Cancer is a significant health issue impacting humans. Currently, systemic therapies such as chemotherapy have significantly increased the life expectancy of cancer patients. However, some patients are unable to endure systemic treatment due to its significant adverse effects, leading to an increased focus on local therapies including radiation and ablation therapy. Ablation therapy is a precise, low-toxicity, and minimally invasive localized therapy that is increasingly acknowledged by clinicians and cancer patients. Many cancer patients have benefited from it, with some achieving full recovery. Currently, numerous studies have shown that ablation therapy is effective due to its ability to kill cancer cells efficiently and activate the body's anti-cancer immunity. It can also convert "cold cancers" into "hot cancers" and enhance the effectiveness of immunotherapy when used in combination. In this article, we categorize ablation therapy into thermal ablation, cryoablation, photodynamic therapy (PDT), irreversible electroporation (IRE), etc. Thermal ablation is further divided into Radiofrequency ablation (RFA), microwave ablation (WMA), high-frequency focused ultrasound (HIFU), photothermal therapy (PTT), magnetic heat therapy (MHT), etc. We systematically review the most recent advancements in these ablation therapies that are either currently used in clinic or are anticipated to be used in clinic. Then, we also review the latest development of various ablative therapies combined with immunotherapy, and its future development. CLINICAL RELEVANCE STATEMENT: Ablation therapy, an invasive localized treatment, offers an alternative to systemic therapies for cancer patients who cannot tolerate their adverse effects. Its ability to kill cancer cells efficiently and activate anti-cancer immunity. This article reviews recent advancements in ablation therapies, including thermal, cryoablation, PDT, and IRE, and their potential clinical applications, both standalone and in combination with immunotherapy.

Radiotherapy (RT) is one of the main therapies for hepatocellular carcinoma (HCC), but its effectiveness has been constrained due to the resistance effect of radiation. Thus, the factors involved in radioresistance are evaluated and the underlying molecular mechanisms are also done. In this present study, we identified Integrin β6 (ITGB6) as a potential radioresistant gene through an integrative analysis of transcriptomic profiles, proteome datasets and survival using HCC cases treated with IR. We show that ITGB6 functionally contributed to radioresistance by activating autophagy through a series of in vitro and in vivo methods, such as clonogenic assays, autophagy flux (LC3B-GFP-mCherry reporter) analysis and a subcutaneous transplantation model. Mechanically, ITGB6 binds to Annexin A2 (ANXA2) and enhanced its stability by competitively antagonizing proteasome mediated ANXA2 degradation, thereby promoting autophagy and radioresistance. Notably, HCC radioresistance was significantly improved by either blocking ITGB6 or autophagy, but the combination was more effective. Importantly, ITGB6/ANXA2 axis triggered autophagic program endowed HCC cells with radioresistant activity in a radiated patient-derived xenograft (PDX) model and hydrodynamic injection in liver-specific Itgb6-knockout mice, further supported by clinical evidence. Together, our data revealed that ITGB6 is a radioresistant gene stabilizing the autophagy regulatory protein ANXA2, providing insights into the biological and potentially clinical significance of ITGB6/ANXA2 axis in radiotherapy planning of HCC.

HCC is the fourth leading cause of cancer-related mortality with increasing incidence worldwide. Historically, treatment for early disease includes liver transplantation, surgical resection, and/or other local therapies, such as thermal ablation. As a result of technical advances and high-quality prospective data, the use of definitive external beam radiotherapy with ablative doses has emerged. Intermediate-stage disease has been generally addressed with arterially directed therapies (eg, chemoembolization or radioembolization) and external beam radiotherapy, while advanced stages have been addressed by systemic therapy or best supportive care. The role of each local/locoregional therapy has rapidly evolved in the context of novel pharmacotherapies, including immunotherapies and antiangiogenic agents. The combinations, indications, and timing of treatments vary widely among specialties and geographies. Here, we aim to synthesize the best quality evidence available regarding the efficacy and safety of different liver-directed modalities, with a focus on recent prospective clinical data of external beam radiotherapy within the context of other available liver-directed therapies across Barcelona Liver Classification (BCLC) stages.

To assess the efficacy and safety of radiofrequency ablation (RFA) versus stereotactic body radiotherapy (SBRT) in treating recurrent small hepatocellular carcinoma (HCC).

In this trial, patients with recurrent small HCC (single lesion ≤5 cm) were randomly assigned to receive either SBRT or RFA. The primary end point was local progression-free survival (LPFS), and secondary end points were progression-free survival (PFS), overall survival (OS), local control rate, and safety.

Between August 2019 and April 2022, 166 patients were assigned to SBRT (n = 83) and RFA (n = 83) groups. After a median follow-up time of 42.8 and 42.9 months in the SBRT and RFA groups, respectively, SBRT demonstrated a significantly better LPFS than that of RFA (hazard ratio [HR], 0.45 [95% CI, 0.24 to 0.87]; P = .014). The 2-year LPFS rates were 92.7% (95% CI, 87.3 to 98.5) with SBRT and 75.8% (95% CI, 67.2 to 85.7) with RFA. The median PFS time of the SBRT and RFA groups was 37.6 (95% CI, 26.0 to 49.2) and 27.6 (95% CI, 20.3 to 34.8) months, respectively (HR, 0.76 [95% CI, 0.50 to 1.15]; P = .190). Nine patients in the SBRT group and 10 in the RFA group died during the follow-up. The 2-year OS rates were 97.6% (95% CI, 94.3 to 100.0) in the SBRT group and 93.9% (95% CI, 88.9 to 99.2) in the RFA group (HR, 0.91 [95% CI, 0.37 to 2.22]; P = .830). The incidences of both acute and late adverse events were comparable between the groups (P = .436 and P = .715, respectively).

