• ablation
• external beam radiation
• hepatectomy
• immunotherapy
• liver transplantation
• multimodal therapy
• patient selection
• toxicity
• transarterial therapies
• tyrosine kinase inhibitor

• HCC
• SBRT
• SIRT
• liver cancer
• radiation-induced liver disease
• radiotherapy combinations

• Humans
• Carcinoma, Hepatocellular/radiotherapy
• Liver Neoplasms/radiotherapy
• Radiosurgery/methods
• Microspheres
• Radiotherapy Dosage
• Male
• Combined Modality Therapy/methods
• Yttrium Radioisotopes/therapeutic use
• Proof of Concept Study
• Radiotherapy Planning, Computer-Assisted/methods
• Radiation Injuries/prevention & control

• R00 CA267560 NCI NIH HHS
• NIH
• R00CA267560 NCI NIH HHS

• adverse events
• distant recurrence
• hepatocellular carcinoma
• local recurrence
• radiofrequency ablation
• stereotactic body radiation therapy
• subsequent treatments
• survival

• Clinical target volume
• Clinicopathologic correlation
• Hepatocellular carcinoma
• Microinvasion
• Radiotherapy

• Humans
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/radiotherapy
• Carcinoma, Hepatocellular/diagnostic imaging
• Carcinoma, Hepatocellular/surgery
• Liver Neoplasms/pathology
• Liver Neoplasms/radiotherapy
• Liver Neoplasms/diagnostic imaging
• Male
• Female
• Middle Aged
• Neoplasm Invasiveness
• Prognosis
• Hepatectomy/methods
• Aged
• Tumor Burden
• Follow-Up Studies
• Retrospective Studies
• Adult
• Radiotherapy Planning, Computer-Assisted/methods
• Liver Cirrhosis/pathology

• No. YHJH201908 Third Affiliated Hospital of Sun Yat-sen University, Clinical Research Program

• Humans
• Antineoplastic Agents/therapeutic use
• Proteasome Inhibitors/pharmacology
• Proteasome Inhibitors/therapeutic use
• Neoplasms/radiotherapy
• Neoplasms/drug therapy
• Deubiquitinating Enzymes/metabolism
• Radiation Tolerance

• LRP6
• circFBLIM1
• exosome
• hepatocellular carcinoma
• miR-338

• Humans
• Carcinoma, Hepatocellular/genetics
• Liver Neoplasms/genetics
• Low Density Lipoprotein Receptor-Related Protein-6/genetics
• Apoptosis
• MicroRNAs/genetics
• Cell Proliferation
• Cell Line, Tumor
• Glycolysis

• auto-planning
• dose sparing
• liver cancer
• number of half arcs
• stereotactic body radiation therapy
• volumetric-modulated arc therapy

• China
• Diagnosis
• Guidelines
• Hepatocellular carcinoma
• Primary liver cancer
• Treatment

Liver cancer is one of the most common cancers in the world. Of all types of liver cancer, hepatocellular carcinoma (HCC) is known to be the most frequent primary liver malignancy and has seriously compromised the health status of the general population. Locoregional thermal ablation techniques such as radiofrequency and microwave ablation, have attracted attention in clinical practice as an alternative strategy for HCC treatment. However, their aggressive thermal effect may cause undesirable complications such as hepatic decompensation, hemorrhage, bile duct injury, extrahepatic organ injuries, and skin burn. In recent years, photodynamic therapy (PDT), a gentle locoregional treatment, has attracted attention in ablation therapy for patients with superficial or luminal tumors as an alternative treatment strategy. However, some inherent defects and extrinsic factors of PDT have limited its use in clinical practice for deep-seated HCC. In this contribution, the aim is to summarize the current status and challenges of PDT in HCC treatment and provide potential strategies to overcome these deficiencies in further clinical translational practice.

• Hepatocellular carcinoma
• Photodynamic therapy
• Photosensitizers
• Aggregation-induced emission
• Targeted therapy
• Nanoparticles

• hepatocellular carcinoma
• pd-1 inhibitor
• radiotherapy
• sorafenib
• transcatheter arterial chemoembolization

• Adrenal Gland Neoplasms/pathology
• Adrenal Gland Neoplasms/therapy
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• Combined Modality Therapy/methods
• Heart Atria/pathology
• Heart Atria/surgery
• Hepatectomy
• Humans
• Immune Checkpoint Inhibitors
• Liver Neoplasms/complications
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Thrombectomy
• Thrombosis/surgery
• Vena Cava, Inferior/pathology
• Vena Cava, Inferior/surgery
• Venous Thrombosis/surgery

• DNA damage
• Hepatitis B virus (HBV) X protein
• Liver cancer
• SMC5/6
• Talazoparib
• Veliparib.
• gammaH2AX

• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/radiotherapy
• Carcinoma, Hepatocellular/virology
• Cell Death/drug effects
• Cell Death/radiation effects
• Cell Line, Tumor
• Combined Modality Therapy
• Hepatitis B/complications
• Hepatitis C/complications
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/radiotherapy
• Liver Neoplasms/virology
• Poly(ADP-ribose) Polymerase Inhibitors/pharmacology

• Cancer
• Carcinoma
• China
• Diagnosis
• Liver
• Treatment

Circular RNAs (circRNAs) play an important regulatory role in various cancers, including hepatocellular carcinoma (HCC). This study aimed to investigate the function of hsa_circ_0006942 (circ-ATP5H) in hepatitis B virus (HBV)-associated HCC and its underlying mechanism.

