• Hepatocellular carcinoma
• Radiosensitivity
• Radiotherapy

• Drug delivery system
• Hepatocellular carcinoma
• Hydrogel
• Microsphere
• Nanoparticle
• Radiotherapy

• Carcinoma, Hepatocellular/radiotherapy
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/drug therapy
• Liver Neoplasms/radiotherapy
• Liver Neoplasms/therapy
• Liver Neoplasms/drug therapy
• Humans
• Animals
• Theranostic Nanomedicine/methods
• Nanostructures/chemistry
• Nanostructures/therapeutic use
• Radiation-Sensitizing Agents/chemistry
• Radiation-Sensitizing Agents/therapeutic use
• Drug Delivery Systems
• Radioimmunotherapy
• Tumor Microenvironment/drug effects

• Hepatocellular carcinoma
• Radiotherapy
• Sorafenib
• Tumor thrombosis

• Barcelona Clinic Liver Cancer stage C
• Hepatocellular carcinoma
• Radiation therapy
• Tyrosine kinase inhibitor

• Adverse event
• External radiotherapy
• Hepatic artery infusion chemotherapy
• Hepatocellular carcinoma
• Sorafenib
• Transarterial chemoembolization

• Humans
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/radiotherapy
• Sorafenib/therapeutic use
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Chemoembolization, Therapeutic
• Treatment Outcome

• 2020JDTD0036 Department of Science and Technology of Sichuan Province

• Hepatocellular carcinoma
• Immunotherapy
• Radioimmunotherapy
• Radiotherapy

• Humans
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/pathology
• Immunotherapy
• Treatment Outcome

• National Natural Science Foundation of China
• Natural Science Foundation of Beijing Municipality
• Intramural funding from the Beijing University Third Hospital
• National Key Clinical Specialty Discipline Construction Program of China

• Advanced hepatocellular carcinoma
• Lenvatinib
• Macrovascular invasion
• Stereotactic body radiotherapy

• Humans
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/radiotherapy
• Liver Neoplasms/drug therapy
• Liver Neoplasms/radiotherapy
• Propensity Score
• Radiosurgery/adverse effects
• Ubiquitin-Protein Ligases

• 82003211 This research was funded by National Natural Science Foundation of China.

• Hepatocellular carcinoma
• Lenvatinib
• Portal vein tumor thrombosis
• Stereotactic body radiotherapy

• 82003211 National Natural Science Foundation of China

• ZFL
• cell cycle
• cytotoxicity
• environmental hazard
• genotoxicity
• tyrosine kinase inhibitors
• zebrafish liver cells

• Animals
• Humans
• Antineoplastic Agents/toxicity
• Hepatocytes/drug effects
• Liver
• Pyrimidines/toxicity
• Sorafenib/toxicity
• Tyrosine Protein Kinase Inhibitors/toxicity
• Zebrafish

• P1-0245 Slovenian Research Agency
• J1-8140 Slovenian Research Agency
• Z1-1854 Slovenian Research Agency

• External radiotherapy
• Hepatocellular carcinoma
• Hepatoma
• Meta-analysis
• Sorafenib

• Hepatocellular carcinoma
• Portal vein tumor thrombosis
• Radiotherapy
• Sorafenib
• Surgery
• Transarterial chemoembolization

We performed a systematic review and meta-analysis to compare external beam radiation therapy modalities for hepatocellular carcinoma (HCC) with macrovascular invasion (MVI).

Studies were selected from online databases from the date of inception to November 2021. The outcomes of interest were overall survival (OS), objective response rate (ORR), and local control rate (LCR).

Forty-four studies (n = 3730) were selected from 1050 articles. The pooled 1-year OS were 60.9%, 45.3%, and 44.9 for particle radiotherapy (PRT) group, conventional radiotherapy (CRT), and stereotactic body radiotherapy (SBRT) group, respectively; p = 0.005 and 0.002 for PRT vs. CRT and SBRT, respectively. Both the PRT group and the SBRT group have the advantage over the CRT group in the pooled ORR. The PRT group showed significantly higher than the CRT group (p = 0.007) in LCR. For combination therapy, CRT plus transarterial chemoembolization can prolong survival than CRT alone (p = 0.006 for 1-year OS; p = 0.014 for 2-year OS). Among grade ≥ 3 complications, the most frequent type of toxicity in CRT, SBRT, PRT group was hematological toxicity, hepatotoxicity, dermatological toxicity, respectively.