SBRT achieved better LPFS than that of RFA in patients with single recurrent HCC ≤5 cm, especially in HCC ≤2 cm, whereas PFS, OS, and safety were comparable between the two treatments.

Hepatocellular carcinoma (HCC), one of the most lethal cancers of the liver, has limited treatment options at advanced stages. Here, bismuth gadolinium (BiGd) nanoparticles (NPs) conjugated with anti-vascular endothelial growth factor antibody (aVEGF) are designed and tested for targeted image-guided radiation therapy against HCC. The BiGd NPs are synthesized using the sol-gel technique, functionalized with silica NPs, and labeled with fluorescent protamine-rhodamine B. For tumor targeting, the NPs are conjugated with aVEGF, and an in vitro study confirms the binding of the aVEGF-BiGd nanoconjugate to McA-RH7777 hepatoma cells. Biocompatibility of the aVEGF-BiGd nanoconjugate is evaluated using McA-RH7777 cells, with no cytotoxicity observed even at 250 μg/mL. Also, aVEGF-BiGd demonstrates in vivo microcomputed tomography contrast enhancement. NPs and/or radiation therapy (RT) is conducted in female BALB/c nude mice with subcutaneously implanted McA-RH7777 cells, and a significant reduction in tumor size is observed in the mice treated with the aVEGF-BiGd nanoconjugate and RT compared to other groups (p < 0.01). The combined effect of nanoconjugate and RT exhibits decreased vascularity, cell proliferation, and increased apoptosis. This study demonstrates the potential of the developed hybrid BiGd nanoconjugate for targeted and image-guided radiotherapy of HCC.

Radio-resistance is a principal culprit in radiation therapy for hepatocellular carcinoma (HCC). Insights on the regulation genes of radio-resistance and underlying mechanisms in HCC are awaiting profound investigation. This study is designed to explore the role and mechanism of WD repeat and HMG-box DNA binding protein 1 (WDHD1) in HCC progression. WDHD1 mRNA level was detected using real-time quantitative polymerase chain reaction (RT-qPCR). WDHD1, ubiquitin-specific protease 28 (USP28), E-cadherin, N-cadherin, and vimentin protein levels were determined by Western blot. Cell viability, cell cycle progression, migration, invasion, and apoptosis were assessed using the cell counting kit-8 (CCK-8) assay, flow cytometry, wound healing assay, and Transwell assay. The radio-sensitivity of HCC cells was analyzed using a colony formation assay. After UbiBrowser database analysis, the interaction between USP28 and WDHD1 was verified using GST pull-down and Co-immunoprecipitation (CoIP) assay. Xenograft assay was used to test the effect of USP28 on radio-sensitivity in vivo. WDHD1 and USP28 were highly expressed in HCC patients and cell lines. Moreover, WDHD1 knockdown could repress HCC cell proliferation, migration, invasion, epithelial to mesenchymal transition (EMT), and enhance the radiosensitivity. Mechanistically, USP28 mediated the deubiquitination and stabilization of WDHD1 through its direct interaction. USP28 silencing increased the radiosensitivity of HCC in vivo. USP28 contributed to HCC development and radio-resistance through deubiquitinating WDHD1, providing a promising therapeutic target for HCC treatment.

Radiotherapy is one of the main treatment modalities for advanced hepatocellular carcinoma (HCC). Ferroptosis has been shown to promote the radiosensitivity of HCC cells, but it remains unclear whether epigenetic regulations function in this process. In this study, we found that the overexpression of METTL3 was associated with poor prognosis. Knockdown of METTL3 promoted radiosensitivity of HCC by inducing ferroptosis. Mechanistically, METTL3 targeted adenine (+1795) on the SLC7A11 mRNA, and the m6A reader IGF2BP2 promoted SLC7A11 mRNA stability by recognizing and binding to the m6A site. Additionally, METTL3 decreased the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 axis. Furthermore, in vivo studies showed that HCC models with low METTL3/IGF2BP2 expression have higher radiosensitivity. In conclusion, our study suggests that METTL3 regulates the stability of SLC7A11 mRNA in an m6A/IGF2BP2-dependent manner and the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 pathway, both of which require the m6A methyltransferase activity of METTL3. METTL3 or IGF2BP2 may be promising targets for radiotherapy of HCC.

Few studies have focused on the efficacy of stereotactic body radiation therapy (SBRT) in treating early hepatocellular carcinoma (HCC) for curative intention. This study aims to determine the best option among resection, ablation, and SBRT in dealing with single HCC no more than 5 cm.

This multicenter retrospective cohort study included 985 patients from 3 hospitals: 495, 335, and 155 in the resection, ablation, and SBRT groups, respectively, between January 2014 and December 2021. Subgroup analysis and propensity score matching (PSM) were performed.

