• epithelial–mesenchymal transition
• hepatocellular carcinoma
• proteoglycan 4
• starvation
• transcatheter arterial chemoembolization

• National Natural Science Foundation of China
• Science and Technology Department of Henan Province

Locoregional therapies (LRTs) of hepatocellular carcinoma (HCC) represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC. Among these, TACE is used throughout the stage Ib to IIIb of HCC treatment. In recent years, immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research. At the same time, targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC, and their clinical application has been quite mature. HCC is the sixth most common malignant tumor in the world. When it comes to its treatment, different therapies have different indications, and their individual efficacies are not satisfactory, which makes the exploration of the use of combination therapy in HCC treatment become a new trend. In this paper, the status of the three therapies and the progress of their combined application are briefly reviewed.

• Combination therapy
• Hepatocellular carcinoma
• Immunotherapy
• Locoregional therapy
• Targeted therapy

• cone-beam computed tomography
• drug-eluting micro-spheres
• hepatocellular carcinoma
• immunotherapy
• transarterial chemoembolization

• Guangzhou recommendations
• consensus
• hepatocellular carcinoma
• minimally-invasive therapy
• multidisciplinary comprehensive treatment

Transarterial chemoembolization (TACE) is, currently, the recommended treatment for hepatocellular carcinoma (HCC). However, long-term chemoembolization triggers the inflammatory response and may lead to postembolization syndrome (PES). Although several types of degradable microspheres have been developed to reduce drug toxicity and PES incidence, the clinical outcomes remain unsatisfactory. Previously, we have developed a new type of spherical, calibrated, biodegradable, radiopaque microspheres (SCBRM) and demonstrated their safety and efficacy in a pig model. Thus, the goal of this feasibility study was to determine the clinical safety and efficacy of the new SCBRM in intermediate-stage HCC patients. In this study, 12 intermediate-stage HCC patients underwent TACE using SCBRM with a calibrated size of 100–250 μm. The disease control rates at 1 month and 3 months after TACE-SCBRM treatment were 100% and 75.0%, respectively. The objective response rates at 1 month and 3 months after treatment were 66.7% and 58.3%, respectively. Very few adverse events were observed with one patient developing nausea. One day after the treatment, alanine aminotransferase, alanine aminotransferase, and total bilirubin levels were slightly elevated in the patients, but all returned to baseline on day 7. The median and mean overall survival times were 33 months (interquartile range, 12.8–42.0) and 29.2 ± 14.3 months, respectively. The 1-year and 2-year survival rates were 91.7% and 58.3%, respectively. In conclusion, TACE with the new SCBRM microspheres is clinically safe and effective, and it represents a promising approach in the management of intermediate-stage HCC.

• Drug-eluting beads
• Epirubicin
• Hepatocellular carcinoma
• Transcatheter arterial chemoembolization

This study aimed to explore the morphology, loadability, and releasing profiles of CalliSpheres microspheres in delivering oxaliplatin.

Varied amount (20, 40, 60, and 80 mg oxaliplatin) and concentration (1.25, 2.5, 5.0 mg/mL oxaliplatin) of oxaliplatin were mixed with CalliSpheres microspheres with 3 sizes (50-150 μm, 100-300 μm, and 300-500 μm) to measure the loadability. Of all, 20 mg oxaliplatin-loaded CalliSpheres microspheres with 3 sizes was prepared to measure the releasing profiles, meanwhile, fetal bovine serum was added to determine the effect of serum on oxaliplatin releasing. The morphology and size distribution of CalliSpheres microspheres with 3 sizes before and after 20 mg oxaliplatin loading were detected.

Oxaliplatin amount was negatively correlated with loading efficiency with highest loadability in 20 mg oxaliplatin group (maximum 40% in 50-100 µm CalliSpheres microspheres, 52% in 100-300 µm CalliSpheres microspheres, and 52% in 300-500 µm CalliSpheres microspheres), while oxaliplatin concentration was positively associated with loading efficiency. Similar drug-releasing profiles were observed among oxaliplatin-loaded CalliSpheres microspheres with 3 sizes, and a rapid drug release was discovered in CalliSpheres microspheres with 3 sizes as well. We also found that fetal bovine serum did not affect the drug-releasing profiles of oxaliplatin-loaded CalliSpheres microspheres. In addition, CalliSpheres microspheres was modified a little to ellipse shape and less smooth after oxaliplatin loading, and it was enlarged to some extent.

