Portal vein tumor thrombosis (PVTT) is frequent in hepatocellular carcinoma (HCC). Although hepatectomy is the primary treatment for HCC, no consensus exists on its role in PVTT between Eastern and Western clinicians. This study aims to assess the efficacy of hepatectomy in HCC patients with PVTT by analyzing perioperative outcomes and prognosis.

This retrospective, single-center study reviewed HCC patient data from Queen Mary Hospital, Hong Kong (1989-2020). Propensity score matching (PSM) was applied to match patients with and without PVTT undergoing hepatectomy, comparing perioperative and survival outcomes between groups.

Among 3981 HCC patients, 1842 had PVTT and were not operated (not-operated group), while 2139 underwent hepatectomy. Of the operated patients, 156 had PVTT (PVTT group) and 1983 did not (no-PVTT group). Median overall survival (mOS) in the not-operated group was 2.7 months, compared to 13.0 months in the PVTT group. After 1:3 PSM, the no-PVTT group (n = 468) had longer mOS (47.0 vs. 13.0 months, p < 0.001) and disease-free survival (10.6 vs. 4.2 months, p < 0.001). The PVTT group had longer operative times (449 vs. 390 min, p < 0.001), higher complication rates (37.8 % vs. 28.2 %, p = 0.024), and closer surgical margins (0.6 vs. 1.0 cm, p = 0.036), but similar hospital mortality (p = 0.898). mOS for low-AFP (<17400 ng/ml) and high-AFP (≥17400 ng/ml) patients was 16.2 vs. 8.2 months, respectively (p < 0.001).

Aggressive treatment of PVTT is necessary. For certain PVTT patients, hepatectomy may be potentially effective, with acceptable perioperative safety and seemingly no technical barriers.

To evaluate the efficacy and safety of a multimodal therapeutic approach involving transarterial chemoembolization (TACE) in conjunction with helical iodine-125 (I-125) seed implant, lenvatinib, and programmed cell death-1(PD-1) inhibitors for hepatocellular carcinoma (HCC) complicated by main portal vein tumor thrombus (MPVTT).

HCC patients with MPVTT treated with TACE coupled with helical I-125 implant, lenvatinib, PD-1 inhibitors between September 2019 and August 2022 were retrospectively analyzed, and constituted as study group. Those treated with TACE, helical I-125 seed implant, and sorafenib between December 2016 and August 2020 served as the historical control group. All patients received sorafenib or lenvatinib combined with PD-1 inhibitors within 3-7 days after TACE and helical I-125 seed implantation. The longest follow-up period for all patients in both groups was 36 months from the date of helical I-125 seed implantation. Primary outcome was overall survival time (OS), and secondary outcomes were progression free survival time (PFS), objective response rate (ORR), and disease control rate (DCR). The Cox proportional hazards regression model was employed to identify independent prognostic factors influencing OS and PFS. The value P < 0.05 was deemed statistically significant.

A total of 53 patients were enrolled, with 22 assigned to the study group and 31 to the control group. The study group exhibited superior overall ORR(54.5% vs. 25.8%, P = 0.033) and overall DCR (77.3% vs. 64.5%, P = 0.319). Notably, the ORR and DCR of MPVTT were higher in the study group (86.4% vs. 51.6%, P = 0.008; and 95.5% vs. 83.9%, P = 0.382, respectively). Median OS (16.1 ± 6.1 months vs. 10.2 ± 0.8 months, P = 0.008) and PFS (13.6 ± 3.0 months vs. 6.1 ± 0.6 months, P = 0.014) were prolonged in the study group. The maximal tumor size, alpha fetoprotein level, and treatment modality were independent predictors for OS, while the maximal tumor size and treatment modality were independent determinants for PFS. Study group showed frequent hypothyroidism and reactive cutaneouscapillary (P < 0.01), with comparable grade 3/4 adverse events between groups.

The integration of the helical I-125 seed implant with TACE, lenvatinib, and PD-1 inhibitors is the safe and efficacious approach in the management of HCC complicated by MPVTT.

Centrally located hepatocellular carcinoma (HCC) is a subtype HCC with special location adjoined hepatic portals. It is difficult to be radically resected with sufficient surgical margin. We discussed whether neoadjuvant therapy could increase surgical margin and reduce recurrence.

From January 2018 to September 2023, 106 centrally located HCC patients who underwent radical liver resection were retrospectively included. Neoadjuvant therapy included transarterial chemoembolization (TACE) with programmed death 1 (PD-1) inhibitors plus tyrosine kinase inhibitor (TKI). Surgical margin and long-term outcomes were compared between patients with and without neoadjuvant therapy.

40 patients underwent neoadjuvant therapy and 66 patients underwent surgery alone. In neoadjuvant therapy group, 3 (7.5 %) patients achieved progression disease, 9 (22.5 %) patients achieved stable disease, 13 (32.5 %) achieved partial response and 15 (37.5 %) achieved complete response based on the mRECIST criterion. Ultimately, 36 patients (90 %) underwent subsequent surgical resection in the neoadjuvant therapy group. The neoadjuvant therapy had the advantages of declining alpha fetoprotein level (5.9 ng/mL vs 50.1 ng/mL, P = 0.001), microvascular invasion rate (MVI) (12.5 % vs 30.3 %, P = 0.036), reducing tumor size to 5.1 ± 2.1 cm from 6.2 ± 2.2 cm (P = 0.021), and increasing more patients with surgical margin>1 cm (30.0 % vs 7.6 %, P = 0.002). The neoadjuvant therapy group reduced tumor recurrence and prolonged overall survival. Multivariate analysis found that neoadjuvant therapy was an independent protective factor for overall survival and recurrence free survival.