The SBRT group had unfavorable clinical features including larger tumor size, poorer liver function, and more relapsed tumors. The 1-year, 3-year, and 5-year recurrence-free survival (RFS) rates were 84.3%, 66.8%, and 56.2% with resection, 73.3%, 49.8%, and 37.2% with ablation and 73.2%, 56.4%, and 53.6% with SBRT, respectively ( P <0.001). The 3-year overall survival (OS) rates were 89.0%, 89.2%, and 88.8% in the resection, ablation, and SBRT group, respectively ( P =0.590). The three modalities resulted in similar RFS and OS after adjusting for clinical factors. Resection provided ideal local tumor control, successively followed by SBRT and ablation. SBRT led to comparable RFS time compared to resection for tumors <3 cm (HR=0.75, P =0.205), relapsed tumors (HR=0.83, P =0.420), and patients with poor liver function (HR=0.70, P =0.330). In addition, SBRT was superior to ablation regarding RFS when tumors were adjacent to intrahepatic vessels (HR=0.64, P =0.031). SBRT were more minimally invasive, however, gastrointestinal disorders, hepatic inflammation, and myelosuppression occurred more frequently.

All three approaches could be applied as curative options. Resection remains the best choice for preventing tumor recurrence, and SBRT showed advantages in treating small, recurrent and vascular-type lesions as well as patients with relatively poor liver function.

Radiotherapy stands as an effective method in the clinical treatment of hepatocellular carcinoma (HCC) patients. However, both primary and acquired radioresistance limit its clinical application in HCC. Therefore, investigating the mechanism of radioresistance may provide other options for treating HCC. Based on single-cell RNA sequencing (scRNA-seq) and HCC transcriptome datasets, 227 feature genes with prognostic value were selected to establish the tSNE score. The tSNE score emerged as an independent prognostic factor for HCC and correlated with cell proliferation and radioresistance-related biological functions. UBAP2 was identified as the most relevant gene with the tSNE score, consistently elevated in human HCC samples, and positively associated with patient prognosis. Functionally, UBAP2 knockdown impeded HCC development and reduced radiation resistance in vitro and in vivo. The ectopic expression of SLC27A5 reversed the effects of UBAP2. Mechanically, we uncovered that UBAP2, through the ubiquitin-proteasome system, decreased the homologous recombination-related gene RAD51, not the non-homologous end-joining (NHEJ)-related gene CTIP, by degrading the antioncogene SLC27A5, thereby generating radioresistance in HCC. The findings recapitulated that UBAP2 promoted HCC progression and radioresistance via SLC27A5 stability mediated by the ubiquitin-proteasome pathway. It was also suggested that targeting the UBAP2/SLC27A5 axis could be a valuable radiosensitization strategy in HCC.

Risk stratification of regional recurrence (RR) is clinically important in the design of adjuvant treatment and surveillance strategies in patients with clinical stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT). This study aimed to develop a radiomics model predicting occult lymph node metastasis (OLNM) using surgical data and apply it to the prediction of RR in SBRT-treated early-stage NSCLC patients.

Patients with clinical stage I NSCLC who underwent curative surgery with systematic lymph node dissection from January 2013 to December 2018 (the training cohort) and from January 2019 to December 2020 (the validation cohort) were included. A preoperative computed tomography-based radiomics model, a clinical feature model, and a fusion model predicting OLNM were constructed. The performance of the 3 models was quantified and compared in the training and validation cohorts. Subsequently, the radiomics model was used to predict RR in a cohort of consecutive SBRT-treated early-stage NSCLC patients from 2 academic medical centers.

A total of 769 patients were included. Eight computed tomography features were identified in the radiomics model, achieving areas under the curves of 0.85 (95% CI, 0.81-0.89) and 0.83 (95% CI, 0.80-0.88) in the training and validation cohorts, respectively. Nevertheless, adding clinical features did not improve the performance of the radiomics model. With a median follow-up of 40.0 (95% CI, 35.2-44.8) months, 32 of the 213 patients in the SBRT cohort developed RR and those in the high-risk group based on the radiomics model had a higher cumulative incidence of RR (P < .001) and shorter regional recurrence-free survival (P = .02), progression-free survival (P = .004) and overall survival (P = .006) than those in the low-risk group.

The radiomics model based on pathologically confirmed data effectively identified patients with OLNM, which may be useful in the risk stratification among SBRT-treated patients with clinical stage I NSCLC.

Radiofrequency ablation (RFA) is a micro-invasive treatment for early-stage HCC patients. Stereotactic body radiation therapy (SBRT) has also been proven an effective and safe treatment for HCC patients. This multi-center study is to compare the efficacy of computed tomography (CT)-guided RFA and CT-based SBRT in naïve HCC patients with tumor diameters ≤5 cm.

This retrospective cohort study included 1001 treatment-naïve HCC patients from three hospitals or medical centers. The patients received RFA (n = 481) or SBRT (n = 520) treatment between December 2011 and May 2019. Furthermore, subgroup analyses of all patients were conducted based on Couinaud's classification of liver segments.

After matching, the local control (LC) rates of the SBRT group were better than those of the RFA group (p=0.024*), which mainly referred to the patients whose tumors were located in the S7/S8 (p=0.006*). Among patients with tumors located in S1, nineteen patients (19/21) underwent SBRT. The 1-, 3- and 5-year LC rates were 100%, 87.8% and 87.8% in the SBRT group, and the 1-, 3- and 5-year OS rates were 100%, 69.8% and 69.8%, respectively. Moreover, the OS rates in S5/S6 group in RFA were higher than those in SBRT group.

