWA + anti-PD-1. The contralateral tumor volume and mice survival time were recorded. Flow cytometry and immunohistochemistry were used for evaluation of the immune cells subgroup change of contralateral tumor. In addition, tumor rechallenge tests were conducted on unilateral tumor-bearing mice to examine the systemic immune effects of the combination therapy. RESULTS: We found that MWA treatment alone failed to produce a significant abscopal effect. In contrast, the combination group had longer survival than the MWA or anti-PD-1 group alone, with slower distant tumor growth. Moreover, the tumor-specific immune responses induced by combination therapy are stronger than anti-PD-1 or MWA alone. Combination therapy also elevated the levels of Th1-type cytokines in peripheral blood. In addition, after tumor rechallenge, the combination group showed more rejection to the reimplanted tumors (6 out of 10 mice). CONCLUSIONS: The combination of MWA and anti-PD-1 therapy resulted in the inhibition of distant tumor growth and the construction of a systemic anti-tumor immune environment that can reduce recurrence.

Drug-eluting bead transarterial chemoembolization followed by apatinib is effective and safe in treating hepatocellular carcinoma patients with BCLC stage C.

BACKGROUND: The present study aimed to evaluate the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) followed by apatinib in treating hepatocellular carcinoma (HCC) patients with Barcelona Clinic Liver Cancer (BCLC) stage C. METHODS: Totally, 110 HCC patients with BCLC stage C treated with DEB-TACE followed by apatinib were consecutively enrolled. Treatment response (including complete response rate (CR), objective response rate (ORR) and disease control rate (DCR)), survival data (progression-free survival (PFS), overall survival (OS)), and adverse events were documented during the follow-up. RESULTS: CR, ORR and DCR were 25.5%, 77.2% and 79.1% at 3 months, then were 29.1%, 59.1% and 71.0% at 6 months, respectively. Regarding survival, median PFS (95%CI) was 6.3 (5.0-7.7) months, meanwhile 1-year and 2-year PFS were 19.8% and 3.3%, respectively; median OS (95%CI) was 16.9 (10.2-23.7) months, then 1-year, 2-year and 3-year OS were 66.5%, 34.7% and 14.2%, respectively. Further subgroup analysis indicated that nodule size, Child-Pugh stage, Eastern Cooperative Oncology Group performance status score and level of portal vein invasion were negatively correlated with PFS or OS, which were further validated by univariate and multivariate Cox's regression analysis. Most adverse events by DEB-TACE and apatinib treatment were mild and well-tolerable. CONCLUSION: DEB-TACE followed by apatinib is effective and safe in treating BCLC stage C HCC patients, indicating its role as an acceptable option in HCC management.

Covered vs. uncovered self-expandable metal stents for palliation of malignant afferent loop obstruction: a multicenter study.

BACKGROUND AND AIMS: Endoscopic stent placement is a palliative therapy for malignant digestive tract obstruction. However, its use for malignant afferent loop obstruction (mALO) has not been adequately investigated. METHODS: From March 2009 to December 2020, 137 patients with mALO who underwent endoscopic stent placement at three tertiary care centers were retrospectively enrolled. The primary aim of this study was to compare stent dysfunction (SD) between the covered self-expandable metal stent (CSEMS) and uncovered self-expandable metal stent (UCSEMS) groups, with subgroup analysis among patients with extrinsic and intrinsic tumors separately. RESULTS: Twenty-three patients developed SD in the CSEMS group and 29 patients in the UCSEMS group (log-rank p = .974). The primary contributors to SD included a higher risk of stent migration in the CSEMS group and stent ingrowth in the UCSEMS group (p = .003; p < .001). Among patients with extrinsic tumors, the CSEMS group showed a significantly higher probability of overall SD (p = .008) and stent migration (p = .001) with a shorter time to SD (log-rank p = .006) than the UCSEMS group. Among patients with intrinsic tumors, the CSEMS group showed a significantly lower incidence of overall SD (p < .001) and stent ingrowth (p < .001) with a longer time to SD (log-rank p = .011) than the UCSEMS group. CONCLUSIONS: Our results showed no significant difference in SD between the CSEMS and UCSEMS groups for palliation of mALO. Furthermore, subgroup analysis suggested using CSEMSs for patients with intrinsic tumors, and UCSEMSs for those with extrinsic tumors.

Donafenib-Loaded Callispheres Beads Embolization in a VX2 Liver Tumor: Investigating Efficacy, Safety, and Improvement of Tumor Angiogenesis After Embolization.