Among patients with HCC with MVI, the 1-year OS and the 2-year OS were both higher in the PRT group than in the CRT, SBRT groups. The ORR was similar between the PRT and SBRT groups. The combination therapy based on radiotherapy is expectable. PRT is associated with less complications than photon radiotherapy.

• conformal radiation therapy
• hepatocellular carcinoma
• macrovascular invasion
• particle therapy
• portal vein tumor thrombosis
• radiation therapy
• stereotactic body radiotherapy

Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related mortality worldwide. While ablation, resection and orthotopic liver transplantation are indicated at an early stage of the disease, Sorafenib (Sfb) is the current most administrated first-line treatment for advanced HCC, even though its therapeutic benefit is limited due to the appearance of resistance. Deep knowledge on the molecular consequences of Sfb-treatment is essentially required for optimizing novel therapeutic strategies to improve the outcomes for patients with advanced HCC. In this study, we analyzed differential gene expression changes in two well characterized liver cancer cell lines upon a Sfb-treatment, demonstrating that both lines responded similarly to the treatment. Our results provide valuable information on the molecular action of Sfb on diverse cellular fundamental processes such as DNA repair, translation and proteostasis and identify rationalization issues that could provide a different therapeutic perspective to Sfb.

Hepatocellular carcinoma (HCC) is one of the most frequent and essentially incurable cancers in its advanced stages. The tyrosine kinase inhibitor Sorafenib (Sfb) remains the globally accepted treatment for advanced HCC. However, the extent of its therapeutic benefit is limited. Sfb exerts antitumor activity through its cytotoxic, anti-proliferative and pro-apoptotic roles in HCC cells. To better understand the molecular mechanisms underlying these effects, we used RNA sequencing to generate comprehensive transcriptome profiles of HepG2 and SNU423, hepatoblastoma- (HB) and HCC-derived cell lines, respectively, following a Sfb treatment at a pharmacological dose. This resulted in similar alterations of gene expression in both cell lines. Genes functionally related to membrane trafficking, stress-responsible and unfolded protein responses, circadian clock and activation of apoptosis were predominantly upregulated, while genes involved in cell growth and cycle, DNA replication and repair, ribosome biogenesis, translation initiation and proteostasis were downregulated. Our results suggest that Sfb causes primary effects on cellular stress that lead to upregulation of selective responses to compensate for its negative effect and restore homeostasis. No significant differences were found specifically affecting each cell line, indicating the robustness of the Sfb mechanism of action despite the heterogeneity of liver cancer. We discuss our results on terms of providing rationalization for possible strategies to improve Sfb clinical outcomes.

• Combined modality therapy
• Hepatocellular carcinoma
• Immunotherapy
• Locoregional therapy
• Transarterial chemoembolization
• Transarterial radioembolization

• Carcinoma, Hepatocellular/diagnostic imaging
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• Combined Modality Therapy
• Humans
• Immunotherapy
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/therapy

• Brain metastasis
• Breast cancer
• FLT-PET
• Sorafenib
• Whole brain radiotherapy

• Brain/diagnostic imaging
• Brain Neoplasms/diagnostic imaging
• Brain Neoplasms/drug therapy
• Brain Neoplasms/radiotherapy
• Breast Neoplasms/drug therapy
• Female
• Humans
• Neuroimaging
• Positron-Emission Tomography
• Sorafenib

• P30 CA008748 NCI NIH HHS

• combined
• concurrent
• external beam radiation therapy
• hepatocellular carcinoma
• sorafenib
• toxicity

• NRF-2019M2D2A1A01031560 National Research Fund of Korea

Lenvatinib is a systemic treatment for patients with advanced hepatocellular carcinoma (HCC). Stereotactic body radiation therapy (SBRT) is an advanced technique of hypofractionated external beam radiotherapy (EBRT) that can be applied in patients with HCC. The current study showed that the area under the concentration–time curve of lenvatinib concentration (AUC_lenvatinib) increased by 148.8% with radiotherapy (RT)_2Gy×3f’x (EBRT for the whole liver), and 68.9% with RT_9Gy×3f’× (SBRT targeting a 1.5 × 1.5 cm region in the center of the liver) in the sequential regimen compared to the concurrent regimen in rats. Additionally, the AUC_lenvatinib was decreased by 50% in the concurrent regimen of both RT techniques with lenvatinib compared to the control group. The biodistribution of lenvatinib in the organs at risk was markedly decreased in the concurrent regimens. The radiation–drug interactions were between lenvatinib and RT, and showed sequential preferably.

