4149 Background: Selective internal radiation therapy (SIRT) with yttrium-90 microspheres is an established locoregional therapy for unresectable hepatocellular carcinoma (HCC) and may induce immunogenic modulation, providing a rationale for PD-(L)1 blockade combinations. However, outcomes with SIRT–PD-(L)1 doublets suggest room for improvement. Lenvatinib has biological plausibility to augment radiation- and immunotherapy-mediated effects via VEGFR/FGFR pathway inhibition. We evaluated the efficacy and safety of sequential SIRT followed by lenvatinib plus sintilimab and explored serum protein biomarkers for outcome stratification. Methods: SIRLENS-90 (NCT05992584) is a single-center, open-label, single-arm phase II trial in unresectable BCLC B/C HCC (ECOG 0–1, Child–Pugh 5–7) suitable for SIRT after mapping and 99m Tc-MAA simulation. Patients received yttrium-90 resin SIRT (partition-model dosimetry) followed 3–7 days later by lenvatinib (8/12 mg daily) plus sintilimab (200 mg IV Q3W). Primary endpoint: PFS by mRECIST. Secondary endpoints: PFS by RECIST v1.1, OS, ORR, DCR, and safety (CTCAE v5.0). Exploratory Olink proteomics and LASSO-penalized Cox modeling derived a baseline risk score. Results: Thirty patients were treated (mean age 57 years [(SD 9.9], 93% male, 87% HBV-related; 43% BCLC B, 57% BCLC C; 43% macrovascular invasion; 53% bilobar disease; 37% extrahepatic metastases; mean max tumor diameter 9.6 cm [SD 3.8; range 3.2–16.1]). Median follow-up was 23.4 months. Median PFS was 15.8 mo (95% CI 8.3–20.7) by mRECIST (6-, 12-, and 18-mo rates: 77%, 53%, 40%) and 17.0 mo (95% CI 8.3–20.7) by RECIST v1.1. Median OS was not reached (12-, 18-, and 24-mo OS rates: 83%, 73%, 68%). ORR was 83% (95% CI 65–94) by mRECIST and 60% (95% CI 41–77) by RECIST v1.1; DCR was 90% (95% CI 74–98) by both. Intrahepatic ORR was 93% (95% CI 78–99) by mRECIST. Grade 3–4 treatment-related AEs occurred in 47%, with treatment-related SAEs in 10% and no treatment-related deaths. A baseline risk score incorporating IL-5 (protective), CXCL11 (adverse), extrahepatic metastasis, and bilobar disease stratified PFS (log-rank P = 0.001) and OS ( P = 0.02), with optimism-corrected C-index 0.758 (for PFS). Conclusions: Yttrium-90 SIRT followed by lenvatinib plus sintilimab demonstrated encouraging activity with manageable toxicity in unresectable intermediate-to-advanced HCC. The cytokine-integrated baseline risk score is hypothesis-generating and warrants external validation. Clinical trial information: NCT05992584 .

The incidence and mortality of hepatocellular carcinoma (HCC) in China are among the highest in the world, imposing a heavy social burden. Liver resection and liver transplantation are the primary radical treatments for HCC, although most patients are no longer able to meet the surgical requirements at initial diagnosis. Yttrium-90 microsphere selective internal radiation therapy (90Y-SIRT) has the advantages of shrinking tumors, enlarging residual liver, regressing portal vein tumor thrombus and improving the quality of life, which can be used for conversion, downstaging and bridging therapy for HCC before surgical treatment, enabling patients regain the chance of radical treatment and reducing the postoperative recurrence rate. This review focuses on the clinical application and progress of 90Y-SIRT in this field.