This study discloses drug loadability, releasing profiles, and morphology change of CalliSpheres microspheres for delivering oxaliplatin, which provides potential evidences for application of oxaliplatin-loaded drug-eluting beads in clinical practice.

• CalliSpheres microspheres
• loadability
• morphology
• oxaliplatin
• releasing profiles

• Adult
• Aged
• Carcinoma, Hepatocellular/radiotherapy
• Female
• Follow-Up Studies
• Humans
• Liver Neoplasms/radiotherapy
• Male
• Medical Audit/statistics & numerical data
• Middle Aged
• Radiosurgery/methods
• Retrospective Studies
• Treatment Outcome

Currently, no standard of care or therapies have been established for patients with advanced HCC. We evaluated the efficacy and safety of conventional transarterial chemoembolization using gelatin sponges or microspheres plus lipiodol-doxorubicin (cTACE) and TACE with doxorubicin-loaded drug eluting beads (DEB-TACE).

This retrospective study included 273 patients who received cTACE (n = 201) or DEB-TACE. Tumor response, survival, and adverse events were evaluated over a 5-year follow-up period.

During 5-year follow-up, a greater percentage of patients treated with cTACE died than those treated with DEB-TACE (76.1% vs. 66.7%) (P = 0.045). At the last evaluation, all surviving patients had disease progression and no differences were seen between treatment groups. However, the time to disease progression differed between groups; median time to disease progression was 11.0 months for cTACE and 16.0 months for DEB-TACE (P = 0.019). The median survival time was 37 months in both treatment groups. No significant differences were observed between cTACE and DEB-TACE therapies in subgroups of patients with BCLC stage A or stage B + C either in survival time or time to disease progression (P values > 0.05). No significant differences were observed in survival status or disease progression between cTACE and DEB-TACE in patient subgroups with either tumor number > 5 or with the sum of the diameter of largest five HCC tumors being > 7 cm.

DEB-TACE demonstrates greater long-term benefits than cTACE in treating treatment-naïve patients with HCC. Results of this long-term study support the use of DEB-TACE in treating HCC.

• DEB-TACE
• Drug-eluting bead transcatheter arterial chemoembolization
• Hepatocellular carcinoma
• TACE
• Transcatheter arterial chemoembolization

Talin-1 is a known oncogene-associated protein. In this study, we set out to determine its role and mechanisms in hepatocellular carcinoma (HCC) progression. We found Talin-1 to be highly expressed in HCC cells relative to non-cancer liver epithelial cells and to promote tumor growth and metastasis. We used Whole Human Genome Oligo Microarray analysis with HCC cells and HCC cells in which Talin-1 was knocked down using shRNA to identify transcripts regulated by Talin-1. Of the 40,000 tested genes, 3099 were differentially expressed after Talin-1 knockdown; expression of 1924 genes was increased, while expression of 2175 was decreased. Gene ontology (GO) profiling indicated that Talin-1 promotes many HCC progression-related activities, including ion transport and membrane depolarization, cell growth, and cell adhesion. We also characterized the network of gene transcripts regulated by Talin-1 and their role in promoting HCC progression. Our findings confirm the role of Talin-1 in carcinogenesis and provided a set of novel therapeutic targets for the treatment of HCC.

• Talin-1
• hepatocellular carcinoma
• ion transport
• membrane depolarization
• tumor growth and metastasis

According to Barcelona Clinic Liver Cancer classification transarterial chemoembolization is indicated in patients with Hepatocellular Carcinoma in the intermediate stage. Drug-eluting microspheres can absorb and release the chemotherapeutic agent slowly for 14 days after its intra-arterial administration. This type of transarterial chemoembolization approach appears to provide at least equivalent effectiveness with less toxicity.

This is a prospective, single-center study, which evaluated 21 patients with intermediate and advanced hepatocellular carcinoma who underwent transarterial chemoembolization with drug-eluting microspheres. The follow up period was 2 years. Inclusion criteria was Child-Pugh A or B liver disease patients, intermediate or advanced hepatocellular carcinoma and performance status equal or below 2. Transarterial chemoembolization with drug-eluting microspheres was performed at 2-month intervals during the first two sessions. The third and subsequent sessions were performed according to the image findings on follow-up, on a “demand schedule”. Tumor response and time to progression were evaluated along the two-year follow up period.

