Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice.

Background: Liver metastasis is the major cause of colorectal cancer related death. Mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T-cell therapy has been illustrated effective and safe through regional delivery of breast cancer, ovarian cancer and malignant mesothelioma tumors. Herein, we investigated the safety, efficacy, and immune microenvironment of regional delivery of MSLN (CAR) T-cell in the treatment of colorectal carcinoma liver metastases (CRLM). Methods: Second-generation MSLN CAR T-cells were administered by portal vein (PV) or caudal vein (CV, systemic administration) delivery in an orthotopic MSLN+ CRLM nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/γc-/- (NSG) mouse model. A total of 20 mice were randomly divided into control group, non-transduced T cell (NT)-CV group, NT-PV group, MSLN CAR T-cell CV (MSLN-CV) group, and MSLN CAR T-cell PV (MSLN-PV) group, with each group containing four mice to examine the safety and efficacy. The bioluminescence intensity (BLI) of tumor burden, tumor tissue macroscopic and microscopic observation were used to evaluate treatment efficacy. The safety was examined by body weight, survival time, and vital organ damage of mice. CAR T-cell infiltration and cytokine concentration were analyzed by flow cytometry, and immunostaining. The change of immune microenvironment between regional delivery and systemic delivery was investigated on an immune reconstructed CRLM patient-derived xenograft (PDX) model. Additionally, T cell subsets and immunosuppressive markers were examined. Results: PV administration of 1×107/100 µL MSLN CAR T-cells in 20 NSG mice was well tolerated, and no overt toxicity was observed. The tumor burden in the PV group was obviously alleviated. The BLI was (0.73±0.52)×109 in PV group and (1.97±0.11)×109 in CV group (P<0.05), CD8+ granzyme B (GB)+ T cell percentage (MSLN-CV 4.42%±0.47% vs. MSLN-PV 13.5%±4.67%, P<0.01) and cytokine concentration were obviously increased in the MSLN-PV group. In the immune reconstituted CRLM PDX model, intratumor (IT) delivery of MSLN CAR T-cells exhibited much more infiltration of CD4+ and CD8+ T cells accompanied with elevated expression levels of PD-1, LAG-3, and TIM-3. Conclusions: Regional delivery of MSLN-targeted CAR T-cell therapy has encouraging results in the orthotopic CRLM NSG mouse model and PDX model, and converts the tumor microenvironment from cold to hot. This study may provide a new therapeutic approach for CRLM. Further clinical study is needed.

CBCT-based three-dimensional dual-phase vascular image fusion: a novel technique for interventional real-time TIPS guidance.

BACKGROUND: Due to the invisibility of the portal vein (PV), how to puncture the PV accurately and safely in transjugular intrahepatic portosystemic shunt (TIPS) creation remains a challenge of the procedure. OBJECTIVES: We aimed to provide the first evaluation of the safety, feasibility, and efficiency of cone beam computed tomography (CBCT)-based three-dimensional (3D) dual-phase vascular image fusion for interventional real-time guided PV puncture during TIPS procedures. MATERIALS AND METHODS: From January 2021 to May 2021, 13 patients undergoing TIPS were prospectively enrolled in this study. Images of the hepatic artery (HA) and PV in 3D were acquired and overlaid on interventional fluoroscopy images in a dual-phase display mode for real-time PV puncture guidance. The number of PV puncture attempts, puncture time, overlaid image accuracy, dose area product, fluoroscopy time, and interventional complications were recorded. RESULTS: Portal vein puncture guided by CBCT-based 3D dual-phase vascular image fusion was successfully performed on 92.3% (12/13) patients. The mean number of PV puncture attempts was 1.8 ± 0.7 (1-3). The mean puncture time and fluoroscopy time was 3.5 ± 1.2 (2-6) min and 25.1 ± 9.4 (15-45) min, respectively. The mean dose area product was 39.49 ± 7.88 (28.81-52.87) mGym2. The error between the reference position of the fusion image and the interventional PV angiography image was less than 0.5 cm. No interventional complication was observed. CONCLUSION: Our results show that 3D dual-phase vascular image fusion might be a safe and feasible technique for interventional real-time guided PV puncture during TIPS. This novel technique might help to reduce the number of PV puncture attempts and the puncture time as well as lower the risks of interventional complications.

Pneumothorax and pulmonary hemorrhage after C-arm cone-beam computed tomography-guided percutaneous transthoracic lung biopsy: incidence, clinical significance, and correlation.