Yttrium-90 microsphere selective internal radiation therapy (SIRT), also known as transarterial radioembolization, has become one of the pivotal treatments for liver cancer, particularly for selected advantageous patient groups. This review summarizes the characteristics of different patients with liver cancer that could obtain maximum benefit from SIRT and discusses key factors affecting efficacy and safety, including tumor characteristics, liver function, patient performance status, and treatment intent. In evaluating appropriate candidates, mapping serves as a crucial simulation procedure to assess tumor vascular anatomy, predict lung shunting, and guide catheter positioning and dose planning. This procedure substantially enhances therapeutic precision while minimizing the risk of nontarget radiation-related adverse events, such as radiation-induced pneumonitis and gastrointestinal toxicity. Several studies have suggested that SIRT is not only suitable for patients with early or limited hepatocellular carcinoma but can also be used as a bridging therapy for liver transplantation and conversion therapy for unresectable liver cancers. In combination with systemic treatments, SIRT has demonstrated survival benefits in patients with unresectable liver cancer. This review also highlights the importance of further optimizing patient screening through personalized dosimetry and mapping to ensure the precision and safety of treatment. A thorough review of relevant literature and clinical practice offers clinicians comprehensive suggestions on patient screening and clarifies the promise of SIRT in the liver cancer population.

Abstract Background Previous studies evaluating antiangiogenic agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma (HCC) have shown encouraging results. This study was conducted to investigate the efficacy and safety of donafenib combined with sintilimab (Don-Sin) for advanced HCC. Methods This was a single-center, single-arm phase II trial recruiting patients with BCLC stage C HCC. A safety run-in cohort was planned with the first 6 patients receiving oral donafenib 200 mg twice daily and intravenous sintilimab 200 mg once every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated to determine the recommended dose of donafenib for those enrolled thereafter. The primary endpoint of this study was progression-free survival (PFS) per mRECIST. Results 30 patients were enrolled. As 3 patients (50.0%) experienced DLTs during safety run-in, the initial dose of donafenib was adjusted to 200 mg once daily for subsequent patients. The primary endpoint was met with a median PFS of 6.2 (95% confidence interval [CI], 4.4-8.0) months per mRECIST (6.3 [95% CI, 5.4–7.2] months per RECIST 1.1). The objective response rate was 23.3% per mRECIST and 16.7% per RECIST 1.1, while the disease control rate reached 76.7% per mRECIST/RECIST 1.1. The median overall survival was 16.0 (95% CI, 13.5–18.5) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 9 patients (30.0%). Conclusions Don-Sin showed promising antitumor effects with an acceptable safety profile in patients with advanced stage HCC. The preliminary findings need to be further evaluated in phase III randomized controlled trials. Trial registration ClinicalTrials.gov (identifier: NCT05162352; date of registration: December 4, 2021).

Local thermal ablation (TA) can not only reduce the tumor burden of hepatocellular carcinoma (HCC) but also stimulate the host anti-tumor immune response, offering a promising avenue for combination with immune checkpoint blockade (ICB). However, tumor recurrence and ICB resistance are associated with residual tumor masses caused by incomplete TA treatment. Thus, adjuvant therapy that can accurately eliminate residual HCC tumors post-TA is expected to improve prognosis. Bacteria-mediated tumor therapy has showed promising potential for tumor-targeting ability and in situ therapeutic proteins expression in the tumor. Here, we presented a kind of nonpathogenic engineered bacteria (named PD-1@EcM) for the potent tumor-targeting and acidic-controlled production of fusion protein comprising a mouse-derived anti-PD-1 single-chain variable fragment (scFv). A single injection of this engineered bacteria demonstrated a significantly tumor inhibition and extended survival in advanced murine primary and metastatic post-TA treatment HCC model. We observed that this engineered bacteria elicited an enhanced antitumour immune response resulting in an extensive priming of activated CD8+ T cells and polarization of tumor-associated macrophage from M2 phenotype to M1 phenotype. Taken together, this work provides a novel strategy to address major challenges in TA therapy and expand the current applications of bacteria-based platforms for precision therapy.