Concurrent and sequential regimens involving radiotherapy (RT) and lenvatinib were designed with off-target or stereotactic body radiation therapy (SBRT) doses in a freely moving rat model to evaluate the effect of RT on the pharmacokinetics (PK) of lenvatinib. Liver RT concurrent with lenvatinib decreased the area under the concentration–time curve of lenvatinib concentration (AUC_lenvatinib) by 51.1% with three fractions of 2 Gy (RT_2Gy×3f’x, p = 0.03), and 48.9% with RT_9Gy×3f’x (p = 0.03). The AUC_lenvatinib increased by 148.8% (p = 0.008) with RT_2Gy×3f’x, and 68.9% (p = 0.009) with RT_9Gy×3f’x in the sequential regimen compared to the concurrent regimen. There were no differences in the AUC_lenvatinib between RT_2Gy×3f’x and RT_9Gy×3f’x in the concurrent or sequential regimen. Both the RT_2Gy×3f’x and RT_9Gy×3f’x concurrent regimens markedly decreased the biodistribution of lenvatinib in the heart, liver, lung, spleen, and kidneys, which ranged from 31% to 100% for RT_2Gy×3f’x, and 11% to 100% for RT_9Gy×3f’x, compared to the sham regimen. The PK and biodistribution of lenvatinib can be modulated by simultaneous off-target irradiation and SBRT doses. The timing of lenvatinib administration with respect to RT, impacted the PK and biodistribution of the drug. Additionally, off-target and SBRT doses had a similar ability to modulate the effect of systemic therapy.

• biodistribution
• hepatocellular carcinoma
• lenvatinib
• pharmacokinetics
• radiotherapy

Hepatocellular carcinoma (HCC) is difficult to diagnose at an early stage, and its prognosis is generally poor. Sorafenib is the primary treatment for unresectable advanced HCC and targets multiple receptor tyrosine kinases. However, sorafenib only extends the average survival time by 3 months. This observation indicates that sorafenib may need to be combined with other treatments to further improve outcomes. We previously showed that combination of sorafenib with radiotherapy (RT) enhances tumor inhibition in subcutaneous HCC mouse models compared with monotherapy. The present study demonstrated that combining sorafenib and RT could suppress tumor growth in an orthotopic HCC model by regulating apoptosis and NF-κB-related pathways. Moreover, decreased numbers of visible liver tumors and a smaller percentage of spleen metastases were found in the combination group. A transient drop in body weight was initially observed after RT, but progressive recovery of body weight occurred. The current study showed that the combination of sorafenib and RT could be a safe strategy for HCC treatment.

• hepatocellular carcinoma
• orthotopic mouse model
• radiotherapy
• sorafenib

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) patients. This study aims to determine whether combining radiotherapy with sorafenib administration increases its efficacy. The study cohort included 4763 patients with diagnosed advanced HCC who received sorafenib between January 2012 and December 2015, as reported in medical records in the Taiwan Cancer Registry database. The effect of sorafenib with or without radiotherapy on survival was calculated using the Kaplan–Meier method and compared using the log-rank test. A Cox proportional hazards model was used for multivariate analysis. Patients receiving sorafenib plus radiotherapy had greater 1-year survival than did those receiving sorafenib alone (P < 0.001). Uni- and multivariate analyses also showed that radiotherapy increased survival after adjusting for confounders (adjusted HR 0.57; 95% CI 0.51–0.63). Further stratified analysis according to the timing of radiotherapy relative to sorafenib treatment revealed that patients who underwent radiotherapy after sorafenib had greater 1-year survival than did those undergoing radiotherapy within sorafenib use or sorafenib alone (adjusted HR 0.39; 95% CI 0.27–0.54). Combined treatment with sorafenib and radiotherapy results in greater HCC patient survival and should be considered an option for treating this challenging disease.