Neoadjuvant therapy showed advantage of reducing tumor burden and increasing surgical margin for centrally located HCC, resulting in longer overall survival and recurrence free survival.

Hepatocellular carcinoma (HCC) has a poor prognosis, especially in elderly HCC patients. A growing number of studies have confirmed that nomogram based on demographic information, pathologic information, and treatment modalities are effective in predicting the prognosis of cancer patients. We aimed to develop an individualized and clinically useful nomogram for elderly patients.We also aimed to investigate the prognostic significance of different treatment modalities.

A total of 7694 eligible elderly patients with HCC were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2020. The patients were randomized into the training cohort (n = 5385) and the validation cohort (n = 2309) at a 7:3 ratio. Univariate and multivariate COX regression analyses were performed in the training cohort. Based on the results of the regression analysis, a nomogram model for predicting the prognosis of elderly HCC patients was established and verified in the validation cohort. The performance of the nomogram was evaluated by using receiver operating characteristic curve (ROC) and calibration curve.Finally, we grouped patients by surgery, chemotherapy, radiotherapy separately, and then used Propensity Score Matching (PSM) to balance other variables to explore prognostic significance of different treatment modalities for elderly Hepatocellular carcinoma.

Regression analysis showed that Age, Grade, T.stage, N.stage, M.stage, Chemotherapy, Radiotherapy, and Surgery had significant prognosis and developed nomogram based on the above 8 variables.This nomogram showed good accuracy in predicting one-year OS of the training cohort (AUC = 0.745) and was confirmed in the validation cohort (AUC = 0.786). The calibration curve shows that the actual survival probability and the predicted survival probability are in good agreement. A risk classification system was established to risk-stratify elderly patients with HCC, ROC was used to validate the efficacy of nomogram model in differentiating between high and low risk groups(p < 0.01),and verify in the validation cohort(p < 0.01).Finally, after grouping elderly HCC patients according to different treatment modalities, subgroup analysis showed that: The survival time of the surgery group was longer than that of the no-surgery group. Median overall survival was longer in the chemotherapy group than in the no-chemotherapy group, but there was no advantage in long-term prognosis. Median overall survival was also significantly longer in the radiotherapy group than in the no-radiotherapy group, but when analyzed in subgroups, it was found that in the T4 stage and GradeIV subgroups, radiotherapy patients had a worse prognosis than those who did not receive radiotherapy.

The nomogram established based on demographic characteristics and other clinical parameters can be used as an effective tool to predict the prognosis of elderly HCC patients, and its good prediction efficiency can realize the individualized treatment plan formulation and follow-up management of elderly HCC patients.

The mitochondrial solute carrier family 25 (SLC25) is known to play a pivotal role in oncogenesis, yet its specific involvement in hepatocellular carcinoma (HCC) remains poorly elucidated.

In this study, we performed a clustering analysis of HCC patients in the Cancer Genome Atlas database based on the expression levels of SLC25 members, and conducted clinical feature analysis for each patient within the clusters. Subsequently, we developed a prognostic model using a Lasso regression approach with SLC25A19, SLC25A49, and SLC25A51 as features, and generated a risk score for each HCC patient. We then identified SLC25A19 as a potential prognostic marker for HCC through single-cell analysis, and validated this finding using in vitro and in vivo experiments.

Our results revealed significant differences in the expression of most SLC25 family members in HCC patients, enabling the stratification of patients into three clusters, with those in cluster 1 exhibiting the most favorable prognosis and showing a correlation with enhanced immune infiltration. The risk scores derived from the features SLC25A19, SLC25A49, and SLC25A51 effectively predicted the prognosis of HCC patients, with area under the curve (AUC) values exceeding 0.7 in the test group. Single-cell analysis further demonstrated h eightened expression of SLC25A19 in the immune microenvironment of HCC, and in vitro experiments indicated that SLC25A19 may regulate the proliferation, migration, invasion, cycle, and apoptosis of liver cancer cells through the Wnt pathway. In the HepG2 animal model, overexpression of SLC25A19 significantly promotes tumor growth, while knockdown inhibits tumor growth. Analysis of patient tumor tissues shows that SLC25A19 is highly expressed in liver cancer tissues and is associated with CD8+ T cell infiltration.

In conclusion, our comprehensive analysis of the role of SLC25 in HCC unveiled SLC25A19 as a potential regulatory factor in HCC.