OBJECTIVE: This study aimed to assess the incidence and clinical significance of pneumothorax (PTX) and pulmonary hemorrhage (PH) after percutaneous transthoracic lung biopsy (PTLB) guided by C-arm cone-beam computed tomography (CBCT). Furthermore, this study aimed to examine the relationships between PTX and PH with demographics, clinical characteristics, imaging, and PTLB parameters. METHODS: A retrospective analysis was conducted on 192 patients who underwent PTLB at our hospital between January 2019 and October 2022. Incidences of PTX and PH were recorded. PTX was considered clinically significant if treated with chest tube insertion (CTI), and PH if treated with bronchoscopes or endovascular treatments. The various factors on PTX and PH were analyzed using the Chi-squared test and Student t-test. Logistic regression analyses were then used to determine these factors on the correlation to develop PTX and PH. RESULTS: PTX occurred in 67/192 cases (34.9%); CTI was required in 5/67 (7.5%). PH occurred in 63/192 cases (32.8%) and none of these cases required bronchoscopes or endovascular treatments. Lesion diameter (ORPTX = 0.822; ORPH = 0.785), presence of pulmonary emphysema (ORPH = 2.148), the number of samples (ORPH = 1.834), the use of gelfoam (ORPTX = 0.474; ORPH = 0.341) and ablation (ORPTX = 2.351; ORPH = 3.443) showed statistically significant correlation to PTX and PH. CONCLUSIONS: CBCT-guided PTLB is a safe and effective method for performing lung biopsies. The use of gelfoam has been shown to reduce the occurrence of PTX and PH. However, caution should be exercised when combining radiofrequency ablation with PTLB, as it may increase the risk of PTX and PH.

Hypoxia-activated cascade nanovaccine for synergistic chemoembolization-immune therapy of hepatocellular carcinoma.

In this work, a promising treatment strategy for triggering robust antitumor immune responses in transarterial chemoembolization of hepatocellular carcinoma (HCC) is presented. The zeolitic imidazolate framework nanoparticles loaded with hypoxia-activated prodrug tirapazamine and immune adjuvant resiquimod facilitated in situ generation of nanovaccine via a facile approach. The nanovaccine can strengthen the ability of killing the liver cancer cells under hypoxic environment, while was capable of improving immunogenic tumor microenvironment and triggering strong antitumor immune responses by increasing the primary and distant intratumoral infiltration of immune cells such as cytotoxic T cells. Moreover, a porous microcarrier, approved by FDA as pharmaceutical excipient, was designed to achieve safe and effective delivery of the nanovaccine via transarterial therapy in rabbit orthotopic VX2 liver cancer model. The microcarrier exhibited the characteristics of excellent drug loading and occlusion of peripheral artery. The collaborative delivery of the microcarrier and nanovaccine demonstrated an exciting inhibitory effect on solid tumors and tumor metastases, which provided a great potential as novel combination therapy for HCC interventional therapy.

Endovascular management of sinistral portal hypertension-related variceal hemorrhage: a multicenter retrospective study.

PURPOSE: This study aimed to assess the safety and efficacy of endovascular managements, including splenic vein recanalization (SVR), partial splenic embolization (PSE), and percutaneous transsplenic gastric varices embolization combined with PSE (PSE+GVE), for management of SPH-related variceal hemorrhage (VH). METHODS: A total of 61 patients with SPH-related VH from three hospitals were enrolled and classified into three groups: the SVR group (Group 1, n=24), the PSE+GVE group (Group 2, n=17), and the PSE group (Group 3, n=20). Baseline characteristics and clinical outcomes were compared among the groups. RESULTS: The technical success rates for transhepatic and transsplenic SVR were 27.8% and 34.6%, respectively. No major complications were observed during any of the procedures. The median follow-up period was 53.2 months. The 2-year GI rebleeding rates for Group 1, 2, and 3 were 0%, 5.9%, and 35%, respectively. Groups 1 and 2 have a lower GI rebleeding rate (p = 0.002, p = 0.048, respectively) and better results of the degree of GV (p = 0.003, p = 0.044, respectively) compared to Group 3. No significant differences were found in 2-year GI rebleeding rates and the degree of GV between Group 1 and 2 (p = 0.415, p = 0.352, respectively). CONCLUSION: SVR, PSE+GVE, and PSE seem safe and effective for management of SPH-related VH. SVR appears to be the superior treatment option. Transsplenic access may further increase the SVR success rate. PSE+GVE seems to have comparable outcomes in GV control and GI rebleeding rates compared to SVR, while superior to PSE.