Purpose:To evaluate the efficacy and safety of sorafenib combined with tislelizumab (a programmed death-1 inhibitor) and transarterial chemoembolization (TACE) in patients with advanced-stage hepatocellular carcinoma (HCC). Patients and Methods:This was a single-center, single-arm phase II trial. Patients with HCC at Barcelona Clinic Liver Cancer stage C were recruited. Treatment with sorafenib (400 mg orally twice daily) and tislelizumab (200 mg intravenously every 3 weeks) was initiated 3-7 days after the first TACE procedure. Repeated TACE was performed on-demand. The primary endpoint of this study was overall survival (OS). Results:Thirty patients were enrolled. The median OS for the patients was 18.3 (95% CI = 14.6-22.0) months, with 12-, 18-, and 24-month OS rates of 90.0%, 54.0%, and 28.3%, respectively. The objective response rate was 53.3% per modified Response Evaluation Criteria in Solid Tumors (mRECIST) and 20.0% per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The disease control rate was 86.7% per mRECIST/RECIST 1.1. The median progression-free survival was 6.8 (95% CI = 4.5-9.0) months per mRECIST/RECIST 1.1. The median duration of response was 7.1 (95% CI = 6.1-8.1) months per mRECIST (n = 16) and 4.4 (95% CI = 0.9-7.9) months per RECIST 1.1 (n = 6). Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%), and grade 3 TRAEs were observed in 11 patients (36.7%). There were no grade 4/5 TRAEs. Conclusion:Sorafenib combined with tislelizumab and TACE showed promising antitumor activities with a manageable safety profile in patients with advanced-stage HCC. These preliminary findings warrant further evaluation in Phase III randomized trials.

581 Background: Yttrium-90 resin microspheres have been introduced into China in recent years, but the efficacy or safety on Chinese patients are rarely reported. This study aimed to evaluate the efficacy and safety of selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres followed by lenvatinib and PD-1 inhibitor in Chinese patients with large (5.1–10.0 cm in diameter) or huge (>10.0 cm) advanced-stage hepatocellular carcinoma (HCC). Methods: Data of large or huge Barcelona Clinic Liver Cancer stage C HCC patients treated with SIRT followed by lenvatinib plus PD-1 inhibitor from November 2022 to October 2023 were prospectively collected and retrospectively analyzed. Key endpoints included overall survival (OS), progression-free survival (PFS), complete response rate (CRR), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors, and adverse events (AEs) graded based on Common Terminology Criteria for Adverse Events v5.0. Risk factors affecting PFS were analyzed using univariate and multivariate Cox regression models. Results: A total of 30 patients (27 males, 3 females; mean age 54 ± 11 years) were included. The mean longest diameter of the tumor was 9.6 ± 4.2 cm (range: 5.2–17.6 cm). Nineteen (63.3%) patients had more than three intrahepatic lesions, 15 (50.0%) had vascular invasion, and 13 (43.3%) had extrahepatic metastasis. Sixteen (53.3%) patients had undergone prior anticancer therapies. Two patients received two SIRT procedures, and the rest had one. Lenvatinib and PD-1 inhibitor treatment was initiated 3–7 days after the initial SIRT procedure. CRR was 20.0%, ORR was 73.3%, and DCR was 90.0%. Median PFS was 8.0 months (95% CI, 5.6–10.4), and median OS was not reached. OS rates at 6, 12, and 18 months were 93%, 74%, and 74%, respectively. Univariate and multivariate analysis indicated that baseline alpha-fetoprotein levels, baseline eosinophil count, and neutrophil-to-lymphocyte ratio at 1 month after SIRT were independent risk factors for PFS. AEs of any grade occurred in 86.7% of patients, with grade 3 AEs in 23.3%, and no grade 4/5 AEs were recorded. Conclusions: SIRT followed by lenvatinib and PD-1 inhibitor demonstrates promising efficacy and a favorable safety profile in Chinese patients with large or huge advanced-stage HCC.