Hepatocellular carcinoma arises in the setting of cirrhosis in most cases, requiring multidisciplinary input to define resectability. In this regard, more precise surgical management considers patient factors and anatomical states, including resection margins, tumour biology, and perioperative therapy. Together with advances in surgical techniques, this integrated approach has resulted in considerable improvements in patient morbidity and oncological outcomes. Despite this, recurrence rates in hepatocellular carcinoma remain high. As the systemic treatment landscape in hepatocellular carcinoma continues to evolve and locoregional options are increasingly used, we review current and future opportunities to individualise the surgical management of patients with hepatocellular carcinoma.

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.

The primary curative therapies for hepatocellular carcinoma are resection or liver transplantation. For patients requiring downstaging or who are unresectable at presentation, the landscape of local treatment options has vastly changed over the past decades. This change is partly due to the paucity of high-level evidence to guide the selection of liver-directed therapies, where physician preference and treatment patterns have historically resulted in relegating external-beam radiation therapy (EBRT) to a secondary option in the treatment of hepatocellular carcinoma in cases where arterially directed therapies or thermal ablations were not possible. However, technology advancements have substantially improved the ability to treat liver malignancies with high doses of radiation therapy and to minimise doses to uninvolved hepatic parenchyma and other nearby organs. These advancements have enabled safe treatment of hepatocellular carcinoma with EBRT, with low risk of toxicity. Recent randomised trials support the role of EBRT in the treatment of hepatocellular carcinoma from early to advanced stages. These trials identified that EBRT improved several key patient-centred outcomes, including overall survival when using stereotactic body radiotherapy and sorafenib compared with sorafenib alone in unresectable hepatocellular carcinoma, recurrence-free survival with the use of adjuvant EBRT in select patients after hepatocellular carcinoma resection, and quality of life for patients with painful hepatocellular carcinoma masses treated with palliative EBRT. With emerging high-quality evidence, hepatocellular carcinoma therapeutic guidelines should include the growing role of EBRT in improving the quality and quantity of life for patients with liver cancer.

Hepatocellular carcinoma (HCC) is a common malignancy in China, with high recurrence rate and low resection rate among patients first diagnosed. Preoperative treatments including neoadjuvant and conversion therapy have the potential to overcome these challenges. In December 2021, Chinese expert consensus on neoadjuvant and conversion therapies for hepatocellular carcinoma was published. With the emersion of new evidence regarding the neoadjuvant and conversion therapies for HCC, the cooperative group brought together multidisciplinary researchers and scholars with experience in related fields to update the new edition (2023 Edition) for reference in China, including principle of the treatment strategies, the potential populations selection, treatment methods, multidisciplinary team, and future research for preoperative treatments. The new consensus aims to provide guidance for clinical application. Through the use of neoadjuvant therapy and conversion therapy, we can enhance the resection rate and reduce the recurrence of intermediate-to-advanced HCC patients, thereby improving survival outcomes.

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) accompanied by main portal vein tumor thrombosis (mPVTT) is associated with poor prognosis and limited treatment options. This study aimed to evaluate the efficacy and safety of a novel triple therapy approach combining surgery, intraoperative radiotherapy (IORT), and postoperative portal vein infusion chemotherapy (PVC) for HCC with mPVTT.

A retrospective analysis was conducted on 56 patients diagnosed with HCC and mPVTT. Patients were divided into two groups: the surgery-IORT-PVC group (n = 21) and the transcatheter arterial chemoembolization (TACE) combined with hepatic arterial infusion chemotherapy (HAIC) group (n = 35). Baseline characteristics, treatment procedures, postoperative complications, and survival outcomes were compared between the two groups.

The surgery-IORT-PVC group (n = 21) demonstrated superior median overall survival (OS) (not reached vs. 7 months, P < 0.05 4.99(2.543-9.792)) and median progression-free survival (PFS) (not reached vs. 4 months, P < 0.05 5.268(2.765-10.03)) compared to the TACE-HAIC group (n = 35). Additional, the 1-year, 2-year, and 3-year OS (75.6 %, 60.5 %, 60.5 % vs 28.8 %, 8.2 %, 8.2 %) and PFS (73.3 %, 64.1 %, 64.1 % vs 9.5 %, 9.5 %, 9.5 %) of the surgery-IORT-PVC group significantly superior to that of the TACE-HAIC group. Multivariate analysis identified the treatment modality as an independent factor influencing both OS and PFS. Postoperative complications in the surgery-IORT-PVC group were manageable. No severe adverse events were reported in either group.

Overall, this novel treatment modality offers a potential effective therapy modality for patients with HCC and mPVTT who previously had limited therapeutic options.

