Single-cell transcriptome analysis of liver immune microenvironment changes induced by microplastics in mice with non-alcoholic fatty liver.

Recent studies have discovered that tiny particles of microplastics (MPs) at the nano-scale level can enter the body of organisms from the environment, potentially causing metabolic ailments. However, further investigation is required to understand the alterations in the immune microenvironment associated with non-alcoholic fatty liver disease (NAFLD) occurrence following exposure to MPs. Experiments were performed using mice, which were given a normal chow or high-fat diet (NCD or HFD, respectively) plus free drinking of sterile water with or without MPs, respectively. Employing an impartial technique known as unbiased single-cell RNA-sequencing (scRNA-seq), the cellular (single-cell) pathology landscape of NAFLD and related changes in the identified immune cell populations induced following MPs plus HFD treatment were assessed. The results showed that mice in the HFD groups had remarkably greater NAFLD activity scores than those from the NCD groups. Moreover, administration of MPs plus HFD further worsened the histopathological changes in the mice's liver, leading to hepatic steatosis, inflammatory cell infiltrations and ballooning degeneration. Following the construction of a sing-cell resolution transcriptomic atlas of 43,480 cells in the mice's livers of the indicated groups, clear cellular heterogeneity and potential cell-to-cell cross-talk could be observed. Specifically, we observed that MPs exacerbated the pro-inflammatory response and influenced the stemness of hepatocytes during HFD feeding. Importantly, treatment with MPs significantly increase the infiltration of the infiltrating liver-protecting Vsig4+ macrophages in the liver of the NAFLD mouse model while remarkably decreasing the angiogenic S100A6+ macrophage subpopulation. Furthermore, mice treated with MPs plus HFD exhibited significantly increased recruitment of CD4+ cells and heightened exhaustion of CD8+ T cells than those from the control group, characteristics typically associated with the dysregulation of immune homeostasis and severe inflammatory damage. Overall, this study offers valuable perspectives into comprehending the potential underlying cellular mechanisms and regulatory aspects of the microenvironment regarding MPs in the development of NAFLD.

Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2.

Background & Aims: Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods: The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results: FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis. Conclusions: Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD. Impact and implications: Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.

Radiofrequency Ablation of Unifocal Papillary Thyroid Microcarcinoma With BRAF V600E Mutation.

CONTEXT: To date there is no study on the feasibility of radiofrequency ablation (RFA) for papillary thyroid microcarcinomas (PTMCs) with BRAF V600E mutation. OBJECTIVE: This study was designed to evaluate the efficiency, safety, and prognosis of ultrasound (US)-guided percutaneous RFA for unifocal PTMCs with BRAF V600E mutation. MATERIALS AND METHODS: Sixty patients with 60 unifocal BRAF V600E mutation-positive PTMCs who received US-guided RFA between January 2020 and December 2021 were retrospectively analyzed. The mean maximum PTMC tumor diameter was 5.8 ± 1.7 mm (range, 2.5-10.0 mm). All PTMCs were pathologically confirmed by fine needle aspiration or core needle biopsy, and BRAF V600E mutation was confirmed to be positive by real-time fluorescent quantitative polymerase chain reaction. Contrast-enhanced ultrasound (CEUS) was performed immediately after RFA to evaluate whether PTMCs were extendedly ablated. Ultrasound was performed 1, 3, 6, and 12 months after RFA and every 6 months thereafter to evaluate the changes in the ablation zone, local recurrence, and cervical lymph node metastasis (LNM). The complications were recorded and evaluated. RESULTS: Extended ablation was achieved in all enrolled patients. The ablation zone sizes increased immediately after RFA compared with those of tumors before treatment. One month later, the ablation zone sizes were smaller than immediately after RFA. At the last follow-up assessment, 42 nodules (70.0%) completely disappeared and the ablation zones of 18 nodules (30.0%) showed fissure-like changes. No local recurrence or cervical LNM was detected. Voice change (1.7%) was the only major complication. CONCLUSION: RFA is effective and safe in treating unifocal PTMCs with BRAF V600E mutation, especially when surgery is not feasible or refused by patients who are unwilling to continue active surveillance.

Sustained activation of EGFR-ERK1/2 signaling limits the response to tigecycline-induced mitochondrial respiratory deficiency in liver cancer.