Of the 21 patients 90% presented with liver cirrhosis, 62% had Barcelona Clinic Liver Cancer stage B and 38% had Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma. Average tumor size was 6.9 cm. The average number of Transarterial chemoembolization with drug-eluting microspheres procedures was 3 with a total of 64 sessions. The predominant toxicity was mild. Liver function was not significantly affected in most patients. Two deaths occurred within 90 days after Transarterial chemoembolization with drug-eluting microspheres (ischemic hepatitis and hydropic decompensation). Technical success was achieved in 63 of 64 procedures. The mean hospital stay was 1.5 days. The progression free and overall survival at 1 and 2 years were 73.0% and 37.1%, 73.7% and 41.6%, respectively.

Transarterial chemoembolization with drug-eluting microspheres is able to deliver significant tumor response and progression free survival rate with acceptable toxicity. Larger studies are needed to identify exactly which subset of advanced hepatocellular patients may benefit from this treatment.

study ID ISRCTN16295622. Registered October 14th 2016. Retrospectively registered.

Website registration: http://www.isrctn.com/ISRCTN16295622

Transcatheter arterial chemoembolization (TACE) is an effective palliative intervention that is widely accepted for the management of hepatocellular carcinoma (HCC). Post-TACE pulmonary complications resulting in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are rare events. Pulmonary complications after TACE are thought to be related to chemical injury subsequent to the migration of the infused ethiodized oil or chemotherapeutic agent to the lung vasculature, facilitated by arteriovenous (AV) shunts within the hyper-vascular HCC. We review herein the literature on pulmonary complications related to TACE for HCC. Post-TACE pulmonary complications have included pulmonary oil embolism, interstitial pneumonitis, chemical pneumonitis, ALI, ARDS, lipoid pneumonia, acute eosinophilic and neutrophilic pneumonia, bilious pleuritis, pulmonary abscess, pulmonary tumor embolism, and possibly pulmonary metastasis with HCC. The risk factors associated with post-TACE pulmonary complications identified in the literature include large hyper-vascular HCC with AV shunts, large-volume Lipiodol infusion, and embolization via the right inferior phrenic artery. However, the absence of known risk factors is not a guarantee against serious complications. An astute awareness of the potential post-TACE pulmonary complications should expedite appropriate therapeutic interventions and increase potential for early recovery.

• Transcatheter arterial chemoembolization
• Liver cirrhosis
• Pulmonary complications
• Hepatocellular carcinoma
• Acute lung injury
• Acute respiratory distress syndrome
• Pneumonitis
• Pulmonary oil embolism

• Chemoembolization
• Chemotherapy
• Epidemiology
• Hepatocellular carcinoma
• Liver cancer
• Liver transplantation
• Percutaneous ethanol injection
• Radiofrequency ablation
• Treatment

In patients with metastatic colorectal cancer, the liver is the most common site of metastatic disease. In patients with liver-dominant disease, consideration needs to be given to locoregional treatments such as hepatic arterial infusion chemotherapy, transarterial chemoembolisation and selective internal radiation therapy because hepatic metastases are a major cause of liver failure especially in chemorefractory disease. In this review we provide insights on the published literature for locoregional treatment of liver metastases in metastatic colorectal cancer.

• Colorectal cancer
• Liver metastases
• Intrahepatic treatment
• Chemoembolization
• Radioembolisation

The purpose of the study is to investigate the inhibition of hypoxia-induced angiogenesis after embolization in VX2 rabbit liver tumors by liposomal curcumin.

A total of 54 VX2 rabbits were divided into three groups, and each group had three subgroups according to the sacrifice time. The animals in the control group (n=18) underwent sham embolization. Transcatheter arterial embolization (TAE)-treated group (n=18) animals underwent embolization with lipiodol (0.1 mL/kg body weight) and 90–180 µm polyvinyl alcohol (PVA) particles. Liposomal curcumin TAE-treated group (n=18) animals underwent embolization with liposomal curcumin (20 mg/kg body weight) mixed with lipiodol (0.1 mL/kg body weight) and 90–180 µm PVA particles. After embolization, the animals in each subgroup were sacrificed at 6 hours, 24 hours, and 3 days, and the tumor samples were collected. Immunohistochemical staining was performed to evaluate expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) proteins, and microvessel density (MVD). Real-time polymerase chain reaction was performed to examine VEGF mRNA levels.

