Liver cancer, a malignant tumor of the digestive system, is a leading cause of cancer‑related mortality globally. Numerous genetic mutations associated with tumorigenesis have been identified, stemming from genomic instability. However, the clinical implications and therapeutic relevance of these mutations remain poorly understood. The present study evaluated the prognostic significance of titin (TTN) mutations in liver cancer by analyzing the mutation landscape of liver cancer tissues from The Cancer Genome Atlas (TCGA) database. The association between TTN mutations and drug susceptibility was subsequently examined using the OncoPredict algorithm and Cell Counting Kit‑8 (CCK‑8) assays. Furthermore, the impact of TTN mutations on hepatoma cell biology both in vivo and in vitro were assessed by reverse transcription‑quantitative PCR, protein stability assays, colony formation assays, tumor spheroid formation assays and subcutaneous tumor transplantation in BALB/c nude mice. Genetic analysis of the TCGA database revealed that TTN mutations are among the most frequent mutations in liver cancer. Patients with TTN mutations exhibited worse prognoses compared with those with the wild‑type allele. The OncoPredict algorithm and CCK‑8 assays revealed that TTN mutations are associated with altered drug sensitivity, particularly to GSK1904529A, nilotinib, 5‑fluorouracil (5‑FU) and sapitinib. Additionally, TTN mutations were shown to enhance TTN protein stability, decrease intracellular ferrous ion levels and significantly decrease liver cancer sensitivity to 5‑FU both in vitro and in vivo. The findings indicated that TTN mutations increase protein stability and lower intracellular ferrous ion levels, thereby suppressing ferroptosis and contributing to resistance to 5‑FU in hepatoma cells. These results suggest that TTN mutations are associated with poor prognosis in liver cancer and could serve as a predictive biomarker for liver cancer progression, prognosis and drug resistance.

Locoregional therapies play a fundamental role in the treatment of patients with early and intermediate and locally advanced hepatocellular carcinomas. With encouraging recent advances in immunotherapy-based systemic therapies, locoregional therapies are being both promoted and challenged by new systemic therapy options. Combined locoregional and systemic therapies might enhance treatment outcomes compared with either option alone. This Series paper summarises the existing data on locoregional and systemic therapies for hepatocellular carcinoma, and discusses evidence from studies investigating their combination with a focus on their synergistic efficacy and safety.

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.

With the advances in transplant oncology in recent years, the role of liver transplantation has expanded to make curative treatment a possibility for a wider patient population. We highlight strategies in Hong Kong, China that have enabled preoperative prognostication for judicious patient selection, downstaging therapy to definitive treatment, and postoperative therapies that have provided a growing role for liver transplantation in patients with more advanced hepatocellular carcinoma.

Liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90% of primary liver cancers. Advances in diagnostic and therapeutic tools, along with improved understanding of their application, are transforming patient treatment. Integrating these innovations into clinical practice presents challenges and necessitates guidance. These clinical practice guidelines offer updated advice for managing patients with HCC and provide a comprehensive review of pertinent data. Key updates from the 2018 EASL guidelines include personalised surveillance based on individual risk assessment and the use of new tools, standardisation of liver imaging procedures and diagnostic criteria, use of minimally invasive surgery in complex cases together with updates on the integrated role of liver transplantation, transitions between surgical, locoregional, and systemic therapies, the role of radiation therapies, and the use of combination immunotherapies at various stages of disease. Above all, there is an absolute need for a multiparametric assessment of individual risks and benefits, considering the patient's perspective, by a multidisciplinary team encompassing various specialties.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape in advanced hepatocellular carcinoma and increasingly are being evaluated in earlier stage disease. Herein we explore the role of ICIs pre-liver transplant for liver cancers.

Given the high response rates with combination approaches including locoregional treatments, more patients with liver confined disease, without vascular invasion, who have received ICIs are now being rendered eligible for potential liver transplant. This opportunity to expand the population who may benefit from liver transplant has also come with challenges recognizing the global shortage of organs. Post-liver transplant immunosuppression potentially competes with the immune-stimulating effects of ICIs and graft rejection has been a concern. ICIs may provide an opportunity to maintain patients on the waiting list but an understanding of who is likely to benefit is needed, to circumvent possible toxicities. In addition, ICIs are now considered standard of care, in combination with chemotherapy, for advanced cholangiocarcinoma, where the role of liver transplant is evolving.