BACKGROUND: Identification of tumor dependencies is important for developing therapeutic strategies for liver cancer. METHODS: A genome-wide CRISPR screen was performed for finding critical vulnerabilities in liver cancer cells. Compounds screen, RNA sequencing, and human phospho-receptor tyrosine kinase arrays were applied to explore mechanisms and search for synergistic drugs. FINDINGS: We identified mitochondrial translation-related genes associated with proliferation for liver cancer cells. Tigecycline induced deficiency of respiratory chain by disturbing mitochondrial translation process and showed therapeutic potential in liver cancer. For liver cancer cells extremely insensitive to tigecycline, a compounds screen was applied to identify MEK inhibitors as synergistic drugs to tigecycline-insensitive liver cancer cells. Mechanistically, sustained activation of EGFR-ERK1/2-MYC cascade conferred the insensitivity to tigecycline, which was mediated by enhanced secretion of EREG and AREG. Moreover, glycolytic enzymes, such as HK2 and PKM2 were upregulated to stimulate glycolysisin a MYC-dependent manner. Tigecycline induced respiratory chain deficiency in combination with cutting off EGFR-ERK1/2-MYC cascade by MEK inhibitors or EGFR inhibitors, resulting in decrease of both oxidative phosphorylation and glycolysis in liver cancer cells. INTERPRETATION: Our study proved that blocking EGFR-ERK1/2-MYC cascade combined with tigecycline could be a potential therapeutic strategy for liver cancer. FUNDING: This work was funded by grants from the National Natural Science Foundation of China (82073039,82222047, 81920108025), Program of Shanghai Academic/Technology Research Leader (22XD1423100), Shanghai Municipal Science and Technology Project (20JC1411100), 111 Project (B21024), Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212700, SHSMU-ZDCX20210802) and Shanghai Jiao Tong University School of Medicine (YG2019GD01).

Significance of radiofrequency ablation in large solid benign thyroid nodules.

Objective: The aim of this study is to explore efficacy and safety for radiofrequency ablation (RFA) among cases attacked by large benign solid thyroid nodules, mainly focusing on volume reduction, complication rate, and thyroid function. Methods and materials: From June 2015 to November 2019, 24 patients with 25 large benign solid thyroid nodules (more than 25 ml) underwent single or sequential RFA in our institution. Eleven nodules achieved complete ablation after single RFA, whereas the other 14 nodules received sequential RFA. Volume reduction in large nodules was evaluated. Following single or sequential RFA, all patients received clinical and ultrasound evaluations, and the median follow-up duration among them was 23.5 months. Technical success, complication rate, and recurrence rate were assessed as well. Results: In single RFA group, volume reduction ranged from 62.6% to 99.4% (mean ± SD, 93.6 ± 9.9%) 6 months after RFA. In sequential RFA group, volume reduction ranged from 30.6% to 92.9% (mean ± SD, 67.4 ± 17.8%) after the first RFA and was between 83.4% and 98.4% (mean ± SD, 94.8± 3.8%) 6 months after the second RFA. The concentrations of FT3 and FT4 increased slightly 1 day after RFA and returned to normal level 1 month after. Conclusions: Single or sequential RFA is safe and effective in treating large benign solid thyroid nodules (more than 25 ml) that cause obvious compressive symptoms. Hence, compression symptoms and cosmetic conditions could be effectively improved through single or sequential RFA without marginal recurrence.

360° open-ended and navigated magnetic resonance-guided microwave ablation for hepatic tumors in risk areas.

Context: Image-guided local ablation has becoming a promising treatment option for patients unsuitable for surgical resection. Currently, magnetic resonance (MR) imaging has been used as guidance for ablation due to its good soft-tissue contrast, high image quality and absence of ionizing radiation. However, the limited operating space and interrupted and delayed imaging of the conventional MR equipment increased the difficulty of puncture during operation. Therefore, we utilized an easy-to-use optical navigation system with a 0.4 T 360° open MR system to perform MR-guided microwave ablation (MWA) to treat liver tumor patients in risk areas. Aim: To evaluate the safety and efficacy of MR-guided MWA in treating liver tumors using a 0.4 T open and navigated MR system. Materials and Methods: A retrospective analysis was performed on 19 liver tumor patients who underwent MR-guided MWA between August 2014 and August 2017. The complications, complete ablation, and long-term outcomes were analyzed and evaluated. Results: It was found that navigated MRI guidance allowed for precise needle placement in the targeted tumor, and ablation was successfully performed in all patients without serious intraoperative complications and death. Additionally, complete ablation was reached at 94.74% (18/19), with only one patient discovered with residual tumor, and therefore received another MWA session within three months. Conclusion: 360° open MR system combined with navigation systems conveniently enhanced the operation of MR-guided ablation, producing effective outcomes. Therefore, this option may be a safe and effective therapy for liver tumors in patients, especially for those situated in risk areas and those not visible to identify by ultrasound or computerized tomography.