OBJECTIVE: To investigate the efficiency and safety of callispheres beads loaded with donafenib (DCBs) for embolization in a VX2 liver tumor, as well as the improvement of tumor angiogenesis following embolization. METHODS: Forty New Zealand white rabbit VX2 liver tumors were treated with four different drugs via the hepatic artery: NS (normal saline), CB (blank callispheres beads), ACB (adriamycin-loaded callispheres beads) and DCB (DCBs). Hematoxylin-eosin staining was performed to assess tumor necrosis, while MRI was employed to detect the changes in tumor size. The safety was evaluated by the liver and kidney function parameters, and the immunofluorescence and immunohistochemical staining were performed to reflect the tumor hypoxia and tumor angiogenesis following embolization. RESULTS: The DCB group had the smallest tumor growth rate, but the tumor necrosis rate was the highest of the four groups. Compared to the CB and ACB groups, the DCB group did not aggravate the liver damage and had no influence on kidney function. The staining results showed that, although the tumor hypoxia deteriorated after DCBs embolization, the expression of VEGF (vascular endothelial growth factor) reduced, thus inhibiting tumor angiogenesis. CONCLUSION: DCB administration via hepatic artery is an effective and safe treatment for a preclinical liver cancer model, with the unique benefit of suppressing tumor angiogenesis following embolization.

PSMC2/ITGA6 axis plays critical role in the development and progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a type of malignant tumor with sixth highest incidence and causes the third most cancer-related deaths in the world, whose treatment is limited by the unclear molecular mechanism. Currently, the correlation between PSMC2 and HCC is still unclear. Herein, we found that the expression of PSMC2 in HCC tissues was significantly higher than normal tissues. We also discovered the significant association between PSMC2 expression and tumor infiltrate as well as tumor stage. Further investigations indicated that PSMC2 knockdown contributed to impaired proliferation, colony formation, migration, and enhanced cell apoptosis in HCC cells. Moreover, PSMC2 could also suppress tumorigenicity of HCC cells in vivo. Gene microarray analysis followed by ingenuity pathway analysis was performed for exploring downstream of PSMC2 and identified ITGA6 as a potential target. Furthermore, our study revealed that ITGA6 knockdown exhibited similar inhibitory effects with PSMC2 on HCC cells in vitro. More importantly, our results proved the direct interaction and showed the mutual regulation between PSMC2 and ITGA6, and that PSMC2 knockdown could significantly aggravate the inhibition of HCC by ITGA6 depletion. Based on these intriguing results, this is the first time ever that PSMC2 is pinpointed as a tumor promotor to interfere HCC development and progression via interacting with ITGA6 directly.

Arsenic trioxide-loaded CalliSpheres: In vitro study of drug release and antitumor activity, and in vivo study of pharmacokinetics, treatment efficacy and safety in liver cancer.

The aim of the present study was to investigate the arsenic trioxide (ATO) loading/releasing efficiency of CalliSphere beads (CBs), as well as the in vitro anticancer activity, in vivo pharmacokinetics, treatment efficacy and safety of ATO-eluting CBs in liver cancer. The ATO loading and releasing efficiencies in CBs were evaluated. Furthermore, cell viability, invasion, apoptosis, VEGF expression and MMP9 expression were determined in liver cancer cells treated with ATO-eluting CBs or ATO solution. Rabbit liver models were established and underwent TACE with ATO-eluting CBs or ATO/lipiodol emulsion. Subsequently, their ATO pharmacokinetics were determined and macroscopic/microscopic examinations were conducted. In vitro, CB-loaded ATO increased during 40 min with an optimal loading efficiency of 23.0±2.5%, and released ATO rapidly within the first 30 min (31.40±10.0%) then slowed down within the latter 48 h (47.20±4.70%). ATO-eluting CBs exhibited decreased cell viability to some extent and similar invasive cell count, apoptosis rate, VEGF and MMP9 levels compared with ATO solution at various concentrations and time-points. In vivo, ATO concentration was lower in plasma, but higher in tumor tissues, and necrosis was more complete in tumor tissue while milder in normal liver parenchyma after rabbit liver was embolized with ATO-eluting CBs compared with ATO/lipiodol emulsion. ATO-eluting CBs may be a novel and promising therapeutic option in treating liver cancer.

Comparison of Treatment Response, Survival Profiles, as Well as Safety Profiles Between CalliSpheres® Microsphere Transarterial Chemoembolization and Conventional Transarterial Chemoembolization in Huge Hepatocellular Carcinoma.