As the eligibility criteria globally for liver transplant in the setting of malignancy continues to expand, the integration of ICIs becomes increasingly important.

Hepatocellular carcinoma (HCC) carries significant morbidity and mortality. Management of the HCC requires a multidisciplinary approach. Surgical resection and liver transplantation are the gold standard options for the appropriate settings. Stereotactic body radiation therapy (SBRT) has emerged as a promising treatment modality in managing HCC; its use is more studied and well-established in advanced HCC (aHCC). Current clinical guidelines universally endorse SBRT as a viable alternative to radiofrequency ablation (RFA), transarterial chemoembolisation (TACE), and transarterial radioembolisation (TARE), a recommendation substantiated by literature demonstrating comparable efficacy among these modalities. In early-stage HCC, SBRT primarily manages unresectable tumours unsuitable for ablative procedures such as microwave ablation and RFA. SBRT has been incorporated as a modality to downstage tumours or as a bridge to transplant. In the case of intermediate or advanced HCC, SBRT offers excellent results either as a single modality or adjunct to other locoregional modalities such as TACE/TARE. Recent data from late-stage HCC patients illustrate the effectiveness of SBRT in achieving local tumour control while minimising damage to surrounding healthy liver tissue. It has promising local control of approximately 80-90% in managing HCC. Additional prospective data comparing the efficacy of SBRT with the first-line recommended therapies such as RFA, TACE, and surgery are essential. The standard of care for patients with advanced/metastatic disease is systemic therapy (immunotherapy/tyrosine kinase inhibitors). SBRT, in combination with immune-checkpoint inhibitors, has an immune-modulatory effect that results in a synergistic effect. Recent findings indicate that the combination of immunotherapy and SBRT in HCC is well-tolerated and exhibits synergistic effects. Further exploration of diverse immunotherapy and radiotherapy strategies is essential to identify the appropriate time for combination treatments and to optimise dose and fraction regimens. Prospective, randomised studies are imperative to establish SBRT as the primary treatment for HCC.

For patients with hepatocellular carcinoma (HCC), stereotactic body radiation therapy (SBRT) has emerged as a locoregional treatment. Our purpose was to report outcomes in patients with HCC with Child-Pugh A (CP A) versus Child-Pugh B or C (CP B/C) liver dysfunction treated with SBRT.

A retrospective analysis of 80 patients with HCC, with a total of 94 tumors treated with SBRT, was conducted at a single institution. Outcomes were compared between patients with CP A (n = 51) and CP B/C (n = 29) liver dysfunction. Outcomes of interest included local control, overall survival (OS), and toxicity.

Median tumor size was 3.2 cm. There were 59 tumors included in the CP A cohort and 35 tumors in the CP B/C cohort. Median radiation dose was 50 Gy in 5 fractions for the CP A cohort and 40 Gy in 5 fractions for the CP B/C cohort. The rates of pathologic complete response were similar between the 2 groups at 63% for the CP A group and 61% for the CP B/C group. The estimated 1-year local control rates were similar between the 2 groups at 93% for the CP A group and 91% for the CP B/C group (P = .59). The 1-year OS for the CP A group was 85%, whereas the 1-year OS for the CP B/C group was 61% (P = .19). There was a 5.9% rate of grade 3+ toxicity in the CP A group and a 20.7% rate of grade 3+ toxicity in the CPB/C group.

Our findings suggest that SBRT is feasible and effective in patients with both CP A and CP B/C liver dysfunction with similar rates of local control and pathologic complete response despite lower radiation doses in the CP B/C cohort. In patients with more advanced CP B/C cirrhosis, toxicities were higher and must be weighed against possible treatment benefits. Further studies characterizing the optimal role of SBRT in patients with advanced cirrhosis are warranted.

In this review, we explore the role of stereotactic body radiotherapy (SBRT) and other advanced radiotherapy techniques in the treatment of gastrointestinal malignancies, which primarily involves primary and secondary liver cancers and pancreatic cancers. The review examines radiotherapy in both curative and palliative settings, emphasizing the evolution of SBRT and hypofractionation as alternatives to conventional radiotherapy. We review the recent literature evaluating radiotherapy in the management of unresectable, borderline resectable, and metastatic pancreatic cancer, highlighting recent advances in radiotherapy techniques that aim to improve local control, reduce toxicity, and increase resectability in appropriate patients. For primary liver cancers (hepatocellular carcinoma and cholangiocarcinoma), SBRT has emerged as a potential noninvasive alternative to surgery, particularly in patients with unresectable tumors or those awaiting liver transplantation. The review also provides insights into ongoing clinical trials, comparative studies between SBRT and other local therapies such as radiofrequency ablation, and the use of radiotherapy in managing liver metastases from various primary cancers. Throughout, we emphasize limitations in the available literature and highlight areas of ongoing and future investigation.