The levels of circ-ATP5H, miR-138-5p and tumor necrosis factor alpha-induced protein 3 (TNFAIP3) were determined using quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot assay. The copies of HBV DNA were examined using qRT-PCR. The levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were detected via enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter assay was used to analyze the interactions among circ-ATP5H, miR-138-5p and TNFAIP3.

Circ-ATP5H and TNFAIP3 levels were increased, while miR-138-5p level was reduced in HBV-positive HCC tissues and cells. Knockdown of circ-ATP5H hindered HBV DNA replication and decreased HBsAg and HBeAg levels in HBV-infected cells. Circ-ATP5H silencing suppressed HBV replication and expression by regulating miR-138-5p. Moreover, miR-138-5p blocked HBV replication and expression via targeting TNFAIP3. Furthermore, circ-ATP5H up-regulated TNFAIP3 via absorbing miR-138-5p.

Circ-ATP5H promoted HBV replication and expression through modulating miR-138-5p/TNFAIP3 axis, suggesting a new biomarker for HBV-related HCC treatment.

• TNFAIP3
• circ-ATP5H
• hepatitis B virus
• hepatocellular carcinoma
• miR-138-5p

• DLX2
• Hepatocellular carcinoma
• circ_HIPK3
• miR-582-3p

• Animals
• Apoptosis
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Proliferation
• F-Box Proteins/genetics
• F-Box Proteins/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Middle Aged
• Prognosis
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/therapy
• Female
• Humans
• Liver Neoplasms/complications
• Liver Neoplasms/therapy
• Male
• Portal Vein/abnormalities
• Thrombosis/etiology
• Treatment Outcome

• Combined therapies
• Liver transplantation
• Percutaneous ablation therapies
• Portal vein tumor thrombosis
• Sorafenib
• Surgery
• Systemic chemotherapy
• Transarterial chemoembolization
• Transarterial radioembolization

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic/methods
• Contrast Media/administration & dosage
• Disease-Free Survival
• Hepatectomy
• Humans
• Hypertension, Portal/etiology
• Hypertension, Portal/mortality
• Hypertension, Portal/therapy
• Liver Neoplasms/complications
• Liver Neoplasms/mortality
• Liver Neoplasms/therapy
• Liver Transplantation
• Neoadjuvant Therapy/methods
• Neoplasm Invasiveness/pathology
• Neoplasm Recurrence, Local/epidemiology
• Neoplasm Recurrence, Local/pathology
• Neoplasm Recurrence, Local/prevention & control
• Patient Selection
• Portal Vein/diagnostic imaging
• Portal Vein/pathology
• Prognosis
• Survival Analysis
• Thrombectomy
• Time Factors
• Ultrasonography/methods
• Venous Thrombosis/etiology
• Venous Thrombosis/mortality
• Venous Thrombosis/therapy

The increasing set of liver-directed therapies (LDT) have become an integral part of hepatocellular carcinoma (HCC) treatment. These range from percutaneous ablative techniques to arterial embolization, and varied radiotherapy strategies. They are now used for local disease control, symptom palliation, and bold curative strategies. The big challenge in the face of these innovative and sometimes overlapping technologies is to identify the best opportunity of use. In real practice, many patients may take benefit from LDT used as a bridge to curative treatment such as resection and liver transplantation. Varying trans-arterial embolization strategies are used, and comparison between established and developing technologies is scarce. Also, radioembolization utilizing yttrium-90 (Y-90) for locally advanced or intermediate-stage HCC needs further evidence of clinical efficacy. There is increasing interest on LDT-led changes in tumor biology that could have implications in systemic therapy efficacy. Foremost, additional to its apoptotic and necrotic properties, LDT could warrant changes in vascular endothelial growth factor (VEGF) expression and release. However, trans-arterial chemoembolization (TACE) used alongside tyrosine-kinase inhibitor (TKI) sorafenib has had its efficacy contested. Most recently, interest in associating Y-90 and TKI has emerged. Furthermore, LDT-led differences in tumor immune microenvironment and immune cell infiltration could be an opportunity to enhance immunotherapy efficacy for HCC patients. Early attempts to coordinate LDT and immunotherapy are being made. We here review LDT techniques exposing current evidence to understand its extant reach and future applications alongside systemic therapy development for HCC.