Microwave ablation combined with transarterial chemoembolization containing doxorubicin hydrochloride liposome for treating primary and metastatic liver cancers.

Aims: To determine the safety and efficacy of microwave ablation (MWA) and transarterial chemoembolization (TACE) with doxorubicin hydrochloride liposome (DHL) in patients with primary liver cancer (PLC) and metastatic liver cancer (MLC). Materials and methods: The medical records of patients with primary or metastatic liver cancer who underwent MWA combined with TACE containing DHL from March 2019 to March 2022 were collected and analyzed. Treatment-related adverse events (AEs) were recorded. Local tumor response was evaluated according to the modified RECIST criteria. Local tumor progression-free survival (LTPFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: Altogether, 96 patients with liver cancer were included (PLC, n â€‹= â€‹45; MLC, n â€‹= â€‹51). Forty (41.7%) patients experienced AEs during treatment, and eight (8.3%) patients developed grade 3 AEs. Compared to before treatment, the serum total bilirubin level and neutrophil to lymphocyte ratio significantly increased after treatment. The median LTPFS was 14.5 months in patients with PLC and 10.7 months in patients with MLC. The median OS was not reached in patients with PLC or MLC. The 1-month and 3-month disease control rates reached more than 80% in both groups. Conclusion: MWA combined with TACE with DHL may be a safe and effective method for the treatment of liver cancer.

Efficacy and Safety of Transarterial Chemoembolization with a Three-Stage Mixed Chemoembolic Regimen for Large Unresectable Hepatocellular Carcinoma.

Objective: This study aimed to assess the treatment response, survival outcomes, and safety of a novel transarterial chemoembolization (TACE) technique with a three-stage mixed chemoembolic regimen (M-TACE) in patients with large unresectable hepatocellular carcinoma (HCC) measuring more than 5 cm in maximum diameter. Methods: Between January 2017 and March 2023, a total of 82 patients were enrolled in this retrospective cohort study. Treatment response was assessed in the first month after M-TACE; progression-free survival and overall survival (OS) were evaluated. The prognostic factors associated with patient survival were statistically analyzed by the Cox regression model. Adverse events were recorded. Results: The maximum diameter of the tumors ranged from 5.3 cm to 20.0 cm (mean 10.71 cm). The objective response (OR) and disease control rates were 74.4 and 92.7%, respectively, at 1-month follow-up. The median survival time was 22 months (95% CI, 13.10-30.90 months). The OS rates were 82.0% at six months, 62.5% at one year, and 43.0% at two years. Targeted therapy and/or immunotherapy (P=0.001) and tumor response at one month (P=0.020) were protective factors for OS. In terms of safety, no major complications occurred and the only observed decrease within the normal range occurred in albumin and platelet levels one month after the embolization procedure. This decrease in levels did not show a significant relationship with the OR rates. Conclusion: M-TACE demonstrated a promising objective tumor response, making it a viable and effective treatment option for patients with large unresectable HCC.

The influence of shunting left/right portal vein branch on post-TIPS hepatic encephalopathy: a study protocol for multicenter randomized blinded controlled trial.

INTRODUCTION: Gastroesophageal varices (GOV) bleeding is a common and serious complication of advanced liver cirrhosis with a median survival of less than 2 years. Multiple guidelines have pointed out that transjugular intrahepatic portosystemic shunt (TIPS) is the rescue treatment of acute variceal hemorrhage (AVB) after failure of standard therapy and an effective second-line treatment for preventing patients with high risks from rebleeding of GOV. The safety and stability of TIPS have been greatly improved due to the improvements of related technologies and the emergence of various novel devices, but the incidence of hepatic encephalopathy (HE) after shunting (10-50%) hindered the widespread use of TIPS. The target portal vein branch might affect the incidence of HE after TIPS. The aim of this study is to compare the rate of HE in patients with hepatitis B virus (HBV) related cirrhosis receiving TIPS either the left or right branch of the portal vein with 8mm Viatorr stent for preventing rebleeding from GOV. METHODS AND ANALYSIS: This study is a multicenter randomized controlled trial comparing the influence of shunting left or right portal vein branch on post-TIPS hepatic encephalopathy for preventing rebleeding from GOV in patients with HBV-related cirrhosis. A total of 130 patients will be recruited over a period of 24 months across 5 centers in China. Eligible patients will be stratified 1:1 to constructing either a left or right portal vein shunt with an 8-mm Viatorr stent. The primary objective was to compare the incidence of post-TIPS hepatic encephalopathy between the two groups. The secondary objectives were to compare the grade and duration of hepatic encephalopathy, the rate of shunt dysfunction, the rate of variceal rebleeding, the HE-free survival, the cumulative patency rate of the stent, and the overall survival at 12 months and 24 months between two groups. ETHICS AND DISSEMINATION: This study was approved by the ethics committee of Zhongshan Hospital of Fudan University (No. B2018-292R) and was registered at ClinicalTrials.gov (NCT03825848). All participants give written informed consent. TRIAL REGISTRATION: ClinicalTrials.gov NCT03825848. Registered on January 31, 2019 TRIAL STATUS: The first patient was recruited into our study on June 19, 2019. A total of 55 patients were recruited till May 27, 2021 (27 and 28 patients assigned to shunting the left (L Group) and right (R Group) branches of the portal vein, respectively).