BACKGROUND Surgical resection and liver transplantation (LT) are the most effective curative options for hepatocellular carcinoma (HCC). However, few patients with huge HCC (> 10 cm in diameter), especially those with portal vein tumor thrombus (PVTT), can receive these treatments. Selective internal radiation therapy (SIRT) can be used as a conversion therapy for them because it has the dual benefit of shrinking tumors and increasing residual hepatic volume. However, in patients with huge HCC, high lung absorbed dose often prevents them from receiving SIRT. CASE SUMMARY A 35-year-old man was admitted because of emaciation and pain in the hepatic region for about 1 month. The computed tomography scan showed a 20.2 cm x 19.8 cm tumor located in the right lobe-left medial lobes with right portal vein and right hepatic vein invasion. After the pathological type of HCC was confirmed by biopsy, two conversions were presented. The first one was drug-eluting bead transarterial chemoembolization plus hepatic arterial infusion chemotherapy and lenvatinib and sintilimab, converted to SIRT, and the second one was sequential SIRT with continued systemic treatment. The tumor size significantly decreased from 20.2 cm x 19.8 cm to 16.2 cm x 13.8 cm, then sequentially to 7.8 cm x 6.8 cm. In the meantime, the ratio of spared volume to total liver volume increased gradually from 34.4% to 55.7%, then to 62.9%. Furthermore, there was visualization of the portal vein, indicating regression of the tumor thrombus. Finally, owing to the new tumor in the left lateral lobe, the patient underwent LT instead of resection without major complications. CONCLUSION Patients with inoperable huge HCC with PVTT could be converted to SIRT first and accept surgery sequentially.

Background: The management of hepatocellular carcinoma (HCC) with high tumor burden and major portal vein tumor thrombosis (PVTT) remains a great challenge. The authors aimed to investigate the efficacy and safety of lenvatinib plus drug-eluting bead transarterial chemoembolization (DEB-TACE) and hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil and leucovorin (Len+DEB-TACE+HAIC) versus lenvatinib plus DEB-TACE (Len+DEB-TACE) for HCC greater than 7.0 cm accompanied with major PVTT. Materials and methods: This multicenter retrospective cohort study evaluated consecutive patients with HCC (> 7.0 cm) and major PVTT who received Len+DEB-TACE+HAIC (Len+DEB-TACE+HAIC group) or Len+DEB-TACE (Len+DEB-TACE group) between July 2019 and June 2021 from eight institutions in China. Objective response rate (ORR), time to progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between the two groups by propensity score matching (PSM). Results: A total of 205 patients were included. After PSM, 85-paired patients remained in the study cohorts. Patients in the Len+DEB-TACE+HAIC group had higher ORR (61.2% vs. 34.1%, P < 0.001), longer TTP (median, 9.8 vs. 5.9 months, P < 0.001), and prolonged OS (median, 16.7 vs. 12.5 months, P < 0.001) than those in the Len+DEB-TACE group. The ORR and TTP of both intrahepatic tumor (ORR: 64.7% vs. 36.5%, P < 0.001; median TTP: 10.7 vs. 7.0 months, P < 0.001) and PVTT (ORR: 74.1% vs. 47.1%, P < 0.001; median TTP: 17.4 vs. 7.6 months, P < 0.001) were better in the Len+DEB-TACE+HAIC group than the Len+DEB-TACE group. The frequency of grade 3-4 TRAEs in the Len+DEB-TACE+HAIC group were comparable to those in the Len+DEB-TACE group (38.8% vs. 34.1%, P = 0.524). Conclusion: The addition of HAIC to Len+DEB-TACE significantly improved ORR, TTP, and OS over Len+DEB-TACE with an acceptable safety profile for large HCC with major PVTT.