Radiotherapy is rapidly turning into a crucial component of multidisciplinary treatment for liver cancer because many patients are not surgical treatment candidates. Thanks to technical developments, radiotherapy have achieved high precision treatments, making it possible to eliminate tumor cells without severe damage to the liver and other organs. Stereotactic Body Radiation Therapy is an advanced radiotherapy technique able to eradicate malignant tumors wherever they are located in properly selected patients. The best use of radiotherapy, the most fruitful radiotherapy strategy, and the best way to combine it with other treatments for liver cancer are largely unknown. Radiosensitizers, agents that can potentiate radiotherapy, could broaden the radiotherapeutic landscape. Radiotherapy potentiation can be achieved with diverse treatments, not only drugs but also nanoparticles. In order to clear up the performance of radiotherapy in liver cancer management in the future and the best ways to potentiate its effects, considerable medical research is needed.

Stereotactic body radiotherapy (SBRT) is an emerging ablative modality for hepatocellular carcinoma (HCC). Most patients with HCC have advanced disease at the time of diagnosis, and therefore, are not candidates for definitive-intent therapies such as resection or transplantation. For this reason, various alternative local and regional therapies have been used to prevent disease progression, palliate symptoms, and delay liver failure. Stereotactic body radiation therapy is a non-invasive technique of delivering ablative doses of radiation to tumors while sparing normal or non-tumor hepatic tissue. Incorporation of SBRT in multidisciplinary HCC management is gradual, initially applied when other liver-directed therapies have failed or are contraindicated, and tried in combination with other locoregional or systemic therapies for more unfavorable conditions by more experienced teams. In order to improve SBRT therapeutic ratio, there has been much interest in augmenting the effect of radiation on tumors by combining it with chemotherapy, molecularly targeted therapeutics, nanoparticles, and immunotherapy. This review aims to synthesize available evidence to evaluate the clinical feasibility and efficacy of SBRT for HCC, and to explore novel radio-potentiation concepts by combining SBRT with novel therapeutics. It is expected that those approaches would result in improved therapeutic outcomes, even though many questions remain with regard to the optimal way to assemble treatments. Further trials are needed to evaluate and consolidate these promising therapies for HCC.

• hepatocellular cancer
• immunotherapy
• nanoparticles
• protein kinase inhibitors
• radiotherapy

Background: Targeted therapy has transformed the outcome for patients with metastatic renal cell carcinoma. Their efficacy and safety have also been demonstrated in brain metastatic RCC. Preclinical evidence suggests synergism of radiation and tyrosine kinase inhibitors. Consequently, several studies have compared their efficacy in the treatment of RCC brain metastases to the era of brain management with surgery/radiation only.

Objectives: We seek to systematically review and meta-analyze the results of those studies that involved comparative intervention groups of brain management; TKIs, and never used TKIs.

Methods and Materials: Online databases (PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov) were searched for comparative studies. Overall survival as the primary outcome of interest, and local brain control, distant control, and adverse events as secondary outcomes of interest were recorded for meta-analysis. Hazard ratios were pooled together using Review Manager 5.3. Fixed effects or random effects model were adopted according to the level of heterogeneity. Subgroup analysis included studies that involved SRS as the local treatment of management.

Results: Overall 7 studies (n = 897) were included for meta-analysis. TKI use was associated with better survival (HR 0.60 [0.52, 0.69], p < 0.00001) and local brain control (HR 0.34 [0.11, 0.98], p = 0.05). SRS subgroup also revealed significantly better survival (HR 0.61 [0.44, 0.83], p = 0.002) and local brain control (HR 0.19 [0.08, 0.45], p = 0.0002). Distant brain control (HR 0.95 [0.67, 1.35], p = 0.79) and brain progression free survival were unaffected (HR 0.94 [0.56, 1.56], p = 0.80). Only one study (n = 376) reported significantly greater 12-months cumulative incidence of radiation necrosis with TKI use within 30 days of SRS (10.9 vs. 6.4%, p = 0.04).

Conclusions: TKIs use in combination with SRS is safe and effective for treating RCC brain metastases. Larger randomized controlled trials are warranted to validate the results.

• brain control (BC)
• brain metastases (BM)
• metastatic renal cell carcinoma (mRCC)
• overall survival (OS)
• stereotactic radiosurgery (SRS)
• tyrosine kinase inhibitors (TKI)

• portal vein tumor thrombosis
• sorafenib
• stereotactic body radiation therapy

• Adult
• Aged
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/therapy
• Chemoradiotherapy/adverse effects
• Chemoradiotherapy/methods
• Female
• Humans
• Liver Neoplasms/complications
• Liver Neoplasms/mortality
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Portal Vein/pathology
• Progression-Free Survival
• Radiation Dosage
• Radiosurgery/adverse effects
• Radiosurgery/methods
• Retrospective Studies
• Sorafenib/administration & dosage
• Sorafenib/adverse effects
• Sorafenib/therapeutic use
• Taiwan
• Venous Thrombosis/complications

Limited effective intervention for advanced hepatocellular carcinoma (HCC) is available. This study aimed to investigate the potential clinical utility of apatinib, a highly selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, as a radiosensitizer in the treatment of HCC.