Comparing the predictive ability of portoatrial and portocaval gradient after transjugular intrahepatic portosystemic shunt creation for variceal rebleeding.

BACKGROUND: Measuring the portal pressure gradient from the portal vein (PV) to the inferior vena cava (IVC) or to the right atrium (RA) remains controversial. The aim of our study was to compare the predictive ability of portoatrial gradient (PAG) and portocaval gradient (PCG) for variceal rebleeding. METHODS: The data of 285 cirrhotic patients with variceal bleeding undergoing elective transjugular intrahepatic portosystemic shunt (TIPS) in our hospital were analyzed retrospectively. The variceal rebleeding rates were compared between groups categorized by established or modified thresholds. The median follow-up time was 30.0 months. RESULTS: After TIPS, PAG was equal to (n = 115) or more than (n = 170) PCG. The pressure of IVC was defined as an independent predictor for a PAG-PCG difference of ≥ 2 mmHg (p < 0.001, OR 1.23, 95% CI 1.10-1.37). Using a threshold of 12 mmHg, PAG (p = 0.081, HR 0.63, 95% CI 0.37-1.06) could not predict variceal rebleeding but PCG could (p = 0.003, HR 0.45, 95% CI 0.26-0.77). This pattern was unchanged when a ≥ 50% reduction from baseline was also considered as a threshold (PAG/PCG: p = 0.114 and 0.001). Subgroup analyses showed that only in patients with post-TIPS IVC pressure < 9 mmHg (p = 0.018), PAG could predict variceal rebleeding. Because PAG was on average 1.4 mmHg higher than PCG, patients were classified by a PAG of 14 mmHg, and there was no difference in rebleeding rates between these two groups (p = 0.574). CONCLUSIONS: For patients with variceal bleeding, the predictive ability of PAG is limited. The portal pressure gradient should be measured between the PV and IVC.

Long-term efficacy and safety of anticoagulant for cavernous transformation of the portal vein cirrhotic patient with extrahepatic portal vein obstruction.

BACKGROUND/AIMS: Cavernous transformation of the portal vein (CTPV) in cirrhotic patients with extrahepatic portal vein obstruction (EHPVO) was a relatively rare disease and had no consensus on the treatment. Our study aimed to explore the value of anticoagulation with warfarin treatment for CTPV cirrhotic patients with EHPVO. METHODS: From January 2015 to December 2019, the clinical characteristics of cirrhotic patients who were diagnosed as CTPV with EHPVO were retrospectively analyzed. Eligible patients were distributed into the anticoagulation group (n = 46) and control group (n = 38). The change of portal vein thrombosis, hepatic decompensation, survival and adverse events were evaluated between the two groups. RESULTS: The median follow-up of our patients was 51 months in the anticoagulation group and 44 months in the control group. The progress rate of the portal vein was higher in patients from the control groups (n = 12) than in patients from the anticoagulation group (n = 4, p = 0.008). There was no significant difference between the partial recanalization rate and stable rate between the two groups. Patients in anticoagulation group developed less hepatic decompensation than those in control group (13.0% vs 34.2%, p = 0.021). The Kaplan-Meier curve showed that patients in the anticoagulation group had a better prognosis than patients in the control group (P < 0.022). There were no serious complications due to warfarin treatment. CONCLUSION: For CTPV cirrhotic patients with EHPVO, anticoagulation with warfarin treatment was effective and safe. Anticoagulants could prevent portal vein thrombosis progression, hepatic decompensation and death. In addition, our results showed little benefit of anticoagulants on thrombosis recanalization.

Predictive power of portal pressure gradient remeasured shortly after transjugular intrahepatic portosystemic shunt.