The LC rates were better in the SBRT group than in the RFA group for the patients with lesions localized in S7/S8, and SBRT could also be a therapeutic option for patients with lesions in S1. Moreover, patients with tumors located in S5/S6 were better candidates for RFA treatment than SBRT.

Improvements in downstaging therapies have expanded the indications for liver transplantation (LT) for hepatocellular carcinoma (HCC). Patients with more advanced disease are now considered candidates due to advancements in radiation therapy, combination therapies, and immunotherapy. Combination stereotactic body radiation therapy (SBRT) and trans-arterial chemoembolization (TACE) has been shown to be superior to the historic treatment, sorafenib, in patients with macrovascular invasion. These patients are now candidates for LT with stable disease after LRT. Patients with ruptured HCC and prolonged stability have also been shown to have acceptable outcomes. The role of neoadjuvant immunotherapy needs to be further defined and has the potential to further improve tumor control prior to transplant.

Hepatocellular carcinoma (HCC) is a common gastrointestinal malignancy in China. Most tumors develop from chronic inflammation. Artemisia rupestris L. (ARL) has been found to have a significant effect on viral influenza and hepatitis, but the mechanism of action of ARL against liver cancer is unclear.

The study objective was to explore the mechanism of action of ARL for the treatment of hepatocellular carcinoma (HCC) by ethanol extract and in vitro experimental design.

Interactions between ARL and cellular target proteins against HCC were analyzed through network pharmacology and network topology with the utilization of the DAVID database. The rate of HepG2 cells' growth inhibition was assessed using the MTT assay in vitro cellular assay; hoechst33342 detects apoptosis of cells; the ability of HepG2 cells to migrate and invade was assessed using the transwell assay and the cell scratch experiment; and the levels of protein expression in HepG2 cells were assessed using the western blot assay.

Network pharmacology prediction results demonstrated that 22 active ingredients were tested, 176 possible action targets were discovered, and the PI3K/Akt signaling pathway was found to be the most pertinent action pathway for the treatment of hepatocellular carcinoma. In vitro results showed that it can effectively restrict HepG2 cell proliferation, apoptosis, migration, and invasion as well as the regulation of protein expressions.

Conclusively, Quercetin, Linarin, and Kaempferol were found most essential active ingredients from ARL that regulate the antitumor effects against HCC through the PI3K/Akt signaling pathway. The study provides a fundamental basis for further comprehensive evaluation of ARL to treat tumor diseases in general and its therapeutic potential against hepatocellular carcinoma in particular.

Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of its management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the second part of guidelines, focused on the multidisciplinary tumor board of experts and non-surgical treatments of HCC.

The location and morphology of the liver are significantly affected by respiratory motion. Therefore, delineating the gross target volume (GTV) based on 4D medical images is more accurate than regular 3D-CT with contrast. However, the 4D method is also more time-consuming and laborious. This study proposes a deep learning (DL) framework based on 4D-CT that can achieve automatic delineation of internal GTV.

The proposed network consists of two encoding paths, one for feature extraction of adjacent slices (spatial slices) in a specific 3D-CT sequence, and one for feature extraction of slices at the same location in three adjacent phase 3D-CT sequences (temporal slices), a feature fusion module based on an attention mechanism was proposed for fusing the temporal and spatial features. Twenty-six patients' 4D-CT, each consisting of 10 respiratory phases, were used as the dataset. The Hausdorff distance (HD95), Dice similarity coefficient (DSC), and volume difference (VD) between the manual and predicted tumor contour were computed to evaluate the model's segmentation accuracy.

The predicted GTVs and IGTVs were compared quantitatively and visually with the ground truth. For the test dataset, the proposed method achieved a mean DSC of 0.869 ± 0.089 and an HD95 of 5.14 ± 3.34 mm for all GTVs, with under-segmented GTVs on some CT slices being compensated by GTVs on other slices, resulting in better agreement between the predicted IGTVs and the ground truth, with a mean DSC of 0.882 ± 0.085 and an HD95 of 4.88 ± 2.84 mm. The best GTV results were generally observed at the end-inspiration stage.

Our proposed DL framework for tumor segmentation on 4D-CT datasets shows promise for fully automated delineation in the future. The promising results of this work provide impetus for its integration into the 4DCT treatment planning workflow to improve hepatocellular carcinoma radiotherapy.

To use a nomogram to predict the risk of mortality and estimate the impact of current treatment on the prognosis of glioma patients.

A total of 3798 cases were obtained from the Surveillance Epidemiology and End Results database according to the selection criteria. A nomogram was built on the independent clinical factors screened by the variance inflation factor, univariate analyses and a multivariate Cox regression model. Then, categorising the overall population into high-risk, medium-risk and low-risk groups using nomogram-derived risk scores, to study the impact of treatment on different subgroups' survival outcomes. Furthermore, based on the postmatch cohorts, the influences of treatment on survival outcomes were assessed by the log-rank test.