Hepatocellular carcinoma (HCC) with coexisting portal vein tumor thrombus (PVTT) is associated with poor patient outcomes. The efficacy and safety of neoadjuvant therapy in patients with HCC with PVTT remain a subject of debate. In the present study, a comprehensive search of electronic databases, including PubMed, Web of Science, Embase and the Cochrane Library, was conducted to identify studies evaluating the outcomes of neoadjuvant therapy in patients with HCC and PVTT. The primary outcomes assessed were overall survival (OS) and relapse-free survival (RFS), with complication rates as a secondary outcome. A total of six studies comprising 750 patients were included in the present meta-analysis. The neoadjuvant therapy group exhibited significantly superior OS [hazard ratio (HR), 0.39; P<0.001] and RFS (HR, 0.31; P<0.001) compared with the primary hepatectomy control group. Compared with the control group, neoadjuvant radiotherapy improved OS (HR, 0.34; P<0.001) and RFS (HR, 0.24; P=0.004). While the neoadjuvant intervention subgroup exhibited an improved OS compared with controls (HR, 0.37; P=0.001), no significant difference in RFS was observed (HR, 0.11; P=0.095). Geographical analysis revealed that the Chinese subgroup demonstrated a significantly improved OS and RFS (HR, 0.41 for both; P<0.001), compared with the control group. However, the Japanese and Korean subgroups showed no improvement in OS (HR, 0.25; P=0.057) compared with the control group, and the results did not reach statistical significance. There were no significant differences between the groups in terms of blood transfusion, blood loss, operation time, bile leakage, ascites, peritoneal infection, postoperative bleeding, complications or mortality (all P>0.05). Overall, neoadjuvant therapy significantly improved survival outcomes in patients with HCC and PVTT without increasing complication rates, supporting its efficacy and manageable safety profile.

Patients with advanced hepatocellular carcinoma (HCC) and macrovascular invasion (MVI) are recommended to receive systemic therapy according to guidelines. Stereotactic body radiotherapy (SBRT) and surgery are increasingly used in this patient population. This study compares outcomes from these local treatments.

Patients diagnosed with HCC with MVI and treated with surgery or SBRT between 1999 and 2022 were included. Propensity score matching minimized bias from confounders. Overall survival (OS) was analyzed using the Kaplan-Meier method,. and local, regional, and distant recurrences were assessed via competing risk methods. Univariable and multivariable analyses adjusted by the Lasso method evaluated OS predictors.

Among 175 patients, 38 underwent surgery and 137 received SBRT. The median age was 61 years, tumor volume was 158.6 cc, and α-fetoprotein level was 197 IU/mL. Most surgical patients had major resection (74%) via an open approach (97%). The median biologically effective dose (BED) for SBRT was 53.7 Gy. After matching, 35 patients per group had a median OS of 16 months. Local failure was higher in the SBRT group (20%) than in the surgery group (12%) at 1 year (p = 0.028). Distant failure was more frequent in surgery (54%) compared with SBRT (17%) [p = 0.003]. Excluding SBRT patients receiving adjuvant systemic therapy did not change the results. In-hospital mortality was 9% post-surgery and 14% experienced post-SBRT liver impairment.

Both surgery and SBRT offer good long-term OS and control. Surgery provides better local control, while SBRT had lower distant relapse. While SBRT has acceptable toxicity, surgery carries a significant mortality risk.

Radiotherapy offers potential benefits for patients with hepatocellular carcinoma (HCC); however, the distinct role of intraoperative radiotherapy (IORT) during narrow-margin hepatectomy remains inadequately defined. This study aims at assessing the safety and effectiveness of IORT for centrally located HCCs during narrow-margin hepatectomy.

This single-center, retrospective research incorporated 659 patients with centrally located HCCs. After applying exclusion criteria, 607 patients remained and were divided into two groups: IORT integrated with liver resection (IORT+LR, 54 patients) and mere liver resection (LR, 553 patients). Propensity score matching (PSM) was performed to balance baseline characteristics. Post PSM, surgical outcomes, long-term recurrence, survival rates and adverse events were analyzed.

A total of 54 patients were successfully matched, without significant differences upon baseline characteristics (standardized mean difference, SMD <0.15). Post-matching analysis revealed that overall survival (OS) and disease-free survival (DFS) were notably improved in the IORT+LR group (P =0.027 and 0.015, respectively). Multivariate Cox regression identified IORT as an independent prognostic factor for better DFS and OS. Among the 108 patients included after matching, 57 experienced HCC recurrence, 23 in the IORT group and 34 in the LR group, showing a clear difference in recurrence rates (P =0.034). Also, there were no apparent differences in mild/severe complications between IORT and RT groups (96.3% vs 98.2%, P =0.558, respectively).

IORT is an effective and well-tolerated therapy for HCC patients. The combination of narrow-margin hepatectomy and IORT enhances patient prognosis, with IORT identified as an independent prognostic factor.

Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy.

To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone.

This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023.

Personalized SBRT, 27.5 to 50 Gy in 5 fractions.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life.

Of 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77; 90% CI, 0.59-1.01; 1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72; 95% CI, 0.52-0.99; 2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P < .001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively (P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively.

In this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone.

ClinicalTrials.gov Identifier: NCT01730937.

The impact of the distance of the tumor from the main hepatic vessels (DTV), such as the Glissonean pedicle or hepatic veins, on oncological outcomes for Hepatocellular carcinoma (HCC) patients is relatively understudied. Therefore, the objective of this study was to explore the correlation between DTV and survival in patients with HCC after curative hepatic resection.

Consecutive patients who underwent curative-intent liver surgery for HCC between April 2018 and May 2023 were identified from a prospective database. Univariate and multivariate Cox regression analysis were performed to identify independent predictors of recurrence-free survival (RFS). A ROC-curve was used to find the optimal cut-off value for DTV. According to the estimated cut-off value, patients were divided into 2 subgroups, then using the Kaplan-Meier survival curve, RFS and overall survival (OS) were estimated and compared between the 2 subgroups.

