Regorafenib for patients with progression of advanced hepatocellular carcinoma after treatment with atezolizumab plus bevacizumab: a case series.

Background: Immunotherapy has reshaped the systemic treatment of hepatocellular carcinoma (HCC), with atezolizumab plus bevacizumab (TA) regimen and regorafenib being the first-line and second-line treatment options for advanced HCC, respectively. However, the efficacy of using the second-line therapeutic agent regorafenib in patients with HCC that has progressed after TA regimen treatment is unknown, and there is a lack of supporting clinical data. The purpose of this case series was to evaluate the clinical efficacy of the second-line therapeutic agent regorafenib in patients with advanced HCC who progressed after treatment with a first-line TA regimen. Case Description: This case series included five patients with intermediate to advanced HCC treated with regorafenib after progression on a TA regimen. We retrospectively report the clinical data, clinical outcomes, and adverse events of these five patients. According to modified Response Evaluation Criteria in Solid Tumors (mRECIST), one patient achieved partial response (PR), three patients achieved stable disease (SD), and one patient experienced progressive disease (PD); the disease control rate (DCR) reached 80%, and the objective response rate (ORR) reached 20%. Conclusions: In patients with intermediate to advanced HCC who experience disease progression after TA therapy, second-line treatment with regorafenib may be effective in delaying progression and may be associated with better disease control. However, these findings need to be further confirmed in prospective studies with larger cohorts.

Predicting Survival Using Whole-Liver MRI Radiomics in Patients with Hepatocellular Carcinoma After TACE Refractoriness.

PURPOSE: To develop a model based on whole-liver radiomics features of pre-treatment enhanced MRI for predicting the prognosis of hepatocellular carcinoma (HCC) patients undergoing continued transarterial chemoembolization (TACE) after TACE-resistance. MATERIALS AND METHODS: Data from 111 TACE-resistant HCC patients between January 2014 and March 2018 were retrospectively collected. At a ratio of 7:3, patients were randomly assigned to developing and validation cohorts. The whole-liver were manually segmented, and the radiomics signature was extracted. The tumor and liver radiomics score (TLrad-score) was calculated. Models were trained by machine learning algorithms and their predictive efficacies were compared. RESULTS: Tumor stage, tumor burden, body mass index, alpha-fetoprotein, and vascular invasion were revealed as independent risk factors for survival. The model trained by Random Forest algorithms based on tumor burden, whole-liver radiomics signature, and clinical features had the highest predictive efficacy, with c-index values of 0.85 and 0.80 and areas under the ROC curve of 0.96 and 0.83 in the developing cohort and validation cohort, respectively. In the high-rad-score group (TLrad-score > - 0.34), the median overall survival (mOS) was significantly shorter than in the low-rad-score group (17 m vs. 37 m, p < 0.001). A shorter mOS was observed in patients with high tumor burden compared to those with low tumor burden (14 m vs. 29 m, p = 0.007). CONCLUSION: The combined radiomics model from whole-liver signatures may effectively predict survival for HCC patients continuing TACE after TACE refractoriness. The TLrad-score and tumor burden are potential prognostic markers for TACE therapy following TACE-resistance.

A Novel Rat Model to Simulate the Benign Esophageal Stricture Induced by Endoscopic Submucosal Dissection.

Objective: This study aimed to establish a rat model that simulates benign esophageal strictures induced by endoscopic submucosal dissection (ESD). Materials and Methods: Sixteen male Sprague-Dawley rats were randomly divided into mucosal resection (n = 8) and sham-operated groups (n = 8). The rats in the mucosal resection group underwent a 5-mm three-fourths mucosal resection by way of a 3-mm incision in the distal esophagus under direct visualization via laparotomy. Rats in the sham-operated group underwent a 3-mm incision of the muscularis propria layer in the distal esophagus via laparotomy without mucosal resection. Dysphagia score, weight gain, mucosal constriction rate, and histology were evaluated 2 weeks after surgery. Results: Technical success was achieved in all the animals. One rat in the mucosal resection group died of infection, and no other complications were observed. Weight gain (P < 0.001) and luminal diameter derived from the esophagograms (P < 0.001) were significantly lower in the mucosal resection group than those in the sham-operated group. Dysphagia score (P < 0.001) and mucosal constriction rate (P < 0.001) were significantly higher in the mucosal resection group than those in the sham-operated group. The inflammation grade (P = 0.002), damage to the muscularis propria (P < 0.001), number of nascent microvessels (P = 0.006), and degree of α-SMA positive deposition (P = 0.006) were significantly higher in the mucosal resection group. Conclusion: A rat model of benign esophageal stricture induced by ESD was successfully and safely established by mucosal resection.