Four human HCC cell lines SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B were treated with apatinib, irradiation or combination treatment. Colony formation assay, flow cytometry and nuclear γ-H2AX foci immunofluorescence staining were performed to evaluate the efficacy of combination treatment. RNA sequencing was conducted to explore the potential mechanism. The impact of combination treatment on tumor growth was assessed by xenograft mice models.

Colony formation assay revealed that apatinib enhanced the radiosensitivity of HCC cell lines. Apatinib suppressed repair of radiation-induced DNA double-strand breaks. Flow cytometry analysis showed that apatinib increased radiation-induced apoptosis. Apatinib radiosensitized HCC via suppression of radiation-induced PI3K/AKT pathway. Moreover, an in vivo study indicated apatinib combined with irradiation significantly decreased xenograft tumor growth.

Our results indicate that apatinib has therapeutic potential as a radiosensitizer in HCC, and PI3K/AKT signaling pathway plays a critical role in mediating radiosensitization of apatinib.

• Apatinib
• Hepatocellular carcinoma
• Irradiation
• PI3K/AKT pathway
• Radiosensitization

Radiation therapy (RT) is widely used in cancer care strategies. Its effectiveness relies mainly on its ability to cause lethal damage to the DNA of cancer cells. However, some cancers have shown to be particularly radioresistant partly because of efficient and redundant DNA repair capacities. Therefore, RT efficacy might be enhanced by using drugs that can disrupt cancer cells' DNA repair machinery. Here we review the recent advances in the development of novel inhibitors of DNA repair pathways in combination with RT. A large number of these compounds are the subject of preclinical/clinical studies and target key enzymes involved in one or more DNA repair pathways. A totally different strategy consists of mimicking DNA double-strand breaks via small interfering DNA (siDNA) to bait the whole DNA repair machinery, leading to its global inhibition.

• DNA damage
• inhibition
• radioresistance
• radiotherapy
• repair systems

• Hepatocellular carcinoma
• Image-guided radiotherapy
• Radiotherapy
• Stereotactic body radiotherapy

• 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

ERK1 and ERK2 (ERKs), two extracellular regulated kinases (ERK1/2), are evolutionary-conserved and ubiquitous serine-threonine kinases involved in regulating cell signalling in normal and pathological tissues. The expression levels of these kinases are almost always different, with ERK2 being the more prominent. ERK1/2 activation is fundamental for the development and progression of cancer. Since their discovery, much research has been dedicated to their role in mitogen-activated protein kinases (MAPK) pathway signalling and in their activation by mitogens and mutated RAF or RAS in cancer cells. In order to gain a better understanding of the role of ERK1/2 in MAPK pathway signalling, many studies have been aimed at characterizing ERK1/2 splicing isoforms, mutants, substrates and partners. In this review, we highlight the differences between ERK1 and ERK2 without completely discarding the hypothesis that ERK1 and ERK2 exhibit functional redundancy. The main goal of this review is to shed light on the role of ERK1/2 in targeted therapy and radiotherapy and highlight the importance of identifying ERK inhibitors that may overcome acquired resistance. This is a highly relevant therapeutic issue that needs to be addressed to combat tumours that rely on constitutively active RAF and RAS mutants and the MAPK pathway.

• ERK1/2 splicing isoforms
• ERK2 mutants
• MAPK inhibitor
• MAPK signalling
• chemo- and radio-resistance

• Combination approaches
• Hepatocellular carcinoma
• Local-ablative treatment
• Mini-review
• Stereotactic body radiation therapy

• extracellular-signal-regulated kinase
• hepatocellular carcinoma
• nuclear factor-κB
• sorafenib
• trichostatin A

• anaphylaxis
• antitumor activity
• hepatocellular carcinoma
• natural killer cell
• neoplasm metastasis