In univariate analysis, DTV, tumor size, resection margins, microvascular invasion (MVI) and tumor grading were associated with RFS. In multivariate analysis, DTV, tumor size, and MVI were confirmed as independent predictors of RFS. In the ROC-analysis the optimal cutoff value of DTV was 20 mm. Patients with a DTV < 20 mm had a larger tumor size and a more advanced histopathological grading. There was no difference in the presence of MVI in both groups, while a significantly more patients experienced recurrence after hepatectomy in the DTV < 20 mm group. Accordingly, patients with a DTV < 20 mm experienced a shorter median RFS and OS.

DTV is a promising predictor of RFS and OS in HCC.

Hepatectomy is the optimal treatment for less than 20 % patients with hepatocellular carcinoma (HCC). A combination of hepatic artery infusion chemotherapy and systemic therapy-based conversion therapy provides a chance of resection for those with unresectable HCC. Yet, the prognosis for those successfully conversion resection is still unknown. The study is to determine the factors predicted prognosis of patients after conversion hepatic resection.

A total of 343 HCC patients underwent hepatectomy following conversion therapy from August 2018 to April 2023. Univariate and multivariate analysis were used to screen for independent factors affecting patients' prognosis.

One hundred and fifty-seven (45.8 %) patients developed recurrence or metastasis at a median time of 16.7 months (95 % CI 12.4-21.0 months) from hepatectomy. Univariate and multivariate analysis identified tumor number, alpha fetoprotein (AFP) response, tumor response, and successful downstaging were independent recurrent-free survival related predictors. Albumin bilirubin (ALBI) score and AFP response were independent death related predictors.

Clinical parameters reflecting the depth of conversion therapy response, were promising in predicting prognosis for HCC patients after conversion hepatic resection.

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.

HCC recurrence frequently occurs after curative surgery. Histological microvascular invasion (MVI) predicts recurrence but cannot provide preoperative prognostication, whereas clinical prediction scores have variable performances.

Recurr-NET, a multimodal multiphasic residual-network random survival forest deep-learning model incorporating preoperative CT and clinical parameters, was developed to predict HCC recurrence. Preoperative triphasic CT scans were retrieved from patients with resected histology-confirmed HCC from 4 centers in Hong Kong (internal cohort). The internal cohort was randomly divided in an 8:2 ratio into training and internal validation. External testing was performed in an independent cohort from Taiwan.Among 1231 patients (age 62.4y, 83.1% male, 86.8% viral hepatitis, and median follow-up 65.1mo), cumulative HCC recurrence rates at years 2 and 5 were 41.8% and 56.4%, respectively. Recurr-NET achieved excellent accuracy in predicting recurrence from years 1 to 5 (internal cohort AUROC 0.770-0.857; external AUROC 0.758-0.798), significantly outperforming MVI (internal AUROC 0.518-0.590; external AUROC 0.557-0.615) and multiple clinical risk scores (ERASL-PRE, ERASL-POST, DFT, and Shim scores) (internal AUROC 0.523-0.587, external AUROC: 0.524-0.620), respectively (all p < 0.001). Recurr-NET was superior to MVI in stratifying recurrence risks at year 2 (internal: 72.5% vs. 50.0% in MVI; external: 65.3% vs. 46.6% in MVI) and year 5 (internal: 86.4% vs. 62.5% in MVI; external: 81.4% vs. 63.8% in MVI) (all p < 0.001). Recurr-NET was also superior to MVI in stratifying liver-related and all-cause mortality (all p < 0.001). The performance of Recurr-NET remained robust in subgroup analyses.

Recurr-NET accurately predicted HCC recurrence, outperforming MVI and clinical prediction scores, highlighting its potential in preoperative prognostication.

The five-year recurrence rate for patients with hepatocellular carcinoma (HCC) is as high as 70%. Patients with high-risk recurrence factors experience significantly poorer prognosis. Local regional therapies, including transarterial chemoembolisation (TACE), hepatic arterial infusion chemotherapy (HAIC), radiotherapy, and emerging immunotherapy, are commonly used adjuvant treatment options. We conducted an indirect comparison of these adjuvant therapies for such patients.

We conducted a systematic search in public databases for relevant studies and assessed the efficacy and safety of the corresponding therapies by consolidating disease-free survival (DFS), overall survival (OS), and adverse events (AEs).

A total of eight randomised controlled trials were ultimately included. The Gelman-Rubin plot and kernel density estimation indicate that the stability of the combined model is satisfactory.

immunotherapy is not inferior to local regional therapies in delaying tumour recurrence, however, the higher incidence of AEs remains a significant concern. Adjuvant radiotherapy demonstrated superior efficacy in delaying tumour recurrence compared to adjuvant TACE, although further support from phase III clinical trial evidence is required.

https://www.crd.york.ac.uk/prospero/, identifier CRD42024576316.