Prognostic Effect of Sarcopenia in Hepatocellular Carcinoma Patients Targeted with Interventional Therapy Combined with Immunotherapy and Targeted Therapy.

Objective: To investigated the association between sarcopenia and the prognosis and adverse events of hepatocellular carcinoma (HCC) patients undergoing interventional therapy combined with immunotherapy and targeted therapy. Methods: Between January 2019 and December 2022, patients with unresectable HCC who received interventional therapy combined with immunotherapy and targeted therapy were included in this study. Total skeletal muscle area at the L3 level was normalized for height in m2 as the skeletal muscle index (SMI). All patients were divided into low and high SMI group according to the median SMI. Results: Ninety-six consecutive patients were included eventually, with 49 patients in the high-SMI group and 47 patients in the low-SMI group. In the low-SMI group, the median overall survival (OS) was 459.00 days (95% CI, 334.76-583.24 days), and the 3-, 6-, and 12-month OS rates were 100%, 89.4% and 68.1%, respectively. In the high-SMI group, the median OS was not reached, and the 3-, 6-, and 12-month OS rates were 100%, 98% and 79.5%, respectively (p<0.05). SMI and Barcelona Clinic Liver Cancer (BCLC) C stage were independent prognostic factors for OS (p<0.05). In the low-SMI group, 26 patients had treatment-related adverse events (TRAEs), resulting in dose adjustment or treatment suspension for 10 patients. In the high-SMI group, 33 patients had TRAEs, and 18 patients received dose adjustment or treatment suspension; the between-group difference was nonsignificant (p>0.05). Conclusion: SMI is associated with the prognosis of HCC patients receiving interventional therapy combined with immunotherapy and targeted therapy, and sarcopenia is an independent risk factor for OS. However, sarcopenia does not seem to predict the occurrence of adverse events.

The Role of GNMT and MMP12 Expression in Determining TACE Efficacy: Validation at Transcription and Protein Levels.

Purpose: Transarterial chemoembolization (TACE) represents a significant therapeutic modality for hepatocellular carcinoma (HCC). We aimed to develop a gene signature to accurately predict patient TACE response and explore the underlying mechanisms. Methods: Three independent datasets were utilized, including GSE104580, GSE14520 and external validation from the Cancer Hospital Chinese Academy of Medical Sciences. GSE104580 was randomly partitioned into a training set and a validation set, whereas GSE14520 was categorized into a resection group and a TACE group. Logistic regression was used to develop a TACE effectiveness model. Immunohistochemistry is utilized to confirm the protein expression trends of the signature genes. Immune infiltration and functional enrichment analyses were conducted to investigate the potential underlying mechanisms. Results: A 2-gene signature consisting of glycine N-methyltransferase (GNMT) and matrix metalloproteinase-12 (MMP12) was constructed, and based on this, all the patients were assigned TACE effectiveness scores and categorized into high effectiveness (HE) and low effectiveness (LE) groups. The HE group exhibited a better prognosis than the LE group in the various cohorts (p < 0.05). In the external validation set, immunohistochemistry confirmed the expression of the signature genes exhibiting an upregulated trend of GNMT in the HE group and MMP12 in the LE group, the LE group also exhibited a poorer prognosis [for overall survival (OS), HE group: 881 days vs LE group: 273 days (p < 0.05), and for progression-free survival (PFS), HE group: 458 days vs LE group: 136 days (p < 0.05)]. Multivariate analysis in all the datasets identified LE status as an independent risk factor for OS, disease-free survival (DFS) and PFS. The infiltration level of M0 macrophages and activated mast cells in the LE group was significantly higher than in the HE group. The hypoxia signaling pathway and glycolysis pathway were significantly enriched in the LE group. Conclusion: The loss of GNMT and the overexpression of MMP12 may be critical factors influencing TACE efficacy.

New perspectives on ferroptosis and its role in hepatocellular carcinoma.