Age, race, stage of disease, histological type, histological grade, surgery, radiotherapy and chemotherapy were identified as the independent prognostic factors. A nomogram with good discrimination and consistency was built. Generally, the patients who underwent surgery, radiotherapy and chemotherapy were more likely to achieve better prognosis than those who did not, except for those who received radiotherapy in the low-risk cohort and those who underwent surgery in the high-risk cohort. Furthermore, the isocitrate dehydrogenase 1/2 (IDH1/2) wild-type patients with surgery, radiotherapy or chemotherapy tended to have higher survival probabilities, while some inconsistent results were observed in the IDH mutant-type cohort.

Surgery, radiotherapy and chemotherapy improved the prognosis, while appropriate selection of topical treatment for the low-risk or high-risk patients deserves further consideration. IDH status gene might be a reliable indicator of therapeutic effectiveness.

The treatment of unresectable or metastatic HCC has been significantly advanced in recent years by developments in both radiotherapy and systemic cancer therapies. Independently, both Stereotactic Ablative Body Radiotherapy (SBRT) and Immune Checkpoint Inhibitors (ICIs) are licensed for the treatment of these tumours. Building on the successes seen in other solid tumours, there is significant interest in exploring combination treatments. In this review article we briefly present the evidence base for the use of these treatments in patients with HCC. With reference to our current understanding of the immuno-oncology and radiobiology of HCCs, we demonstrate why combining these two modalities is of interest. Finally, we discuss the clinical trials that are currently underway or planned and the direction that future research may take.

Stereotactic body radiation therapy (SBRT) has demonstrated safe and effective results for primary liver tumors. Magnetic Resonance guided Radiotherapy (MRgRT) is an innovative radiotherapy modality for abdominal tumors. The aim of this study is to report on acute and late toxicities and initial oncological results for primary liver tumors treated with MRgRT.

We prospectively included in our cohort all patients treated by MRgRT for a primary liver tumor at the Montpellier Cancer Institute. The primary endpoint was acute and late toxicities assessed according to CTCAE v 5.0. The mean prescribed dose was 50 Gy in 5 fractions.

Between October 2019 and April 2022, MRgRT treated 56 patients for 72 primary liver lesions. No acute or late toxicities of CTCAE grade greater than 2 attributable to radiotherapy were noted during follow-up. No cases of radiation-induced liver disease (RILD), either classical or non-classical, occurred. After a median follow-up of 13.2 months (95% CI [8.8; 15.7]), overall survival was 85.1% (95% CI: [70.8; 92.7]) at 1 year and 74.2% at 18 months (95% CI [52.6; 87.0]). Local control was 98.1% (95% CI: [87.4; 99.7]) and 94.7% (95% CI: [79.5; 98.7]) at 12 and 18 months, respectively. Among the HCC subgroup, no local recurrences were observed.

MRgRT for primary liver tumors is safe without severe adverse events and reach excellent local control. Numerous studies are underway to better assess the value of MRI guidance and adaptive process in these indications.

There is no clear consensus on the relative ranking of interventional and radiation techniques with indications similar to those of radiofrequency ablation (RFA) for the treatment of early hepatocellular carcinoma (HCC). We used a network meta-analysis to compare the efficacy of non-surgical treatments for early HCC.

We searched databases for randomized trials assessing the efficacy of loco-regional treatments for HCCs ≤5 cm with no extrahepatic spread or portal invasion. The primary outcome was the pooled hazard ratio (HR) for overall survival (OS), and secondary outcomes included overall and local progression-free survival (PFS). A frequentist network meta-analysis was performed, and the relative ranking of therapies was assessed with P-scores.

Nineteen studies comparing 11 different strategies in 2,793 patients were included. Chemoembolization plus RFA improved OS better than RFA alone (HR 0.52, 95% confidence interval [CI] 0.33-0.82; P-score=0.951). Cryoablation, microwave ablation, laser ablation, and proton beam therapy had similar effects on OS compared with RFA. For overall PFS, but not local PFS, only chemoembolization plus RFA performed significantly better than RFA (HR 0.61, 95% CI 0.42-0.88; P-score=0.964). Injection of percutaneous ethanol or acetic acid was significantly less effective than RFA for all measured outcomes, while no differences in progression outcomes were identified for other therapies included in the network.

Our results suggest that chemoembolization combined with RFA is the best option for local treatment of early HCC. Cases with potential contraindications for RFA may benefit from a tailored approach using thermal or radiation modalities.

Surgical resection, stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA) have seldom been compared for small hepatocellular carcinoma (HCC). We explored the treatment outcomes of SBRT for small HCC by conducting a network meta-analysis (NMA). We compared the efficacy and safety of surgical resection, RFA and SBRT for liver-confined small HCC (three or fewer lesions with a diameter ≤5 cm). The study endpoint included the odds ratios of the 1-, 3- and 5-year progression/recurrence/disease-free survival (disease progression-free survival; DPFS) and overall survival rates, as well as severe complications. Forty-five studies included 21 468 patients. In the NMA with comparable data, SBRT had comparable 1-, 3- and 5-year DPFS but significantly worse pooled long-term overall survival (3- and 5-year overall survival) than surgical resection (odds ratio 1.39, 95% confidential interval 1.3-1.89; odds ratio 1.33, 95% confidence interval 1.06-1.69, respectively). SBRT was associated with significantly better pooled 1-year DPFS compared with RFA (odds ratio 0.39, 95% confidence interval 0.15-0.97), with the remaining outcomes being comparable. SBRT had significantly less incidence of severe complications compared with surgical resection (odds ratio 0.62, 95% confidence interval 0.42-0.88) and RFA (odds ratio 0.2, 95% confidence interval 0.03-0.94). In conclusion, for small HCCs (≤5 cm) with one to three nodules, SBRT may be favourable to reduce the risks of severe complications. In terms of DPFS, SBRT may be recommended as an alternative first-line therapy for RFA and surgical resection. The results regarding overall survival should be interpreted with caution, considering the potentially uneliminated bias. There is a clear need for well-designed randomised trials to conclusively identify real differences in efficacy between these treatments, especially SBRT and surgical resection.