Safety and efficacy of microwave versus radiofrequency ablation for large hepatic hemangioma: a multicenter retrospective study with propensity score matching.

OBJECTIVES: To compare the safety and efficacy of microwave ablation (MWA) and radiofrequency ablation (RFA) for such hemangiomas (5-9.9 cm in diameter). METHODS: This multicenter retrospective cohort study investigated the differences in technical success, ablation time, complete ablation, complications, hospital stay, and clinical response between MWA and RFA. A total of 452 patients with hepatic hemangiomas were screened. Propensity score matching was performed. Univariable and multivariate regression analyses were used. RESULTS: Among the 452 patients, 394 met the eligibility criteria and completed the follow-up. After the propensity score matching analysis, 72 pairs of patients were created. No technical failures were found. The RFA group had a longer ablation time (48.63 ± 18.11 min versus [vs.] 37.18 ± 15.86 min, p < 0.001), higher morbidity of hemoglobinuria (77.78% vs. 50.00%, p < 0.001), and longer hospital stay (5.01 ± 1.56 days vs. 4.34 ± 1.42 days, p < 0.05) than the MWA group. The treatment methods (p = 0.032, OR = 0.105, 95% CI = 0.013-0.821), size of the hemangioma (p = 0.021, OR = 5.243, 95% CI = 1.285-21.391), and time of ablation (p = 0.031, OR = 1.145, 95% CI = 1.013-1.294) were significant independent risk factors associated with hemoglobinuria. No recurrence or delayed complications were observed. There were no differences in complete ablation, clinical response, and health-related quality of life between the groups. CONCLUSIONS: MWA and RFA appear to be effective treatments for large hepatic hemangiomas. However, MWA had a shorter ablation time than RFA, and MWA was associated with fewer hemolysis-related complications and shorter hospital stays. KEY POINTS: • MWA and RFA appear to be effective treatments for large hepatic hemangiomas. • MWA had a shorter ablation time than RFA. • MWA was associated with fewer hemolysis-related complications and shorter hospital stays.

Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy.

Colorectal cancer (CRC) patients are still lacking viable treatments. Chimeric antigen receptor (CAR) T cells have shown promise in hematologic malignancies, but their efficacy in solid tumors has been limited due to the immunosuppressive tumor microenvironment. We found that cancer antigen- EpCAM expression increased in the metastatic stage compared with the primary stage in cancers and the activation of Wnt and TGFß pathways was positively correlated with EpCAM expression in multiple cancers, including colorectal cancer. We constructed CAR T cells targeting EpCAM that successfully showed selective cytotoxicity in highly EpCAM-expressing cancer cell lines. The combination of EpCAM CAR-T with the Wnt inhibitor-hsBCL9CT-24 displayed synergetic effect against EpCAM-positive colon cells in vitro and also in vivo. A mechanistic study showed that hsBCL9CT-24 treatment could modulate the tumor environment and improve infiltration of T cells, while possibly promoting the effector T cells at the early stages and postponing the exhaustion of CAR T cells at advanced stages. Overall, these results demonstrated that the combination of EpCAM CAR T-cell therapy with the Wnt inhibitor can overcome the limitations of CAR T cells in treating solid tumors.

Ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma originating in the caudate lobe: A pilot clinical study.

OBJECTIVE: This study aimed to evaluate the efficacy, feasibility, and tolerability of ultrasound (US)-guided percutaneous microwave ablation (MWA) for treating hepatocellular carcinoma (HCC) originating in the caudate lobe. MATERIALS AND METHODS: The treatment and survival parameters of 32 patients with HCC in the caudate lobe, who met the inclusion criteria and had received US-guided percutaneous MWA in our department from November 2010 to October 2015, were retrospectively analyzed. Imaging examination (contrast-enhanced computed tomography or magnetic resonance) 1 month after MWA was used to evaluate the efficacy of US-guided MWA. RESULTS: Thirty-two patients underwent percutaneous MWA for caudate lobe HCC. The average tumor size was 3.42 ± 0.27 (range: 1-6.8) cm. The initial complete ablation (CA) rate was 87.5% (28/32), and the total CA rate was 96.88% (31/32). Furthermore, the median length of hospitalization was 4 days (range: 2-10 days), and no major complication was observed in this study. The overall survival rates were 87.5%, 50%, and 28.13% at 1, 2, and 3 years, respectively. The progression-free survival after MWA was 93.75%, 53.15%, and 28.13% at 6, 12, and 18 months, respectively. CONCLUSIONS: US-guided percutaneous MWA was a safe and effective treatment. It is a promising alternative therapy for HCC originating in the caudate lobe.