• Antineoplastic Agents/administration & dosage
• Antineoplastic Protocols
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/secondary
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic/methods
• Combined Modality Therapy/methods
• Heart Atria/pathology
• Heart Neoplasms/pathology
• Heart Neoplasms/secondary
• Heart Neoplasms/therapy
• Humans
• Killer Cells, Natural/drug effects
• Killer Cells, Natural/radiation effects
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Lung/pathology
• Lung Neoplasms/pathology
• Lung Neoplasms/secondary
• Lung Neoplasms/therapy
• Male
• Middle Aged
• Niacinamide/administration & dosage
• Niacinamide/analogs & derivatives
• Phenylurea Compounds/administration & dosage
• Radiotherapy, Adjuvant/methods
• Remission Induction/methods
• Response Evaluation Criteria in Solid Tumors
• Sorafenib
• Tumor Burden

Patients with unresectable hepatocellular carcinoma (HCC) usually have poor prognosis because current monotherapy including surgery, chemotherapy and radiotherapy (RT) are not effective. Combination therapy may be effective to overcome this clinical problem. Here, we proposed the combination of sorafenib and RT, which have been applied in HCC treatment, could improve the treatment outcome of HCC. Our previous study showed that sorafenib could suppress the expression of NF-κB which is related to the chemo- and radio-resistance. Nevertheless, the expression of NF-κB is oscillatory and is affected by the treatments. Thus, understanding the oscillation of NF-κB expression would be beneficial for determining the optimal treatment schedule in combination therapy. Here established Huh7/NF-κB-tk-luc2/rfp cell line, in which NF-κB indicates a NF-κB promoter, was utilized to noninvasively monitor the expression of NF-κB overtime in vitro and in vivo. The results show that pretreatment of sorafenib with RT suppresses the expressions of NF-κB and its downstream proteins induced by radiation through downregulation of phosphorylated extracellular signal-regulated kinase (pERK) most significantly compared with other treatment schedules. The results were further verified with Western blotting, EMSA, and NF-κB molecular imaging. These findings suggest that pretreatment of sorafenib with RT may be the ideal treatment schedule for the treatment of HCC.

• MEK/ERK/NF-κB signaling
• hepatocellular carcinoma
• molecular imaging
• radiation
• sorafenib

• hepatocellular carcinoma
• lymph node metastasis
• nomogram
• prognostic factor
• survival

• conformal radiotherapy
• hepatocellular carcinoma
• intensity-modulated radiotherapy
• radiotherapy

• chemotherapy
• drug resistance
• hepatocellular carcinoma
• multimodal treatment

• gross tumor volume
• hepatocellular carcinoma
• hypofractionated radiotherapy
• radiation dose
• stereotactic body radiotherapy

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/radiotherapy
• Disease-Free Survival
• Female
• Follow-Up Studies
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms/diagnosis
• Liver Neoplasms/pathology
• Liver Neoplasms/radiotherapy
• Male
• Middle Aged
• Prognosis
• Radiotherapy Dosage
• Republic of Korea
• Retrospective Studies
• Treatment Outcome
• Tumor Burden

• low shear stress
• atherosclerosis
• autophagy
• apoptosis
• mechanism

• Hepatocellular carcinoma
• radioembolization
• sorafenib
• unresectability

• Biomarkers
• Hepatocellular carcinoma
• Molecular targeted agents
• Radiation therapy

• Chemotherapy
• Erythema
• Hepatocellular carcinoma
• Radiotherapy
• Toxicity

• Hepatic arterial chemotherapy
• Hepatocellular carcinoma
• Portal vein tumor thrombosis
• Radiotherapy
• Sorafenib
• Transarterial chemoembolization
• Transarterial radioembolization

• ADAM17 Protein/administration & dosage
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• Combined Modality Therapy
• Embolization, Therapeutic
• Humans
• Liver Neoplasms/complications
• Liver Neoplasms/therapy
• Niacinamide/administration & dosage
• Niacinamide/analogs & derivatives
• Niacinamide/therapeutic use
• Phenylurea Compounds/administration & dosage
• Phenylurea Compounds/therapeutic use
• Portal Vein
• Radiotherapy, Conformal
• Sorafenib
• Venous Thrombosis/etiology
• Venous Thrombosis/therapy

• Aged
• Carcinoma, Hepatocellular/radiotherapy
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• Combined Modality Therapy
• Disease Progression
• Disease-Free Survival
• Female
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms/radiotherapy
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Neoplasm Staging
• Palliative Care
• Prognosis
• Radiotherapy/adverse effects
• Retrospective Studies
• Survival Analysis
• Treatment Outcome