Hepatocellular carcinoma (HCC) poses a unique challenge due to its predilection for developing on compromised livers, often limiting surgical options. Stereotactic body radiotherapy (SBRT) has emerged as a promising local treatment modality for HCC. This study aims to assess the effectiveness of SBRT in HCC patients not suitable for surgery, focusing on local control, optimal radiation dosing, and prognostic factors.

In this retrospective analysis, 52 HCC patients treated with SBRT were examined. The study assessed local control, progression-free survival (PFS), and overall survival (OS) while conducting dosimetric analyses. The relationship between mean liver dose and Child-Pugh score (CPS) progression was also explored.

SBRT demonstrated 93.4% freedom from local progression (FFLP) at 12 months. Notably, a near minimum dose (D98%) below 61 Gy as an equivalent dose in 2‑Gy fractions with α/β 10 Gy (EQD2α/β10) was associated with reduced FFLP (p-value 0.034). Logistic regression analysis revealed a dose-response relationship for FFLP and D98% with 95% and 98% probability of FFLP at a dose of 56.9 and 73.1 Gy, respectively. The study observed OS rates of 63.7% at 1 year and 34.3% at 3 years. Patients with portal vein tumor thrombus (PVTT) and larger tumors (≥ 37 cm3) experienced decreased PFS and OS. Multivariate analysis identified PVTT, larger tumor volume, and performance status as independent predictors of reduced OS. Notably, classical radiation-induced disease (cRILD) was absent, but nonclassical (nc) RILD occurred in 7.7% of patients. Regression analysis linked a mean EQD2α/β3-8 dose to the liver (12.8-12.6) with a 10% likelihood of ncRILD.

SBRT offers a compelling option for achieving high local control and promising survival outcomes in HCC. The study supports a radiation dose range of 61-73.1 Gy, coupled with a mean liver dose under 12.6-12.8 Gy as EQD2, to achieve favorable FFLP rates, with acceptable toxicity rates.

Hepatocellular carcinoma (HCC), the most prevalent liver tumor, is usually linked with chronic liver diseases, particularly cirrhosis. As per the 2020 statistics, this cancer ranks 6th in the list of most common cancers worldwide and is the third primary source of cancer-related deaths. Asia holds the record for the highest occurrence of HCC. HCC is found three times more frequently in men than in women. The primary risk factors for HCC include chronic viral infections, excessive alcohol intake, steatotic liver disease conditions, as well as genetic and family predispositions. Roughly 40-50% of patients are identified in the late stages of the disease. Recently, there have been significant advancements in the treatment methods for advanced HCC. The selection of treatment for HCC hinges on the stage of the disease and the patient's medical status. Factors such as pre-existing liver conditions, etiology, portal hypertension, and portal vein thrombosis need critical evaluation, monitoring, and appropriate treatment. Depending on the patient and the characteristics of the disease, liver resection, ablation, or transplantation may be deemed potentially curative. For inoperable lesions, arterially directed therapy might be an option, or systemic treatment might be deemed more suitable. In specific cases, the recommendation might extend to external beam radiation therapy. For all individuals, a comprehensive, multidisciplinary approach should be adopted when considering HCC treatment options. The main treatment strategies for advanced HCC patients are typically combination treatments such as immunotherapy and anti-VEGFR inhibitor, or a combination of immunotherapy and immunotherapy where appropriate, as a first-line treatment. Furthermore, some TKIs and immune checkpoint inhibitors may be used as single agents in cases where patients are not fit for the combination therapies. As second-line treatments, some treatment agents have been reported and can be considered.

Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been widely researched and is well established worldwide. The cornerstone of this treatment lies in the various criteria formulated by expert consensus and experience. The variations among the criteria are staggering, and the short- and long-term out comes are controversial.

To study the differences in the current practices of LT for HCC at different centers in India and discuss their clinical implications in the future.