Early-stage HCC can be treated with thermal ablation or stereotactic body radiation therapy (SBRT). We retrospectively compared local progression, mortality, and toxicity among patients with HCC treated with ablation or SBRT in a multicenter, US cohort.

We included adult patients with treatment-naïve HCC lesions without vascular invasion treated with thermal ablation or SBRT per individual physician or institutional preference from January 2012 to December 2018. Outcomes included local progression after a 3-month landmark period assessed at the lesion level and overall survival at the patient level. Inverse probability of treatment weighting was used to account for imbalances in treatment groups. The Cox proportional hazard modeling was used to compare progression and overall survival, and logistic regression was used for toxicity. There were 642 patients with 786 lesions (median size: 2.1 cm) treated with ablation or SBRT. In adjusted analyses, SBRT was associated with a reduced risk of local progression compared to ablation (aHR 0.30, 95% CI: 0.15-0.60). However, SBRT-treated patients had an increased risk of liver dysfunction at 3 months (absolute difference 5.5%, aOR 2.31, 95% CI: 1.13-4.73) and death (aHR 2.04, 95% CI: 1.44-2.88, p < 0.0001).

In this multicenter study of patients with HCC, SBRT was associated with a lower risk of local progression compared to thermal ablation but higher all-cause mortality. Survival differences may be attributable to residual confounding, patient selection, or downstream treatments. These retrospective real-world data help guide treatment decisions while demonstrating the need for a prospective clinical trial.

Several breakthroughs in hepatocellular carcinoma (HCC) therapy across tumor stages provide hope to improve its dismal prognosis. Although surgical and local ablative therapies have few significant changes in technique, an improved understanding of tumor biology has facilitated increase numbers of patients who are now eligible to undergo curative-intent procedures. Most notably, acceptable post-transplant outcomes can be achieved in well selected patients whose tumors are downstaged into Milan Criteria. Adjuvant therapy in patients at high risk of recurrence also significantly improves recurrence-free survival after resection or ablation. For patients with liver-localized disease who are not eligible for curative-intent procedures, transarterial chemoembolization (TACE) was historically the treatment modality of choice, regardless of tumor burden; however, there is now increased recognition of patients who are "TACE unsuitable" and may be better treated with systemic therapy. The greatest evolution in HCC treatment options has occurred with systemic therapy, where several new agents are now available in the first- and second-line setting, including immune checkpoint inhibitor combinations. Objective responses are observed in approximately 30% of patients and median survival is approaching 2 years. The availability of immune checkpoint inhibitors has renewed interest in combination therapies for earlier tumor stages, with several phase III trials ongoing. Considering increasing complexities of HCC care, requiring decisions between therapies delivered by different providers, multidisciplinary care is critical and is associated with improved clinical outcomes. In this review, we detail major breakthroughs in HCC therapy, how these breakthroughs can be applied in clinical practice, and remaining areas in need of further research.

Hepatocellular carcinoma (HCC) is the most common liver tumor, with a continually rising incidence. The curative treatment for HCC is surgical resection or liver transplantation; however, only a small portion of patients are eligible due to local tumor burden or underlying liver dysfunction. Most HCC patients receive nonsurgical liver-directed therapies (LDTs), including thermal ablation, transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and external beam radiation therapy (EBRT). Stereotactic ablative body radiation (SABR) is a specific type of EBRT that can precisely deliver a high dose of radiation to ablate tumor cells using a small number of treatments (or fractions, typically 5 or less). With onboard MRI imaging, MRI-guided SABR can improve therapeutic dose while minimizing normal tissue exposure. In the current review, we discuss different LDTs and compare them with EBRT, specifically SABR. The emerging MRI-guided adaptive radiation therapy has been reviewed, highlighting its advantages and potential role in HCC management.

SBRT is an emerging locoregional treatment modality for hepatocellular carcinoma (HCC). Although local tumor control rates seem encouraging, large-scale survival data comparing SBRT to surgical resection are lacking. We identified patients with stage I/II HCC from the National Cancer Database amenable for potential surgical resection. Patients undergoing hepatectomy were matched by propensity score (1:2) with patients who underwent SBRT as primary treatment. A total of 3787 (91%) and 366 (9%) patients underwent surgical resection or SBRT between 2004 and 2015, respectively. After propensity matching, the 5-year overall survival was 24% (95% CI 19-30%) in the SBRT group versus 48% (95% CI 43-53%) in the surgery group (p < 0.001). The association of surgery with overall survival was consistent in all subgroups. In patients treated with SBRT, a biologic effective dose (BED) of ≥100 Gy (31%, 95% CI 22%-40%) compared with BED < 100 Gy (13%, 95% CI 8-22%) was associated with a higher 5-year overall survival rate (hazard ratio of mortality of 0.58, 95% CI 0.43-0.77; p < 0.001). Surgical resection may be associated with prolonged overall survival compared with SBRT in patients with stage I/II HCC.