PURPOSE: CalliSpheres® microspheres (CSM) are the first drug-eluting beads (DEB) developed in China. This study aimed to compare treatment response, survival, and safety profiles between DEB transarterial chemoembolization (DEB-TACE) with CSM and conventional TACE (cTACE) in huge hepatocellular carcinoma (HCC) patients. METHODS: A total of 71 patients with huge HCC who underwent DEB-TACE or cTACE were consecutively enrolled in this retrospective cohort study. Treatment response was assessed at first month (M1), third month (M3), and sixth month (M6) after TACE therapy; progression-free survival (PFS) and overall survival (OS) were evaluated; liver function indexes were recorded before TACE operation (M0), at first week (W1), M1 and M6 after TACE therapy; adverse events which occurred after TACE operation were recorded. RESULTS: DEB-TACE presented with higher objective response rate (60.0% vs. 29.7%, p < 0.05) and disease control rate (86.7% vs. 59.4%, p < 0.05) compared with cTACE at M3. Regarding survival profiles, PFS [median: 3.3 months (95% CI: 2.8-3.7) vs. 2.1 months (95% CI: 1.7-2.5)] as well as OS [median: 7.8 months (95% CI: 4.6-11.0) vs. 5.7 months (95% CI: 5.0-6.3)] were longer in DEB-TACE group compared with cTACE group (both p < 0.01). Multivariate Cox's regression further illustrated that DEB-TACE vs. cTACE was an independent protective factor for PFS and OS (both p < 0.01). As for safety profiles, patients' liver function injury was reduced in the DEB-TACE group compared with the cTACE group. The incidence of fever was lower, and CINV was less severe in the DEB-TACE group compared with the cTACE group (both p < 0.05), while no difference in occurrence of liver abscess, increase of ascites, or moderate pain between two groups was observed. CONCLUSION: DEB-TACE with CSM presents with better treatment response, survival profiles, as well as safety profiles compared with cTACE in treatment for huge HCC patients.

Apatinib Plus Camrelizumab With/Without Chemoembolization for Hepatocellular Carcinoma: A Real-World Experience of a Single Center.

OBJECTIVE: This study was conducted in order to compare the efficacy and safety of transarterial chemoembolization (TACE) plus apatinib plus camrelizumab (TACE+AC) and apatinib plus camrelizumab (AC) in the treatment of unresectable hepatocellular carcinoma (HCC) in a real-world setting. METHODS: In this single-center retrospective study, the data of patients with unresectable HCC who had received TACE+AC or AC treatment during March 2017 to May 2021 were assessed. Patients in the AC group received intravenous administration of camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg/day treatment. Patients in the TACE+AC group received the same dose of camrelizumab and apatinib 1 week after TACE. The primary endpoint of the study was overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) as the secondary endpoints. RESULTS: A total of 108 patients were enrolled in the study. There were 52 patients in the AC group and 56 patients in TACE+AC group. Median OS was significantly longer in the TACE+AC group than in the AC group (24.8 vs. 13.1 months; P = 0.005). Patients in the TACE+AC group achieved a higher ORR [24 (42.9%) vs. 9 (17.3%), P = 0.004] than those in the AC group. Patients in the TACE+AC group also achieved a higher disease control rate (DCR) [48 (85.7%) vs. 30 (57.7%), P = 0.001] than patients in the AC group. There was no significant difference in the incidence of AEs related to apatinib and camrelizumab between the two groups, except for gastrointestinal reaction (P > 0.05, all; P < 0.05, gastrointestinal reaction). CONCLUSION: TACE plus apatinib plus camrelizumab significantly improved OS, ORR, and DCR over apatinib plus camrelizumab in patients with unresectable HCC. AEs were tolerable and manageable.

Combined use of microwave ablation and cell immunotherapy induces nonspecific immunity of hepatocellular carcinoma model mice.

Microwave ablation (MWA) has been widely used in the treatment of solid tumors. Studies have been less conducted on the efficacy of MWA used with cell immunotherapy in treating hepatocellular carcinoma (HCC). The current study aimed at exploring the efficacy of MWA in combination with cell immunotherapy in treating HCC. Hepa1-6 HCC mice were treated by MWA, blockade, or the combined therapy (MWA used with blockade), or left untreated. Survival rates of the mice were plotted by Kaplan-Meier Curve, followed by log-rank test. 25 days after the operation, surviving mice were monitored for tumor recurrence, and tumor volumes were calculated every 5 days. Immunohistochemistry and flow cytometry were performed to detect the numbers of CD4+ and CD8+ cells in the tumors and spleens of mice. The expressions of related cytokines were detected and measured by ELISPOT and ELISA. The results showed that MWA combined with anti-PD-1/anti-CTLA-4 not only increased the survival time, protected the mice against tumor recurrence, but also enhanced the intratumoral infiltration of cytotoxic T lymphocyte and systemic T-cell immune responses induced by MWA through activation of synergistically specific antitumor immunity. In addition, the combined therapy increased T-helper 1 cell (Th1-type) cytokines, but reduced Th2-type cytokines, resulting in the polarization of Th1 cells. T-cell immune responses of HCC cells were activated by MWA. In addition, the combined therapy of MWA and anti-PD-1/anti-CTLA-4 induced Th1-type immune response, and showed specific antitumor immunity.