BACKGROUND & AIMS: Cirrhotic portal hypertension (CPH) is the leading cause of mortality in patients with cirrhosis. Over 50% of patients with CPH treated with current clinical pharmacotherapy still present variceal bleeding or sometimes death owing to insufficient reduction in portal pressure. Elevated intrahepatic vascular resistance (IHVR) plays a fundamental role in increasing portal pressure. Because of its potent effect in reducing portal pressure and maintaining normal portal inflow to preserve liver function, lowering the IHVR is acknowledged as an optimal anti-CPH strategy but without clinical drugs. We aimed to investigate the protective effect of microbial-derived Urolithin A (UroA) in IHVR and CPH. METHODS: Carbon tetrachloride or bile duct ligation surgery was administered to mice to induce liver fi brosis and CPH. 16S rRNA gene sequencing was used for microbial analysis. Transcriptomics and metabolomics analyses were employed to study the host and cell responses. RESULTS: UroA was remarkably deficient in patients with CPH and was negatively correlated with disease severity. UroA deficiency fi ciency was also confirmed fi rmed in CPH mice and was associated with a reduced abundance of UroA-producing bacterial strain ( Lactobacillus murinus, , L. murinus). ). Glutaminolysis of hepatic stellate cells (HSCs) was identified fi ed as a previously unrecognized target of UroA. UroA inhibited the activity of glutaminase1 to suppress glutaminolysis, which counteracted fi brogenesis and contraction of HSCs and ameliorated CPH by relieving IHVR. Supplementation with UroA or L. murinus effectively ameliorated CPH in mice. CONCLUSIONS: We for the first time identify the deficiency of gut microbial metabolite UroA as an important cause of CPH. We demonstrate that UroA exerts an excellent anti-CPH effect by suppressing HSC glutaminolysis to lower the IHVR, which highlighted its great potential as a novel therapeutic agent for CPH.

BACKGROUND & AIMS:Our retrospective study has suggested encouraging outcomes of lenvatinib combined with PD-1 inhibitor and transarterial chemoembolization (TACE) on advanced hepatocellular carcinoma (HCC). This phase II trial was conducted to prospectively investigate the efficacy and safety of lenvatinib, sintilimab (a PD-1 inhibitor) plus TACE (Len-Sin-TACE) in patients with advanced stage HCC. METHODS:This was a single-arm phase II trial. Patients with BCLC stage C HCC were recruited. They received lenvatinib (bodyweight ≥60 kg, 12 mg; bodyweight <60 kg, 8 mg) orally once daily, sintilimab (200 mg) intravenously once every 3 weeks, and on demand TACE. The primary endpoint was progression-free survival (PFS) per mRECIST. RESULTS:Thirty patients were enrolled. The primary endpoint was met with a median PFS of 8.0 (95% confidence interval [CI]: 6.1-9.8) months per mRECIST, which was the same as that per RECIST 1.1. The objective response rate was 60.0% per mRECIST and 30.0% per RECIST 1.1. The disease control rate was 86.7% per mRECIST/RECIST 1.1. The median duration of response was 7.4 (95% CI: 6.6-8.2) months per mRECIST (n = 18) and 4.3 (95% CI: 4.0-4.6) months per RECIST 1.1 (n = 9). The median overall survival was 18.4 (95% CI: 14.5-22.3) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 12 patients (40.0%). There were no grade 4/5 TRAEs. CONCLUSIONS:Len-Sin-TACE showed promising antitumour activities with a manageable safety profile in patients with advanced stage HCC. The preliminary results need to be further evaluated with phase III randomized trials.