Hepatocellular carcinoma (HCC) a leading cause of cancer mortality worldwide and approximately one-third of patients present with intermediate-stage disease. The treatment landscape of intermediate-stage HCC is rapidly evolving due to developments in local, locoregional and systemic therapies. Treatment recommendations focused on this heterogenous disease stage and that take into account the Canadian reality are lacking. To address this gap, a pan-Canadian group of experts in hepatology, transplant, surgery, radiation therapy, nuclear medicine, interventional radiology, and medical oncology came together to develop consensus recommendations on management of intermediate-stage HCC relevant to the Canadian context.

A modified Delphi framework was used to develop consensus statements with strengths of recommendation and supporting levels of evidence graded using the AHA/ACC classification system. Tentative consensus statements were drafted based on a systematic search and expert input in a series of iterative feedback cycles and were then circulated via online survey to assess the level of agreement.

The pre-defined ratification threshold of 80 % agreement was reached for all statements in the areas of multidisciplinary treatment (n = 4), intra-arterial therapy (n = 14), biologics (n = 5), radiation therapy (n = 3), surgical resection and transplantation (n = 7), and percutaneous ablative therapy (n = 4). These generally reflected an expansion in treatment options due to developments in previously established or emergent techniques, introduction of new and more active therapies and increased therapeutic flexibility. These developments have allowed for greater treatment tailoring and personalization as well as a paradigm shift toward strategies with curative intent in a wider range of disease settings.

Laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) remains controversial, especially for tumors larger than 5 cm. We compared the short- and long-term outcomes of laparoscopic and open liver resection (OLR) for large HCC.

Patients with large HCC after curative hepatectomy were enrolled. To compare the short-term outcomes, propensity score matching (PSM) and inverse probability treatment weighting (IPTW) were performed to reduce the effect of confounding factors, respectively. Subsequently, Cox-regression analyses were conducted to identify the independent risk factors associated with decreased recurrence-free survival (RFS) and poor overall survival (OS).

There were 265 patients enrolled in the final analysis: 146 who underwent OLR and 119 who underwent LLR. There was no significant difference between the OLR and LLR groups according to PSM and IPTW analysis (all P > 0.05). Multivariable analysis revealed that LLR was not independently associated with poorer OS (HR 1.15, 95% CI 0.80-1.67, P = 0.448) or RFS (HR 1.22, 95% CI 0.88-1.70, P = 0.238).

There were no significant differences in perioperative complications or long-term prognosis between LLR and OLR for large HCC, which provides evidence for standard laparoscopic surgical practice with adequate surgeon experience and careful patient selection.

Aim: The aim of this meta-regression was to assess the impact of mean/median age, mean/median tumor size, percentage of males in total sample, and total sample size on the comparative effectiveness of radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT). Methods: Ten studies reporting on the composite outcome of overall survival and local control were included. Results: A significant relationship was found between age and overall survival at 1 and 2 for both RFA and SBRT. A significant relationship was noted also between age and local control at 1 and 2 years for RFA. Conclusion: Patients treated with SBRT had a wider range of tumor sizes and larger tumor sizes; no relationship was observed between tumor size and overall survival or local control by SBRT.

To investigate the clinical efficacy of intensity-modulated radiotherapy (IMRT) combined with transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) patients with extrahepatic oligometastasis and the prognosis of patients receiving this treatment.

Twenty-one HCC patients with extrahepatic oligometastasis were retrospectively analyzed; seven patients received IMRT only, and 14 received IMRT plus TACE. TACE treatment was administered before IMRT (50 mg epirubicin, oxaliplatin 100 mg, and mitomycin 10 mg). The short-term efficacy of this treatment and patient prognosis were evaluated.

Complete response (CR) and partial response (PR) in the intrahepatic region were achieved in three and 14 patients, respectively. The objective response rate (ORR) approached 81%. CR and PR were achieved in six and 10 patients with extrahepatic metastases, respectively, for an ORR of 100%. Pain was completely relieved in all patients with bone metastases. The median overall survival (OS) and progression-free survival (PFS) were 21 months and 9.1 months, respectively. The 1-year PFS rate was 43%, and the 1-, 2-, 3-, and 4-year OS rates were 83%, 35%, 9%, and 4%, respectively. Univariate analysis showed that the prognostic factors for patient survival included Child-Pugh class, vascular thrombus, Karnofsky performance status (KPS), radiotherapy dose, ascites, combination therapy, and pattern of progression. Multivariate analysis showed that vascular thrombus, combination therapy, and pattern of failure were prognostic factors for PFS, and the KPS was the only prognostic factor for OS. No grade 3-4 adverse reactions were observed.

IMRT combined with TACE is safe and feasible without major toxicities for the treatment of advanced HCC patients with extrahepatic oligometastasis and results in excellent objective efficacy and a potential survival benefit. The KPS is the only predictive factor for OS. This approach is expected to be a useful palliative option for selected HCC patients with extrahepatic metastases.