The levels of HIF-1α and VEGF, and MVD in tumors of liposomal curcumin TAE-treated group were significantly decreased compared to the TAE-treated group (P<0.05). There was a slight decrease in tumor size in the liposomal curcumin TAE-treated group at third-day time points compared to the TAE-treated group; the difference was not statistically significant (P>0.05). The HIF-1α protein correlated considerably with VEGF mRNA (r=0.705, P=0.001) and protein (r=0.655, P=0.003), and MVD (r=0.521, P=0.027). A significant correlation between VEGF protein and MVD was noted as well (r=0.519, P=0.027).

Liposomal curcumin downregulates HIF-1α protein levels and inhibits hypoxia-induced angiogenesis after embolization in VX2 rabbit liver tumors.

• angiogenesis
• embolization
• hypoxia-inducible factor-1α
• liver tumor

• Combination
• Eastern
• Guidelines
• Hepatocellular carcinoma
• Treatment

• Asia/epidemiology
• Asian People
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/ethnology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/therapy
• Combined Modality Therapy
• Guideline Adherence
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/ethnology
• Liver Neoplasms/mortality
• Liver Neoplasms/therapy
• Practice Guidelines as Topic
• Practice Patterns, Physicians'/standards
• Practice Patterns, Physicians'/trends
• Treatment Outcome

• hepatocellular cancer
• drug delivery
• tumor endothelium

• Animals
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/metabolism
• Antibodies, Monoclonal/pharmacokinetics
• Antibody Specificity
• Biological Availability
• CD146 Antigen/immunology
• CD146 Antigen/metabolism
• Carcinoma, Hepatocellular/blood supply
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Drug Carriers
• Endothelial Cells/immunology
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Epitopes
• Humans
• Injections, Intravenous
• Liver Circulation
• Liver Neoplasms/blood supply
• Liver Neoplasms/drug therapy
• Liver Neoplasms/immunology
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Microcirculation

• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic/adverse effects
• Chemoembolization, Therapeutic/methods
• Disease Management
• Humans
• Liver Neoplasms/therapy
• Odds Ratio
• Publication Bias
• Treatment Outcome

• chemotherapy
• mTOR inhibition
• microtubular stabilization and destabilization
• microtubule-binding agents

• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/surgery
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• Combined Modality Therapy
• Disease Progression
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/surgery
• Liver Neoplasms/therapy
• Niacinamide/adverse effects
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Phenylurea Compounds/adverse effects
• Phenylurea Compounds/therapeutic use
• Sorafenib
• Survival Analysis
• Time Factors

• CYP2B1
• Carcinomatosis
• Compartment based therapy
• Drug-eluting beads
• Glioblastoma
• Hyperthermic intraperitoneal chemotherapy
• Ifosfamide
• Intraperitoneal
• Pancreatic cancer

• Animals
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/metabolism
• Carcinoma/drug therapy
• Carcinoma/genetics
• Carcinoma/metabolism
• Carcinoma/secondary
• Cell- and Tissue-Based Therapy/methods
• Chemoembolization, Therapeutic
• Cytochrome P-450 CYP2B1/genetics
• Cytochrome P-450 CYP2B1/metabolism
• Drug Carriers
• Genetic Therapy/methods
• Humans
• Ifosfamide/administration & dosage
• Ifosfamide/metabolism
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Peritoneal Neoplasms/drug therapy
• Peritoneal Neoplasms/genetics
• Peritoneal Neoplasms/metabolism
• Peritoneal Neoplasms/secondary
• Prodrugs/administration & dosage
• Prodrugs/metabolism

Curative therapies for hepatocellular carcinoma (HCC), such as resection and liver transplantation, can only be applied in selected patients with early tumors. More advanced stages require local or systemic therapies. Resection of HCC offers the only hope for cure. Even in patients undergoing resection, recurrences are common. Chemoembolization, a technique combining intra-arterial chemotherapy with selective tumor ischemia, has been shown by randomized controlled trials to be efficacious in the palliative setting. There is now renewed interest in transarterial embolization/transarterial chemoembolization (TACE) with regards to its use as a palliative tool in a combined modality approach, as a neoadjuvant therapy, in bridging therapy before transplantation, for symptomatic indications, and even as an alternative to resection. There have also been rapid advances in the agents being embolized trans-arterially (genes, biological response modifiers, etc.). The current review provides an evidence-based overview of the past, present and future trends of TACE in patients with HCC.

• Liver tumors
• Embolization
• Chemoembolization
• Review