Hepatocellular carcinoma (HCC) patients with macrovascular invasion (MVI) have dismal prognosis and there are no standard perioperative therapies. This phase 2 trial (ChiCTR2000036385) aimed to investigate the activity and safety of perioperative tislelizumab plus intensity modulated radiotherapy (IMRT) for resectable HCC with MVI. Thirty treatment-naïve patients with MVI received 3 cycles of tislelizumab intravenously (200 mg, every three weeks) and concurrent IMRT (45 Gray in 15 fractions). Primary endpoints were the overall response rate (ORR) and overall survival (OS). Secondary endpoints were the proportion of patients with a complete or major pathological response (pCR or MPR), recurrence-free survival (RFS) and safety. Of patients enrolled, 15 (50%) underwent curative surgery followed by adjuvant tislelizumab. The ORR was 30.0% (90% CI 16.6%-46.5%) and the median OS was 18.7 months. Of the 15 patients underwent surgical resection, 10 (66.7%) achieved pCR or MPR and 8 (53.3%) remained recurrence-free. The median RFS were not reached with a median follow-up of 21.77 months (95% CI 12.50-31.03) post-surgery. 4 (13.3%) patients experienced grade 3 treatment-related adverse events. The most common events were thrombocytopenia, leukopenia, and anemia. The trial has met the pre-specified endpoints, and these results support further studies of perioperative immunotherapy plus radiotherapy in HCC.

Radiation-induced liver fibrosis (RILF) is a common manifestation of radiation-induced liver injury (RILI) and is caused primarily by activated hepatic stellate cells (HSCs). Circular RNAs (circRNAs) play critical roles in various diseases, but little is known about the function and mechanism of circRNAs in RILF.

RNA pull-down and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to screen binding proteins of hsa_circ_0096498 (circ96498). RNA-binding protein immunoprecipitation, RNA pull-down and nuclear and cytoplasmic protein extraction were conducted to confirm the interaction between circ96498 and eukaryotic initiation factor 4A3 (EIF4A3). RNA sequencing was performed to screen target genes regulated by EIF4A3. HSCs with altered circ96498 and cell division cycle 42 (CDC42) expression were used to assess irradiated HSC activation. Circ96498 inhibition and CDC42 blockade were evaluated in RILF mouse models.

In this study, we identified a radiation-sensitive circ96498, which was highly expressed in the irradiated HSCs of paracancerous tissues from RILI patients. Circ96498 inhibited the proliferation but promoted the apoptosis of irradiated HSCs, suppressed the secretion of proinflammatory cytokines IL-1β, IL-6 and TNF-α, and decreased the expression of profibrotic markers (α-SMA and collagen 1) in irradiated HSCs. Mechanistically, irradiation induced the transport of EIF4A3 into the nucleus, and nuclear EIF4A3 increased the stability of CDC42 mRNA and increased CDC42 expression, thereby promoting HSC activation through the NF-κB and JNK/Smad2 pathways. However, the binding of circ96498 to EIF4A3 impeded the translocation of EIF4A3 into the nucleus, resulting in the inhibition of CDC42 expression and subsequent HSC activation. Furthermore, circ96498 knockdown promoted the development of the early and late stages of RILF in a mouse model, which was mitigated by CDC42 blockade.

Collectively, our findings elucidate the involvement of the circ96498/EIF4A3/CDC42 axis in inhibiting irradiated HSC activation, which offers a novel approach for RILF prevention and treatment.

Lenvatinib (LEN) is a multi-target TKI, which plays a pivotal role in the treatment of advanced hepatocellular carcinoma (HCC). The inevitable occurrence of drug resistance still prevents curative potential and is deleterious for the prognosis, and a growing body of studies is accumulating, which have devoted themselves to unveiling its underlying resistance mechanism and made some progress. The dysregulation of crucial signaling pathways, non-coding RNA and RNA modifications were proven to be associated with LEN resistance. A range of drugs were found to influence LEN therapeutic efficacy. In addition, the superiority of LEN combination therapy has been shown to potentially overcome the limitations of LEN monotherapy in a series of research, and a range of promising indicators for predicting treatment response and prognosis have been discovered in recent years. In this review, we summarize the latest developments in LEN resistance, the efficacy and safety of LEN combination therapy as well as associated indicators, which may provide new insight into its resistance as well as ideas in the treatment of advanced HCC.

Lenvatinib and programmed cell death protein-1 (PD-1) inhibitor on infiltrative hepatocellular carcinoma (HCC) have obtained demonstrated efficacy and still need improvement. Hepatic arterial infusion chemotherapy (HAIC) has shown promising results for advanced HCC. This study aimed to compare the efficacy of HAIC combined Lenvatinib and PD-1 inhibitor versus Lenvatinib combined PD-1 inhibitor for infiltrative HCC.

A total of 232 patients were enrolled. There were 114 patients received Lenvatinib combined PD-1 inhibitor (Len+PD-1 group) and 118 patients received HAIC combined Lenvatinib and PD-1 inhibitor (HAIC+Len+PD-1 group). Overall survival (OS), progression-free survival (PFS) and safety of patients were compared between the two groups by propensity score-matching (PSM).