• HCC
• RFA
• TACE
• VEGF
• Yttrium-90
• combination
• hepatocellular carcinoma
• immunotherapy
• liver-directed therapy
• radiation

Hepatocellular carcinoma (HCC) is the most common tumors in the worldwide, it develops resistance to radiotherapy during treatment, understanding the regulatory mechanisms of radioresistance generation is the urgent need for HCC therapy.

qRT-PCR, western blot and immunohistochemistry were used to examine MCM3 expression. MTT assay, colony formation assay, terminal deoxynucleotidyl transferase nick end labeling assay and In vivo xenograft assay were used to determine the effect of MCM3 on radioresistance. Gene set enrichment analysis, luciferase reporter assay, western blot and qRT-PCR were used to examine the effect of MCM3 on NF-κB pathway.

We found DNA replication initiation protein Minichromosome Maintenance 3 (MCM3) was upregulated in HCC tissues and cells, patients with high MCM3 expression had poor outcome, it was an independent prognostic factor for HCC. Cells with high MCM3 expression or MCM3 overexpression increased the radioresistance determined by MTT assay, colony formation assay, TUNEL assay and orthotopic transplantation mouse model, while cells with low MCM3 expression or MCM3 knockdown reduced the radioresistance. Mechanism analysis showed MCM3 activated NF-κB pathway, characterized by increasing the nuclear translocation of p65, the expression of the downstream genes NF-κB pathway and the phosphorylation of IKK-β and IκBα. Inhibition of NF-κB in MCM3 overexpressing cells using small molecular inhibitor reduced the radioresistance, suggesting MCM3 increased radioresistance through activating NF-κB pathway. Moreover, we found MCM3 expression positively correlated with NF-κB pathway in clinic.

Our findings revealed that MCM3 promoted radioresistance through activating NF-κB pathway, strengthening the role of MCM subunits in the tumor progression and providing a new target for HCC therapy.

The online version of this article (10.1186/s13046-019-1241-9) contains supplementary material, which is available to authorized users.

• HCC
• MCM3
• NF-κB pathway
• Radiotherapy resistance

There is limited data on radiotherapy (RT) for hepatocellular carcinoma (HCC) in patients with Child-Pugh classification B (CP-B). This study aimed to evaluate the treatment outcomes of fractionated conformal RT in HCC patients with CP-B.

We retrospectively reviewed the data of HCC patients with CP-B treated with RT between 2009 and 2014 at 13 institutions in Korea. HCC was diagnosed by the Korea guideline of 2009, and modern RT techniques were applied. Fraction size was ≤ 5 Gy and the biologically effective dose (BED) ≥ 40 Gy₁₀ (α/β = 10 Gy). A total of 184 patients were included in this study.

Initial CP score was seven in 62.0% of patients, eight in 31.0%, and nine in 7.0%. Portal vein tumor thrombosis was present in 66.3% of patients. The BED ranged from 40.4 to 89.6 Gy₁₀ (median, 56.0 Gy₁₀). After RT completion, 48.4% of patients underwent additional treatment. The median overall survival (OS) was 9.4 months. The local progression-free survival and OS rates at 1 year were 58.9% and 39.8%, respectively. In the multivariate analysis, non-classic radiation-induced liver disease (RILD) (p < 0.001) and additional treatment (p < 0.001) were the most significant prognostic factors of OS. Among 132 evaluable patients without progressive disease, 19.7% experienced non-classic RILD. Normal liver volume was the most predictive dosimetric parameter of non-classic RILD.

Fractionated conformal RT showed favorable OS with a moderate risk non-classic RILD. The individual radiotherapy for CP-B could be cautiously applied weighing the survival benefits and the RILD risks.

• Child-Pugh B
• Hepatic toxicity
• Hepatocellular carcinoma
• Radiotherapy

Stereotactic body radiotherapy (SBRT) has shown promising results in the control of macroscopic vascular invasion in patients with hepatocellular carcinoma (HCC); however, its efficacy in comparison to sorafenib when combined with transarterial chemoembolization (TACE) remains to be determined. Between 2009 and 2017, 77 HCC patients with macroscopic vascular invasion receiving TACE–SBRT or TACE–sorafenib combination therapies were enrolled. The best treatment responses, overall survival (OS), and progression-free survival (PFS) of the two treatment arms were compared. Of the patients enrolled, 26 patients (33.8%) received TACE–SBRT treatment, and 51 (66.2%) received TACE–sorafenib treatment. The patients in the TACE–SBRT group were more frequently classified as elder in age (p = 0.012), having recurrent disease (p = 0.026), and showing lower rates of multiple hepatic lesions (p = 0.005) than patients in TACE–sorafenib group. After propensity score matching (PSM), 26 pairs of well-matched HCC patients were selected; patients in the TACE–SBRT group showed better overall response rates in trend compared to those in the TACE–sorafenib group. The hazard ratio (HR) of OS to PFS for the TACE–SBRT approach and the TACE–sorafenib approach was 0.36 (95% CI, 0.17–0.75; p = 0.007) and 0.35 (95% CI, 0.20–0.62; p < 0.001), respectively. For HCC patients with macrovascular invasion, TACE plus SBRT could provide improved OS and PFS compared to TACE–sorafenib therapy.

• hepatocellular carcinoma
• macrovascular invasion
• sorafenib
• stereotactic body radiotherapy
• transarterial chemoembolization

• Liver transplantation
• criteria
• downstaging
• hepatocellular carcinoma (HCC)