We conducted a survey of major centers in India that performed LT in December 2022. A total of 23 responses were received. The centers were classified as high- and low-volume, and the current trend of care for patients und ergoing LT for HCC was noted.

Of the 23 centers, 35% were high volume center (> 500 Liver transplants) while 52% were high-volume centers that performed more than 50 transplants/year. Approximately 39% of centers had performed > 50 LT for HCC while the percent distribution for HCC in LT patients was 5%-15% in approximately 73% of the patients. Barring a few, most centers were divided equally between University of California, San Francisco (UCSF) and center-specific criteria when choosing patients with HCC for LT, and most (65%) did not have separate transplant criteria for deceased donor LT and living donor LT (LDLT). Most centers (56%) preferred surgical resection over LT for a Child A cirrhosis patient with a resectable 4 cm HCC lesion. Positron-emission tomography-computed tomography (CT) was the modality of choice for metastatic workup in the majority of centers (74%). Downstaging was the preferred option for over 90% of the centers and included transarterial chemoembolization, transarterial radioembolization, stereotactic body radiotherapy and atezolizumab/bevacizumab with varied indications. The alpha-fetoprotein (AFP) cut-off was used by 74% of centers to decide on transplantation as well as to downstage tumors, even if they met the criteria. The criteria for successful downstaging varied, but most centers conformed to the UCSF or their center-specific criteria for LT, along with the AFP cutoff values. The wait time for LT from down staging was at least 4-6 wk in all centers. Contrast-enhanced CT was the preferred imaging modality for post-LT surveillance in 52% of the centers. Approximately 65% of the centers preferred to start everolimus between 1 and 3 months post-LT.

The current predicted 5-year survival rate of HCC patients in India is less than 15%. The aim of transplantation is to achieve at least a 60% 5-year disease free survival rate, which will provide relief to the prediction of an HCC surge over the next 20 years. The current worldwide criteria (Milan/UCSF) may have a higher 5-year survival (> 70%); however, the majority of patients still do not fit these criteria and are dependent on other suboptimal modes of treatment, with much lower survival rates. To make predictions for 2040, we must prepare to arm ourselves with less stringent selection criteria to widen the pool of patients who may undergo transplantation and have a chance of a better outcome. With more advanced technology and better donor outcomes, LDLT will provide a cutting edge in the fight against liver cancer over the next two decades.

During the last decade, downstaging for hepatocellular carcinoma has expanded the pool of patients eligible for liver transplantation. The literature is rife with attempts to elucidate best treatment strategies with novel locoregional and systemic therapies continuing to emerge. Several trials have confirmed the large-scale success of downstaging protocols, with equitable long-term survival and recurrence rates after liver transplant. We review the currently available techniques used for downstaging, including their indications, complications, and efficacies. New frontiers have focused on the potential role of immunotherapy in the neoadjuvant setting, although more research is needed to delineate its role in current treatment paradigms.

This review summarizes the clinical evidence supporting the utilization of stereotactic body radiotherapy (SBRT) for liver tumors, including hepatocellular carcinoma, liver metastases, and cholangiocarcinoma. Emerging prospective evidence has demonstrated the benefit and low rates of toxicity across a broad range of clinical contexts. We provide an introduction for the interventional radiologist, with a discussion of underlying themes such as tumor dose-response, mitigation of liver toxicity, and the technical considerations relevant to performing liver SBRT. Ultimately, we recommend that SBRT should be routinely included in the armamentarium of locoregional therapies for liver malignancies, alongside those liver-directed therapies offered by interventional radiology.

Hepatocellular carcinoma (HCC)is a common type of liver cancer with a poor prognosis, especially in patients with advanced stages or underlying liver disease. While surgical resection, liver transplantation, and ablation therapies have traditionally been the mainstay of treatment for HCC, radiation therapy has become increasingly recognized as an effective alternative, particularly for those who are not surgical candidates. Stereotactic Body Radiation Therapy (SBRT) is a highly precise form of radiation therapy that delivers very high doses of radiation to the tumor while sparing surrounding healthy tissue. Several studies have reported favorable outcomes with SBRT in HCC treatment. Moreover, SBRT can be used to treat recurrent HCC after prior treatment, offering a potentially curative approach in select cases. While SBRT has demonstrated its efficacy and safety in treating HCC, future studies are needed to further investigate the potential role of SBRT in combination with other treatments for HCC.