The 6-, 12-, and 24-month OS rates were 93.8%, 65.1% and 13.4% in Len+PD-1 group, and 100%, 77.3% and 32.1% in HAIC+Len+PD-1 group, respectively. The 3-, 6-, and 12-month PFS rates were 86.4%, 45.7% and 14.1% in Len+PD-1 group, and 95.1%, 59.3% and 25.9% in HAIC+Len+PD-1 group, respectively. The HAIC+Len+PD-1 group had obviously better survival than the Len+PD-1 group both in OS (P=0.002) and PFS (P=0.004). Subgroup analysis revealed that OS in patients with metastasis was improved with HAIC+Len+PD-1 treatment. Patients with alpha-fetoprotein (AFP) response after treatment showed better survival than the non-response. In addition, HAIC+Len+PD-1 group showed manageable adverse events (AEs).

Patient with infiltrative HCC, HAIC+Len+PD-1 treatment had longer OS and PFS than Len+PD-1 treatment. Early AFP response was an effective indicator of better survival and tumor response to therapy.

Hepatocellular carcinoma (HCC) is the sixth most prevalent form of cancer globally and the third leading cause of cancer-related mortality. The incidence of portal vein tumor thrombosis (PVTT) in HCC patients is 21% at one year and 46% at three years. The presence of PVTT has consistently been associated with a poor prognosis for HCC patients over the past decades. Notably, HCC prognosis is influenced not only by the presence of PVTT but also by the degree or extent of PVTT. Currently, there is a lack of global consensus or established protocols regarding the optimal management of HCC with associated PVTT. The Barcelona Clinic for Liver Cancer classifies HCC patients with PVTT as stage C, indicating an advanced stage, and limiting treatment recommendations for these patients to systemic therapy. In recent years, there has been an increase in the availability of therapeutic options for HCC patients with PVTT. Treatment modalities include systemic therapy, transarterial chemoembolization, surgical resection, stereotactic body radiotherapy, transarterial radioembolization, and liver transplantation. An ideal therapy for each patient necessitates a multidisciplinary approach. This review article presents the latest updates in managing HCC patients with PVTT.

Hepatectomy could provide better survival benefit for hepatocellular carcinoma (HCC) with type I/II portal vein tumor thrombosis (PVTT). However, the postoperative recurrence remains high. We discussed whether neoadjuvant therapy could reduce HCC recurrence for these patients.

One hundred and thirty-eight resectable HCC with type I-II PVTT were retrospectively included. The neoadjuvant therapy regimens included tyrosine kinase inhibitor (TKI), programmed death 1(PD-1) antibodies and transarterial chemoembolization (TACE). Short-term and long-term outcomes were compared. Propensity score matching (PSM) was performed to minimize the influence of potential confounders.

Thirty-three patients underwent neoadjuvant therapy and 105 patients underwent surgery alone. In the neoadjuvant group, 7 (21.2%) patients achieved stable disease, 13 (39.4%) achieved partial response and 13 (39.4%) achieved complete response based on the modified Response Evaluation Criteria in Solid Tumors criterion. By PSM, the neoadjuvant therapy resulted in less microvascular invasion (24.1% vs 50.0%, P=0.021), satellite nodule (6.9% vs 24.1%, P=0.036) and less patients with alpha-fetoprotein>20(ng/mL) (37.9% vs 69.0%, P=0.006). The neoadjuvant therapy reduced tumor recurrence and prolonged survival. Multivariate analysis found that neoadjuvant therapy was an independent protective factor for overall survival and recurrence free survival.

Neoadjuvant treatment presents a promising treatment option for HCC patients with type I/II PVTT.

The prognosis of infiltrative hepatocellular carcinoma (HCC) is dismal. Hepatic arterial infusion chemotherapy (HAIC) plus Lenvatinib (Len) and immune checkpoint inhibitor (ICI) have shown promising results for HCC. However, this three combination therapy on infiltrative HCC is unknown. In this study, we compared HAIC plus lenvatinib (Len) and programmed cell death protein-1 (PD-1) inhibitor with HAIC plus Len for infiltrative HCC.

This multi-center cohort study included patients with infiltrative HCC who received HAIC combined with Len (HAIC+Len group, n = 173) or HAIC combined with Len and PD-1 inhibitor (HAIC+Len+ICI group, n = 128) as the first-line treatment from January 2019 to December 2021. To balance any intergroup differences, one-to-one propensity score matching (PSM) was applied. Overall survival (OS) and progression-free survival (PFS) were compared between the two groups.

After PSM, the median OS was 14.1 ± 1.0 and 16.1 ± 1.4 months in the HAIC+Len and HAIC+Len+ICI groups, respectively. The median PFS was 4.6 ± 0.4 months in the HAIC+Len group and 7.5 ± 0.8 months in the HAIC+Len+ICI group. The HAIC+Len+ICI group showed significantly better OS (hazard ratio [HR], 0.66; 95% CI, 0.49-0.90; P = 0.008) and PFS (HR, 0.53; 95% confident index [CI], 0.40-0.70; P < 0.001) compared with the HAIC+Len group. Subgroup analysis revealed that for OS in HCC without metastasis, the addition of PD-1 inhibitor was not significant (HR, 0.68; 95% CI, 0.43-1.07; P = 0.091). No difference was observed in OS between low (2-3 cycles) and high (4-6 cycles) level of HAIC cycles (HR, 0.99; 95% CI, 0.67-1.44; P = 0.938).