EGFR activation limits the response of liver cancer to lenvatinib.

Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options1. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit2. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR)  by lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.

Pathologic Diagnosis and Genetic Analysis of Sequential Biopsy Following Coaxial Low-Power Microwave Thermal Coagulation For Pulmonary Ground-Glass Opacity Nodules.

PURPOSE: To evaluate the feasibility, safety, and diagnostic performance of sequential core-needle biopsy (CNB) technique following coaxial low-power microwave thermal coagulation (MTC) for ground-glass opacity (GGO) nodules. MATERIALS AND METHODS: From December 2017 to July 2019, a total of 32 GGOs (with diameter of 12 ± 4 mm) in 31 patients received two times of CNBs, both prior to and immediately after MTC at a power of 20 watts. The frequency and type of complications associated with CNBs were examined. The pathologic diagnosis and genetic analysis were performed for specimens obtained from the two types of biopsy. RESULTS: The technical success rates of pre- and post-MTC CNBs were 94% and 100%, respectively. The complication rate was significantly lower with post-MTC CNB as compared to pre-MTC CNB (42% versus 97%, p < 0.001). Larger amount of specimens could be obtained by post-MTC CNB. The pathological diagnosis rate of post-MTC CNB was significantly higher than that of pre-MTC CNB (100% versus 75%, p = 0.008), whereas the success rates of genetic analysis were comparable between the two groups (100% versus 84%, p = 0.063). Regular ablation could be further performed after post-MTC CNB to achieve local tumor control. CONCLUSION: Sequential biopsy following coaxial low-power MTC can reduce the risk of complications and provide high-quality specimens for pulmonary GGOs. Combining this technique with standard ablation allows for simultaneous diagnosis and treatment within a single procedure.

Long-term results of percutaneous microwave ablation for colorectal liver metastases.

BACKGROUND: Radiofrequency ablation (RFA) has been used for therapy of colorectal liver metastases (CRLMs) several years, with considerable data confirming its safety and efficacy. However, there are few studies focusing on the long-term results of percrtaneous microwave ablation (PMWA) for CRLMs. The aim of this study was to evaluate the long-term survival and prognostic factors in patients with CRLMs undergoing PMWA. METHODS: We retrospectively analyzed treatment and survival parameters of 210 patients with CRLMs who had received PMWA in a single center from January 2010 to December 2017. Prognostic factors for survival were evaluated by means of univariate and multivariate analyses. RESULTS: The median follow-up time after PMWA was 48 months. The median overall survival (OS) time were 40.0 months (95% CI, 31.4 to 48.5 months), with 1-, 2, 3-, 4, and 5-year cumulative survival rates of 98.6%, 73.3%, 53.3%, 42.2%, and 32.9%, respectively. Tumor number (P = 0.004; HR: 1.838; CI: 1.213- 2.784), main tumor size (P = 0.017; HR: 1.631; CI: 1.093- 2.436), and serum CEA level (P = 0.032; HR: 1.559; CI: 1.039-2.340) were found as independent predictors of OS. The median OS time for patients with resectable lesions was 60.91 months (95% CI, 51.36 to 70.47 months), with 5-year cumulative survival rates of 53.5%. CONCLUSION: PMWA is a safe and effective treatment for CRLMs, with a favorable long-term outcome. Multiple lesions, main tumor diameter>3 cm, and serum CEA >30 ng/ml have a significant negative effect on OS.

Prognostic Nomogram for Patients with Hepatocellular Carcinoma After Thermal Ablation.