Objective:To construct hepatocellular carcinoma (HCC) cells lines that can mimic sub-lethal heat shock (HS) in vitro and orthotopic HCC mouse model that received incomplete thermal ablation.Methods:The suspension H22 cells were grown in 6-well plates, and the medium was replaced with fresh complete medium 8 hours before heat treatment. Then, the cells were divided into 4 groups for constant temperature water bath at 37°C, 42°C, 47°C, 50°C for 15 min, respectively. After the heat treatment was completed, the cells were maintained in a 37℃ incubator until detection. The phenotype of epithelial-mesenchymal transition (EMT) was detected by Western blot 48 hours later, and the cell viability was detected by Cell Counting Kit-8 (CCK-8) kit. The liver of mice was exposed by laparotomy along the abdomen midline and H22 cells (5×106) were injected through the hepatic capsule to conduct orthotopic HCC model. When the longest diameter of the tumor reached approximately 8 mm, the mice were randomly divided into complete ablation group (cMWA), incomplete ablation group (iMWA) and Control group treated with sham operation. Microwave ablation along the long axis of tumor was performed to establish the incomplete thermal ablation model of orthotopic HCC. MRI was performed for tumor measurement and liver specimens were collected for histopathological assessment at day 14 after microwave ablation.Results:14 daysafter inoculation of H22 cells, the tumors reached average tumor diameter of 9.32 ± 0.83 mm which was predetermined to be suitable for microwave ablation. 14 days after microwave ablation, the average tumor diameter reached 12.93 ± 1.51mm in iMWA group, which were significantly bigger than preoperative period. In addition, immunofluorescence staining showed a large number of infiltrated neutrophils in the residual tumor of iMWA group. Western blot was used to observe the change in EMT-phenotype, results showed that the expressions of Vimentin and α-SMA were up-regulated and the expressions of E-cadherin were down-regulated.Conclusions:HCC cells lines that can mimic Sub-lethal heat shock (HS) in vitro and orthotopic HCC mouse model that received incomplete thermal ablation were successfully constructed. There was substantial staining for neutrophils infiltration after incomplete ablation. Incomplete ablation may allow HCC cells to become more prone to migrate and to become more invasive.

Hepatocellular carcinoma (HCC) with lung metastasis is associated with poor prognosis and poor therapeutic outcomes. Studies have demonstrated that stiffened stroma can promote metastasis in various tumors. However, how the lung mechanical microenvironment favors circulating tumor cells remains unclear in metastatic HCC. Here, we found that the expression of cell migration-inducing hyaluronan-binding protein (CEMIP) was closely associated with lung metastasis and can promote pre-metastatic niche formation by increasing lung matrix stiffness. Furthermore, upregulated serum CEMIP was indicative of lung fibrotic changes severity in patients with HCC lung metastasis. By directly targeting CEMIP, pirfenidone can inhibit CEMIP/TGF-β1/Smad signaling pathway and reduce lung metastases stiffening, demonstrating promising antitumor activity. Pirfenidone in combination with sorafenib can more effectively suppress the incidence of lung metastasis compared with sorafenib alone. This study is the first attempt to modulate the mechanical microenvironment for HCC therapy and highlights CEMIP as a potential target for the prevention and treatment of HCC lung metastasis. CEMIP mediating an HCC-permissive microenvironment through controlling matrix stiffness. Meanwhile, Pirfenidone could reduce metastasis stiffness and increases the anti-angiogenic effect of Sorafenib by directly targeting CEMIP.

Purpose To investigate the efficacy and safety of tyrosine-kinase inhibitor (TKI) combined with iodine-125 seed brachytherapy (TKI-I) versus TKI alone for patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). Methods Data of patients with TACE-refractory HCC who received TKI (sorafenib or lenvatinib) or TKI-I from September 2018 to December 2020 were retrospectively analyzed. A propensity score matching (PSM) was performed to diminish potential bias. The primary endpoints were overall survival (OS) and time to progression (TTP). Tumor responses and treatment-related adverse events (TRAEs) were also compared between the two groups. Results A total of 132 patients were included in this study. Under PSM, 48 paired patients were selected for comparison. The median OS was 23.2 (95% CI 20.9–25.1) months in the TKI-I group versus 13.9 (95% CI 11.1–16.7) months in the TKI group ( P < 0.001). The median TTP was 12.8 (95% CI 10.1–15.5) months in the TKI-I group versus 5.8 (95% CI 5.0-6.6) months in the TKI group ( P < 0.001). Patients in the TKI-I group had higher objective response rate (68.8% vs. 33.3%, P = 0.001) and disease control rate (89.6% vs. 66.7%, P = 0.007) than those in the TKI group. The incidence and severity of TRAEs in the TKI-I group were comparable to those in the TKI group (any grade, 89.7% vs. 92.2%, P = 0.620; ≥grade 3, 33.8% vs. 32.8%, P = 0.902). Conclusions TKI-I was safe and significantly improved survival over TKI alone in HCC patients with TACE refractoriness.