Relapse and unresectability have become the main obstacle for further improving hepatocellular carcinoma (HCC) treatment effect. Currently, single therapy for HCC in clinical practice is limited by postoperative recurrence, intraoperative blood loss and poor patient outcomes. Multidisciplinary therapy has been recognized as the key to improving the long-term survival rate for HCC. However, the clinical application of HCC synthetic therapy is restricted by single functional biomaterials. In this study, a magnetic nanocomposite hydrogel (CG-IM) with iron oxide nanoparticle-loaded mica nanosheets (Iron oxide nanoparticles@Mica, IM) is reported. This biocompatible magnetic hydrogel integrated high injectability, magnetocaloric property, mechanical robustness, wet adhesion, and hemostasis, leading to efficient HCC multidisciplinary therapies including postoperative tumor margin treatment and percutaneous locoregional ablation. After minimally invasive hepatectomy of HCC, the CG-IM hydrogel can facilely seal the bleeding hepatic margin, followed by magnetic hyperthermia ablation to effectively prevent recurrence. In addition, CG-IM hydrogel can inhibit unresectable HCC by magnetic hyperthermia through the percutaneous intervention under ultrasound guidance.

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.

A wide range of ablative and non-surgical therapies are available for treating small hepatocellular carcinoma in patients with very early or early-stage disease and preserved liver function.

To review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small hepatocellular carcinoma (≤ 3 cm).

Systematic review and network meta-analysis.

Nine databases (March 2021), two trial registries (April 2021) and reference lists of relevant systematic reviews.

Eligible studies were randomised controlled trials of ablative and non-surgical therapies, versus any comparator, for small hepatocellular carcinoma. Randomised controlled trials were quality assessed using the Cochrane Risk of Bias 2 tool and mapped. The comparative effectiveness of therapies was assessed using network meta-analysis. A threshold analysis was used to identify which comparisons were sensitive to potential changes in the evidence. Where comparisons based on randomised controlled trial evidence were not robust or no randomised controlled trials were identified, a targeted systematic review of non-randomised, prospective comparative studies provided additional data for repeat network meta-analysis and threshold analysis. The feasibility of undertaking economic modelling was explored. A workshop with patients and clinicians was held to discuss the findings and identify key priorities for future research.

Thirty-seven randomised controlled trials (with over 3700 relevant patients) were included in the review. The majority were conducted in China or Japan and most had a high risk of bias or some risk of bias concerns. The results of the network meta-analysis were uncertain for most comparisons. There was evidence that percutaneous ethanol injection is inferior to radiofrequency ablation for overall survival (hazard ratio 1.45, 95% credible interval 1.16 to 1.82), progression-free survival (hazard ratio 1.36, 95% credible interval 1.11 to 1.67), overall recurrence (relative risk 1.19, 95% credible interval 1.02 to 1.39) and local recurrence (relative risk 1.80, 95% credible interval 1.19 to 2.71). Percutaneous acid injection was also inferior to radiofrequency ablation for progression-free survival (hazard ratio 1.63, 95% credible interval 1.05 to 2.51). Threshold analysis showed that further evidence could plausibly change the result for some comparisons. Fourteen eligible non-randomised studies were identified (n ≥ 2316); twelve had a high risk of bias so were not included in updated network meta-analyses. Additional non-randomised data, made available by a clinical advisor, were also included (n = 303). There remained a high level of uncertainty in treatment rankings after the network meta-analyses were updated. However, the updated analyses suggested that microwave ablation and resection are superior to percutaneous ethanol injection and percutaneous acid injection for some outcomes. Further research on stereotactic ablative radiotherapy was recommended at the workshop, although it is only appropriate for certain patient subgroups, limiting opportunities for adequately powered trials.

Many studies were small and of poor quality. No comparative studies were found for some therapies.

The existing evidence base has limitations; the uptake of specific ablative therapies in the United Kingdom appears to be based more on technological advancements and ease of use than strong evidence of clinical effectiveness. However, there is evidence that percutaneous ethanol injection and percutaneous acid injection are inferior to radiofrequency ablation, microwave ablation and resection.

PROSPERO CRD42020221357.

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (NIHR award ref: NIHR131224) and is published in full in Health Technology Assessment; Vol. 27, No. 29. See the NIHR Funding and Awards website for further award information.