Antitumor properties of arsenic trioxide-loaded CalliSpheres® microspheres by transarterial chemoembolization in VX2 liver tumor rabbits: suppression of tumor growth, angiogenesis, and metastasis and elongation of survival.

This study aimed to investigate the antitumor effect of arsenic trioxide (ATO)-loaded CalliSpheres® microspheres (CSM) by transarterial chemoembolization (TACE) in rabbits with VX2 liver tumors. A total of 120 VX2 liver tumor rabbits were randomized into four groups (N = 30 for each group), which received ATO-loaded CSM by TACE (CSM-ATO group), ATO by conventional TACE (cTACE-ATO group), transcatheter arterial embolization using CSM (TAE-CSM group), and saline arterial injection (control group). Five rabbits in each group were sacrificed at 12 h, 3 d, 7 d and 14 d, and then tumor proliferation, apoptosis, and angiogenesis/epithelial-mesenchymal transition (EMT) markers were detected. Tumor volume, metastasis status and ascites were assessed at 14 d. Ten rabbits in each group were observed until death for accumulating survival calculation. Tumor volume and ascites were decreased in the CSM-ATO group compared to the cTACE-ATO and TAE-CSM groups. Pulmonary, abdominal wall and omentum metastases were reduced while accumulating survival was increased in the CSM-ATO group compared to the TAE-CSM group. However, no difference in metastasis foci or survival between the CSM-ATO and cTACE-ATO groups was discovered. Meanwhile, tumor apoptosis was promoted while proliferation was suppressed in the CSM-ATO group compared to the cTACE-ATO and TAE-CSM groups. Additionally, HIF-1α, VEGF and microvessel density were decreased in the CSM-ATO group compared to the cTACE-ATO and TAE-CSM groups. Additionally, twist, N-cadherin, vimentin and MMP-9 were reduced while E-cadherin was enhanced in the CSM-ATO group compared to the cTACE-ATO and TAE-CSM groups. In conclusion, ATO-loaded CSM by TACE suppressed tumor growth, angiogenesis, and metastasis and elongated survival in VX2 liver tumor rabbits.

Hepatic Arterial Chemoembolization With Arsenic Trioxide Eluting CalliSpheres Microspheres Versus Lipiodol Emulsion: Pharmacokinetics And Intratumoral Concentration In A Rabbit Liver Tumor Model.

BACKGROUND: The objective of this study was to investigate the plasma pharmacokinetic profiles, intratumoral concentration and tissue distribution of arsenic trioxide (ATO) by drug-eluting beads (DEB)-transcatheter arterial chemoembolization (TACE) compared with conventional TACE (cTACE) in a rabbit liver tumor model. METHODS: Sixty-four rabbits with VX2 liver tumor were established and randomly assigned to four groups equally. The calliSpheres microspheres (CSM)-ATO group received DEB-TACE treatment using ATO-loaded CSM; the cTACE-ATO group received cTACE treatment using ATO mixed with lipiodol; the CSM-normal control (NC) group received DEB-TACE treatment using blank CSM; the TAE-lipiodol group received cTACE treatment using saline mixed with lipiodol. ATO concentration in plasma, tumor and normal tissues, and liver and kidney function indexes were evaluated. RESULTS: The CSM-ATO group exhibited lower plasma ATO concentrations at 10 minutes and 20 minutes post treatment compared with the cTACE-ATO group. Meanwhile, intratumoral ATO concentrations were higher in the CSM-ATO group compared with the cTACE-ATO group at 3-, 7- and 14-days post treatment. In normal liver tissue, heart and muscle tissues, ATO concentrations between the CSM-ATO and cTACE groups were similar at each time point; in kidney and lung tissues, ATO concentrations were lower in the CSM-ATO group at 1-day post treatment while they were similar at 3, 7 and 14 days post treatment. Also, liver or kidney function indexes were of no difference at each time point between CSM-ATO and cTACE-ATO groups. CONCLUSION: Administration of ATO via DEB-TACE decreases systemic concentration while increasing intratumoral concentration of ATO without increasing liver or kidney toxicity compared with cTACE.