Immune checkpoint inhibitor (ICI) shows low response rate in hepatocellular carcinoma (HCC) but the mechanisms underlying ICI resistance remains unclear. Interferon-γ (IFN-γ) has been widely determined as a prototypical antitumor cytokine. However, growing studies suggest that IFN-γ also mediates immunosuppression to promote tumor progression. Herein, we explored whether ICI-induced IFN-γ could activate immunosuppressive TGF-β1 to mediate ICI resistance. We demonstrated that cholesterol biosynthetic enzyme, NSDHL, was decreased in HCC tissues and associated with poor clinical prognosis. ICI-induced IFN-γ decreased NSDHL to activate SREBP1, which promoted TGF-β1 production, reduced T cell toxicity and enhanced Tregs infiltration, leading to ICI resistance. We also found that novel tyrosine kinase inhibitor, regorafenib, significantly reverse the above immunosuppressive effects by regulating NSDHL/SREBP1/TGF-β1 axis, which strengthened the effects of regorafenib plus ICI therapy against HCC. Noteworthily, regorafenib plus ICI therapy was more effective in HCC patients with higher serum TGF-β1. In conclusion, IFN-γ induced TGF-β1 to mediate ICI resistance. Regorafenib promotes anti-tumor immune response of ICI by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis. Serum TGF-β1 may serve as a biomarker for predicting efficacy of regorafenib plus ICI therapy in HCC.

574 Background: Tyrosine kinase inhibitor combined with immune checkpoint inhibitor has been reported to confer a survival benefit in patients with unresectable hepatocellular carcinoma (HCC). This phase II study (NCT04599777) aimed to evaluate the safety and efficacy of sorafenib plus tislelizumab (Sor-Tis) for patients with advanced HCC who received transarterial chemoembolization (TACE). Methods: The key inclusion criteria were: age ≥ 18 years; BCLC C stage HCC; no prior systemic therapy; Child-Pugh score ≤7; ECOG PS ≤1. The key exclusion criteria were: tumor thrombus involving the main portal vein or vena cava; central nervous system metastasis; history of malignancies other than HCC; history of organ and stem cell transplantation. Sorafenib (400 mg Bid) and tislelizumab (200 mg Q3W) was started at 3-7 days after the first TACE (TACE was repeated on demand). The primary endpoint was overall survival (OS). The secondary endpoints included treatment-related adverse events (TRAEs), progression free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: Thirty patients were enrolled in this study. Among these patients, 27 (90.0%) had macrovascular invasion, 12 (40.0%) had extrahepatic metastasis and 14 (46.7%) had intrahepatic tumor number >3. The mean largest tumor diameter was 11.4±3.9 cm. Till cutoff date (September 15th, 2022), the mean follow-up for the patients was 16.6±3.8 months. The median OS was not reached. The ORR per RECIST 1.1 and mRECIST was 20.0% and 53.3%, respectively. The DCR per RECIST 1.1 or mRECIST was 86.7%. During follow-up, 29 patients (96.7%) experienced disease progression (per RECIST 1.1 or mRECIST). The median PFS was 6.8 (95% confidence interval [CI] 4.5-9.0) months. TRAEs occurred in 28 patients (93.3%) and ≥grade 3 TRAEs was observed in 11 patients (36.7%). There was no treatment-related death in these patients. Conclusions: Sor-Tis showed preliminary clinical benefits and was tolerated in advanced HCC patients treated with TACE. This study is still ongoing and further follow-up is required to obtain final survival results. Clinical trial information: NCT04599777 .