ABSTRACT: For a long time, the morbidity and mortality rates of hepatocellular carcinoma (HCC) have remained high. Since the concept of ferroptosis was introduced in 2012, researchers' perspectives have shifted toward finding novel ferroptosis-related treatment strategies, especially for tumors that are resistant to apoptosis. In recent years, there have been an increasing number of studies on ferroptosis, and these studies have found that ferroptosis has great potential and promise for cancer treatment. Ferroptosis is a kind of regulated cell death (RCD); unlike apoptosis, ferroptosis is an iron-dependent type of RCD driven by lipid peroxidation. The whole process of ferroptosis mainly revolves around three pathways (system xc-/ glutathione peroxidase 4 [GPX4]), lipid peroxidation, and iron metabolism), which are also regulated by various metabolic factors. This review will attempt to analyze the relationship between the system xc-/GPX4 pathway, lipid peroxidation, iron metabolism, and ferroptosis from three aspects (triggering, execution, and regulation), and the regulatory factors for ferroptosis will be summarized. In this review, we will also illustrate the relationship between ferroptosis and tumors as well as its application in tumors from the perspective of HCC. Finally, we will summarize the current limitations and needs and provide perspectives related to the focus of development in the future.

Cuproptosis-related immune checkpoint gene signature: Prediction of prognosis and immune response for hepatocellular carcinoma.

Immune checkpoint genes (ICGs), the foundation of immunotherapy, are involved in the incidence and progression of hepatocellular carcinoma (HCC). Cuproptosis is characterized by copper-induced cell death, and this novel cell death pathway has piqued the interest of researchers in recent years. It is worth noting that there is little information available in the literature to determine the relationship between cuproptosis and anti-tumor immunity. We identified 39 cuproptosis-related ICGs using ICGs co-expressed with cuproptosis-related genes. A prognostic risk signature was constructed using the Cox regression and the least absolute shrinkage and selection operator analysis methods. The signature was built using the Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma database. The TCGA and International Cancer Genome Consortium cohorts were classified into two groups; the low- and high-risk groups were determined using a prognostic signature comprised of five genes. The multivariate Cox regression analysis revealed that the signature could independently predict overall survival. Furthermore, the level of immune infiltration analysis revealed the robustness of the prognostic signature-immune cell infiltration relationship observed for Tregs, macrophages, helper T cells, and naive B cells. Both groups showed significant differences in immune checkpoint expression levels. The gene enrichment analysis was used for characterization, and the results revealed that enriching various pathways such as PI3K-AKT-mTOR signaling, glycolysis, Wnt/beta-catenin signaling, and unfolded protein response could potentially influence the prognosis of patients with HCC and the level of immune infiltration. The sensitivity of the two groups of patients to various drug-targeted therapy methods and immunotherapy was analyzed. In conclusion, the findings presented here lay the foundation for developing individualized treatment methods for HCC patients. The findings also revealed that studying the cuproptosis-based pathway can aid in the prognosis of HCC patients. It is also possible that cuproptosis contributes to developing anti-tumor immunity in patients.

[Comparison of Clinical Efficacy of Thermal Ablation vs. Surgical Resection of Metachronous Colorectal Liver Metastasis].

Objective: To compare the treatment efficacy of thermal ablation versus surgical resection of metachronous colorectal liver metastasis (CRLM) and to explore the potential candidates suited for thermal ablation. Methods: The data of 319 patients with CRLM who underwent radical treatment at the Cancer Hospital, Chinese Academy of Medical Sciences between November 2007 and January 2021 were retrospectively collected. The patients were divided into two groups, the thermal ablation group and the surgical resection group, according to the actual treatments they received. Propensity score matching (PSM) was applied to balance the baseline characteristics between the two groups. Cox regression analysis was conducted to identify the risk factors for recurrence and survival. Survival analysis was performed for intergroup comparison. Results: Using PSM at 1∶1 ratio, 92 patients were included in the thermal ablation group and 92 patients were included in the surgical resection group.The median overall survival (OS) in the thermal ablation group was 49 (95% confidence interval, 37-76) months, which was shorter than that of the surgical resection group ( P<0.01). Multivariate Cox regression analysis indicated that the T staging of primary tumor, number of metastatic tumor, maximum diameter of metastatic tumor, preoperative serum carcinoembryonic antigen (CEA) level, and treatment method were independent risk factors affecting OS. Compared with the surgical resection group, the thermal ablation group demonstrated higher hepatic recurrence rate (59.8% vs. 23.9%, P<0.01), shorter disease-free survival (DFS) (10 months vs. 33 months, P<0.01), and shorter length of hospital stay (7 days vs. 14 days, P<0.01). Subgroup analysis, conducted with the data of the 319 patients before PSM, showed that early recurrence patients who underwent thermal ablation or surgical resection had comparable median OS (29 months vs. 42 months, P=0.35). For the non-early recurrence patients, the median OS of the thermal ablation group was shorter than that of the surgical resection group ( P<0.01). Conclusion: For the treatment of CRLM, the efficacy of surgical resection was better than that of thermal ablation. However, the efficacy was comparable between the two treatments for early recurrence patients of CRLM.