Radioresistance is a principal culprit for the failure of radiotherapy in hepatocellular carcinoma (HCC). Insights on the regulation genes of radioresistance and underlying mechanisms in HCC are awaiting for profound investigation. In this study, the suppressor of cytokine signaling 2 (SOCS2) were screened out by RNA-seq and bioinformatics analyses as a potential prognosis predictor of HCC radiotherapy and then were determined to promote radiosensitivity in HCC both in vivo or in vitro. Meanwhile, the measurements of ferroptosis negative regulatory proteins of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), intracellular lipid peroxidation and Fe²⁺ concentration suggested that a high level of ferroptosis contributed to the radiosensitization of HCC. Moreover, SOCS2 and SLC7A11 were expressed oppositely in HCC clinical tissues and tumour xenografts with different radiosensitivities. Mechanistically, the N-terminal domain of SLC7A11 was specifically recognized by the SH2-structural domain of SOCS2. While the L162 and C166 of SOCS2-BOX region could bind elongin B/C compound to co-form a SOCS2/elongin B/C complex to recruit ubiquitin molecules. Herein, SOCS2 served as a bridge to transfer the attached ubiquitin to SLC7A11 and promoted K48-linked polyubiquitination degradation of SLC7A11, which ultimately led to the onset of ferroptosis and radiosensitization of HCC. In conclusion, it was demonstrated for the first time that high-expressed SOCS2 was one of the biomarkers predicting radiosensitivity of HCC by advancing the ubiquitination degradation of SLC7A11 and promoting ferroptosis, which indicates that targeting SOCS2 may enhance the efficiency of HCC radiotherapy and improve the prognosis of patients.

Radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) are available locoregional curative treatments for nonsurgical Hepatocellular carcinoma (HCC) patients. We aimed to compare the clinical efficacy and safety of SBRT versus RFA for HCC.

A computerized bibliographic search was performed using PubMed, Embase, the Cochrane Library and Web of Science to identify comparative studies. The primary outcome was overall survival (OS), and the secondary outcomes were freedom from local progression (FFLP) and treatment-related complications.

In total, there were 17 trials involving 22,180 patients. Patients receiving RFA showed significantly better 1-, 2- year OS (OR 0.69, 95% CI 0.50-0.96, P = 0.141,OR 0.69, 95% CI 0.53-0.89, P = 0.082), whereas SBRT resulted in significantly better 1-, 2-, 3- year FFLP (OR 2.19, 95% CI 1.44-3.34, P = 0.303; OR 1.57, 95% CI 1.12-2.19, P = 0.268; OR 2.22, 95% CI 1.70-2.90, P = 0.470). There were no significant differences for 3-, 5- year OS in both groups (OR 0.94, 95% CI 0.65-1.38, P = 0.001; OR 0.98, 95% CI 0.68-1.34, P = 0.016). The overall treatment-related complication rate did not differ significantly between the two treatment arms, while SBRT was significantly associated with Child-Pugh worsening.

Though SBRT has excellent FFLP, RFA yields superior short-term survival for HCC. But the discrepancy between FFLP and OS requires further investigation.

External beam radiation therapy (EBRT) has increasingly been utilized in the treatment of hepatocellular carcinoma (HCC) due to technological advances with positive clinical outcomes. Innovations in EBRT include improved image guidance, motion management, treatment planning, and highly conformal techniques such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT). Moreover, proton beam therapy (PBT) and magnetic resonance image-guided radiation therapy (MRgRT) have expanded the capabilities of EBRT. PBT offers the advantage of minimizing low- and moderate-dose radiation to the surrounding normal tissue, thereby preserving uninvolved liver and allowing for dose escalation. MRgRT provides the advantage of improved soft tissue delineation compared to computerized tomography (CT) guidance. Additionally, MRgRT with online adaptive therapy is particularly useful for addressing motion not otherwise managed and reducing high-dose radiation to the normal tissue such as the stomach and bowel. PBT and online adaptive MRgRT are emerging technological advancements in EBRT that may provide a significant clinical benefit for patients with HCC.

Worldwide, the incidence of cancer is on the rise. Current cancer treatments include chemotherapy, radiation therapy, and surgery. Chemotherapy and radiation treatment are typically associated with severe adverse effects and a decline in patients' quality of life. Anti-cancer substances derived from plants and animals need to be evaluated therapeutically as it is cost-effective, have fewer side effects, and can improve cancer patients' quality of life. Recently, bovine colostrum (BC) has attracted the interest of numerous researchers investigating its anti-cancer potential in humans. Dressings loaded with BC are beneficial in treating chronic wounds and diabetic foot ulcers. Lactoferrin, a glycoprotein with potent anti-oxidant, anti-inflammatory, anti-cancer, and anti-microbial effects, is abundant in BC. The BC pills successfully promote the regression of low-grade cervical intraepithelial neoplasia when administered intravaginally. The biological, genetic, and molecular mechanisms driving BC remain to be determined. Oral BC supplements are generally well-tolerated, but some flatulence and nausea may happen. To evaluate the therapeutic effects, long-term safety, and appropriate dosages of BC drugs, well-designed clinical trials are necessary. The purpose of this article is to emphasize the anti-cancer potential of BC and its constituents.