PURPOSE: To develop an effective prognostic nomogram for patients with hepatocellular carcinoma (HCC) after thermal ablation. METHODS: A total of 772 patients with intrahepatic primary or recurrent HCC who underwent radiofrequency ablation or microwave ablation between March 2011 and October 2016 were included. 602 patients (mean age, 56.0 ± 11.9 years; 495 male/107 female) were included in the primary cohort to establish a prognostic nomogram. Significant prognostic factors for overall survival (OS) identified by Cox univariate and multivariate regression analyses were used to construct the nomogram. The remaining 170 patients (mean age, 55.9 ± 11.9 years; 145 male/25 female) were used to validate the predictive accuracy of the nomogram. RESULTS: During a mean follow-up period of 26 months (range 1-85 months), the median OS periods were 48.6 months and 44.0 months for the primary and validation cohorts. The 1-, 3-, and 5-year OS rates were 85.5%, 61.4%, and 43.3% in the primary cohort and 84.7%, 59.6%, and 43.3% in the prospective validation cohort, respectively. Multivariate analysis found that pre-ablation treatment, AFP, CEA, CA19-9, ALBI grade, tumor number, and tumor size (hazard ratio > 1, P < 0.05) were independent risk factors for OS. A nomogram was developed based on these seven variables. The calibration curve for predicting the probability of survival showed a good agreement between the nomogram and actual observation both in the primary (concrete index: 0.699) and validation cohorts (concrete index: 0.734). CONCLUSIONS: This simple nomogram based on seven variables including ALBI grade offers personalized prognostic data for HCC patients after ablation. LEVEL OF EVIDENCE: Level 4, case series.

Microwave ablation versus transcatheter arterial embolization for large hepatic hemangiomas: clinical outcomes.

PURPOSE: To evaluate the safety and effect of microwave ablation (MWA) compared with transcatheter arterial embolization (TAE) for the treatment of large hepatic hemangiomas. MATERIALS AND METHODS: A total of 135 patients with symptomatic or/and enlarging hepatic hemangiomas (5-10 cm) from two centers underwent either MWA (n = 82) or TAE (n = 53) as first-line treatment. We compared the two groups in terms of radiologic response, clinical response, operative time, postoperative analgesic requirements, hospital stay and complications. RESULTS: MWA had a significantly higher rate of complete radiologic response (89.0% vs. 37.7%, p<.001) and complete clinical response (88.6% vs. 69.2%, p=.046), fewer minor complications (43.9% vs. 66.0%, p=.019), shorter time of using analgesics (p<.001) and shorter hospital stays (p=.003) than did TAE. The operative time and major complications were comparable between the two groups. CONCLUSION: Both MWA and TAE are safe and effective in treating patients with large hepatic hemangiomas. MWA had a higher rate of complete response than did TAE, and it was associated with fewer minor complications, faster recovery and shorter hospital stay.

An extracorporeal bioartificial liver embedded with 3D-layered human liver progenitor-like cells relieves acute liver failure in pigs.

Clinical advancement of the bioartificial liver is hampered by the lack of expandable human hepatocytes and appropriate bioreactors and carriers to encourage hepatic cells to function during extracorporeal circulation. We have recently developed an efficient approach for derivation of expandable liver progenitor-like cells from human primary hepatocytes (HepLPCs). Here, we generated immortalized and functionally enhanced HepLPCs by introducing FOXA3, a hepatocyte nuclear factor that enables potentially complete hepatic function. When cultured on macroporous carriers in an air-liquid interactive bioartificial liver (Ali-BAL) support device, the integrated cells were alternately exposed to aeration and nutrition and grew to form high-density three-dimensional constructs. This led to highly efficient mass transfer and supported liver functions such as albumin biosynthesis and ammonia detoxification via ureagenesis. In a porcine model of drug overdose-induced acute liver failure (ALF), extracorporeal Ali-BAL treatment for 3 hours prevented hepatic encephalopathy and led to markedly improved survival (83%, n = 6) compared to ALF control (17%, n = 6, P = 0.02) and device-only (no-cell) therapy (0%, n = 6, P = 0.003). The blood ammonia concentrations, as well as the biochemical and coagulation indices, were reduced in Ali-BAL-treated pigs. Ali-BAL treatment attenuated liver damage, ameliorated inflammation, and enhanced liver regeneration in the ALF porcine model and could be considered as a potential therapeutic avenue for patients with ALF.

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials.

PURPOSE: Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. PATIENTS AND METHODS: In two prospective phase I studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1). RESULTS: A total of 13 patients received a median of 19.9 × 108 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. CONCLUSIONS: This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.