Thermal ablation (TA), including radiofrequency ablation (RFA) and microwave ablation (MWA), has become the main treatment for early-stage hepatocellular carcinoma (HCC) due to advantages such as safety and minimal invasiveness. However, HCC is prone to local recurrence, with more aggressive malignancies after TA closely related to TA-induced changes in epithelial-mesenchymal transition (EMT) and remodeling of the tumor microenvironment (TME). According to many studies, various components of the TME undergo complex changes after TA, such as the recruitment of innate and adaptive immune cells, the release of tumor-associated antigens (TAAs) and various cytokines, the formation of a hypoxic microenvironment, and tumor angiogenesis. Changes in the TME after TA can partly enhance the anti-tumor immune response; however, this response is weak to kill the tumor completely. Certain components of the TME can induce an immunosuppressive microenvironment through complex interactions, leading to tumor recurrence and progression. How the TME is remodeled after TA and the mechanism by which the TME promotes HCC recurrence and progression are unclear. Thus, in this review, we focused on these issues to highlight potentially effective strategies for reducing and preventing the recurrence and progression of HCC after TA.

BackgroundImmune checkpoint inhibitor (ICI) shows low response rate in hepatocellular carcinoma (HCC). It remains urgent to elucidate mechanisms underlying ICI resistance and develop more effective strategy for HCC immunotherapy. We determined whether ICI-induced IFN-γ could activate TGF-β1 to mediate ICI resistance in HCC. Based on finding that regorafenib effectively inhibited TGF-β1, we investigated anti-tumor efficacy of regorafenib plus ICI in HCC and explored target population that benefit from this combination.MethodsHCC cell lines were used to access how IFN-γ and regorafenib, alone or in combination, affected TGF-β1 signaling. Therapeutic efficacy of regorafenib and ICI, alone or in combination, was investigated in orthotopic HCC mice. Data from HCC patients were included to verify our findings.FindingsDecreased NSDHL was found in HCC tissues and associated with poor clinical prognosis. ICI-induced IFN-γ inhibited NSDHL to activate SREBP1 and promoted TGF-β1 production, which reduced T cell toxicity and enhanced Tregs infiltration, leading to ICI resistance in HCC. Regorafenib reversed the above immunosuppressive effects caused by IFN-γ-induced TGF-β1 via regulating NSDHL/SREBP1 signaling, which strengthened the effects of regorafenib plus ICI therapy against HCC. Regorafenib plus ICI was more effective in HCC patients with higher serum TGF-β1.Interpretation: IFN-γ-induced TGF-β1 can mediate ICI resistance. Regorafenib promoted anti-tumor efficacy of ICI by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis. Serum TGF-β1 serves as biomarker for predicting efficacy of regorafenib plus ICI therapy in HCC.Funding Information: National Natural Science Foundation of China (81873920, 82172043, 82001929 and 81903071), Science and Technology Project of Guangzhou (202002030135, 202102020393 and 202102010082), Featured Clinical Technique of Guangzhou (0F04022), Youth Innovative Talents Project of Guangdong Province University (2020KQNCX057).Declaration of Interests: The authors have declared no conflict of interest.Ethics Approval Statement: The above study was approved by the Medical Ethics Committee of The Second Affiliated Hospital of Guangzhou Medical University. All animal experiments were performed following the protocols approved by the Institutional Animal Care and Use Committee of Guangzhou Medical University.

To the Editor: Portal vein tumor thrombus (PVTT) is present in 10% to 40% of patients with hepatocellular carcinoma (HCC) at diagnosis and has a profound adverse effect on progno-sis. Sorafenib is recommended as the first-line treatment for patients with advanced HCC, including those who have PVTT. However, its efficacy is modest. A combination of transarterial chemoembolization (TACE) and sorafenib (TACE-S) has been reported to be associated with improved outcomes. But unfortunately, its efficacy in controlling PVTT remained limited, with an objective response rate (ORR) of only 9.7%. Previous studies have demonstrated that iodine125 (I) seed brachytherapy targeting PVTT can lead to a significant reduction in tumor thrombus with few complications. We hypothesized that TACE-S combined with I seed brachytherapy (TACE-S-I) could improve the control of PVTT and confer a greater survival benefit. Therefore, we conducted this study to evaluate the efficacy and safety of TACE-S-I compared with TACE-S in HCC patients with PVTT.