The HAIC+Len+ICI group had a longer PFS and OS compared with the HAIC+Len group, demonstrating an acceptable safety profile. This triple combination strategy may be an alternative treatment for infiltrative HCC management.

This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies.

The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT.

Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS.

For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

The prognosis of hepatocellular carcinoma (HCC) combined with portal and hepatic vein cancerous thrombosis is poor, for unresectable patients the combination of targeted therapy and immune therapy was the first-line recommended treatment for advanced HCC, with a median survival time of only about 2.7-6 months. In this case report, we present the case of a patient with portal and hepatic vein cancerous thrombosis who achieved pathologic complete response after conversion therapy.

In our center, a patient with giant HCC combined with portal vein tumor thrombus and hepatic vein tumor thrombus was treated with transcatheter arterial chemoembolization (TACE), radiotherapy, targeted therapy and immunotherapy, and was continuously given icaritin soft capsules for oral regulation. After 7 months of conversion therapy, the patient's tumor shrank and the tumor thrombus subsided significantly. The pathology of surgical resection was in complete remission, and there was no progression in the postoperative follow-up for 7 months, which provided a basis for the future strategy of combined conversion therapy.

In this case, atezolizumab, bevacizumab, icaritin soft capsules combined with radiotherapy and TACE had a good effect. For patients with hepatocellular carcinoma combined with hepatic vein/inferior vena cava tumor thrombus, adopting a high-intensity, multimodal proactive strategy under the guidance of multidisciplinary team (MDT) is an important attempt to break through the current treatment dilemma.

Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment regimens for advanced hepatocellular carcinoma (HCC) in recent decade. Meanwhile, numerous clinical trials are being performed to exploit more ICIs into initially unresectable HCC and postoperative HCC to expectantly induce adequate tumor downstaging for further resection or implement adjuvant treatment for relapse-free survival, respectively. In this review, we aim to summarize some pragmatic histomorphologic, immunohistochemical, and molecular pathologic parameters which promisingly indicate the response of neoadjuvant/conversion ICI-related therapy and predict the efficacy of adjuvant/therapeutic ICI-related therapy for HCC.

We searched PubMed using the terms hepatocellular carcinoma, immunotherapy, immune checkpoint inhibitor, immune checkpoint blockade, conversion therapy, neoadjuvant therapy, adjuvant therapy, biomarker, pathologic evaluation, pathologic assessment till February 2023.

Although there is no consensus regarding the pathologic evaluation of relevant HCC specimens, it is encouraging that a few of studies have concentrated on this field, and moreover, the methods and parameters noted on other cancer types are also worthy of reference. For the pathologic assessment of HCC specimens underwent immunotherapy, a suitable sampling scheme, identifying immunotherapy-related pathologic response, and quantification of pathologic response rate should be emphasized. For the patients of HCC who are scheduled to receive immunotherapy, tumor-infiltrating lymphocyte, intratumoral tertiary lymphoid structure, programmed cell death ligand 1, Wnt/β-catenin, microsatellite instability and mismatch repair, tumor mutational burden and tumor neoantigen, as well as some other signaling pathways are the potential predictive biomarkers of treatment response of ICI.

The management of HCC in the era of immunotherapy arises a brand-new pathological challenge that is to provide an immunotherapy-related diagnostic report. Albeit many related researches are preclinical or insufficient, they may tremendously alter the immunotherapy strategy of HCC in future.

The phase III REFLECT trial demonstrated that lenvatinib was superior to sorafenib in terms of progression-free survival (PFS), time to progression, and objective response rate (ORR) for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of preoperative lenvatinib therapy for patients with oncologically or technically unresectable HCC.

In this multicenter single-arm phase II trial, patients with advanced HCC and factors suggestive of a poor prognosis (macroscopic vascular invasion, extrahepatic metastasis, or multinodular tumors) were enrolled. Patients with these factors, even with technically resectable HCC, were defined as oncologically unresectable because of the expected poor prognosis after surgery. After 8 weeks of lenvatinib therapy, the patients were assessed for resectability, and tumor resection was performed if the tumor was considered technically resectable. The primary endpoint was the surgical resection rate. The secondary endpoints were the macroscopic curative resection rate, overall survival (OS), ORR, PFS, and the change in the indocyanine green retention rate at 15 min as measured before and after lenvatinib therapy. The trial was registered with the Japan Registry of Clinical Trials (s031190057).

Between July 2019 and January 2021, 49 patients (42 oncologically unresectable patients and 7 technically unresectable patients) from 11 centers were enrolled. The ORR was 37.5% based on mRECIST and 12.5% based on RECIST version 1.1. Thirty-three patients underwent surgery (surgical resection rate: 67.3%) without perioperative mortality. The surgical resection rate was 76.2% for oncologically unresectable patients and 14.3% for technically unresectable patients. The 1-year OS rate and median PFS were 75.9% and 7.2 months, respectively, with a median follow-up period of 9.3 months.

The relatively high surgical resection rate seen in this study suggests the safety and feasibility of lenvatinib therapy followed by surgical resection for patients with oncologically or technically unresectable HCC.