BACKGROUND AND AIMS: The portal pressure gradient (PPG) measured at the time of transjugular intrahepatic portosystemic shunt (TIPS) completion (immediate PPG) is easily disturbed by many factors. This study aimed to assess the diagnostic value of PPG remeasured 2-4 days after TIPS (delayed PPG) by comparison with immediate PPG. METHODS: We retrospectively analyzed cirrhotic patients aged 18-75 years who received TIPS for preventing variceal rebleeding and pressure measurements at different time points. RESULTS: Of 154 eligible patients, 60 (39.0%), 62 (40.3%), and 32 (20.8%) were categorized into group LL (both immediate and delayed PPG < 12 mmHg), LH (immediate PPG < but delayed PPG ≥ 12 mmHg) and HH (both immediate and delayed PPG ≥ 12 mmHg), respectively. Mean immediate and delayed PPG were 9.2 mmHg and 12.8 mmHg (p < 0.001). During a median follow-up of 22 months, the 1-year probability of variceal rebleeding was significantly lower in group LL (1.7%) compared to LH (9.8%, absolute risk difference [ARD]: - 8.2%, p = 0.028) and HH (12.6%, ARD: - 11.1%, p = 0.014), but was not significantly different between groups LH and HH (ARD: - 2.9%, p = 0.671). Delayed PPG (p < 0.001) was identified as an independent predictor of variceal rebleeding in multivariable Cox regression analysis. The area under curves of delayed and immediate PPG in predicting variceal rebleeding were 0.837 and 0.693 for all patients (p = 0.031), and 0.936 and 0.694 for patients without shunt dysfunction (p < 0.001). CONCLUSIONS: In cirrhotic patients with variceal bleeding, delayed PPG has higher predictive power for variceal rebleeding than immediate PPG.

A new alternative technique for the guidance of transjugular intrahepatic portosystemic shunt creation using DSA overlay reference.

BACKGROUND: Portal vein puncture (PVP) is a critical step during transjugular intrahepatic portosystemic shunt (TIPS) and correlates to several complications. Techniques guiding PVP are needed. PURPOSE: To evaluate the safety, feasibility, and efficiency of digital subtraction angiography (DSA) overlay reference during TIPS creation and compare it with transhepatic portal vein (THPV) guiding. MATERIAL AND METHODS: The clinical records of 185 patients at three medical centers who underwent TIPS placement were reviewed. Portal vein access was guided by THPV guiding in 120 cases and DSA overlay reference in 60 cases. The number of punctures, portal vein entry time, procedural adverse events, technical and hemodynamic success rate were analyzed to compare the safety, feasibility, and efficiency of the two methods. RESULTS: The median numbers of punctures in group 1 and group 2 were 2 (1-4) and 2 (1-5), respectively (P = 0.094). There was no statistical difference between two groups in needle passes. The median portal vein entry time of group 1 was 12 min (8-16 min) and 13 min (8-16 min) in group 2. No significant difference was found in the PVP time (P = 0.802). Arterioportal fistula formation occurred in 15 patients in group 1; two patients in group 2 had hepatic artery injury. The patients in group 2 had lower rates of procedural adverse events (P = 0.047). Median dose area product of G1 was lower than G2 statistically (P<0.001). There was no significant difference in total fluoroscopy time (P = 0.856). CONCLUSION: DSA overlay reference has lower procedural adverse events rates compared with THPV guiding TIPS. It seems to be a safe and effective method for guiding PVP.

Development of a Costimulatory Molecule Signature to Predict Prognosis, Immune Landscape, and Response to Immune Therapy for Hepatocellular Carcinoma.

This work was aimed at investigating the predictive value on prognosis, response to immunotherapy, and association with the immune landscape of costimulatory molecules in HCC patients. We acquired the clinicopathological information and gene expression of HCC patients from public available database (TCGA and GEO). The prognostic model in TCGA database was established with LASSO regression and Cox regression analysis. Through the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis, the enrichment analysis was implemented for analyzing the biological function and associated pathways. Immune microenvironment, immune escape, immune therapy, and tumor mutation were analyzed between both risk groups. TNFRSF4, the critical costimulatory molecule, was chosen for the in-depth investigation in vitro experiments. A novel risk signature based on 8 costimulatory molecules associated with prognosis was constructed from TCGA and proved in the database of GEO. The ROC and Kaplan-Meier curves confirmed that this risk model has good predictive accuracy. Our functional analysis demonstrated costimulatory molecular genes might associate with immune-related functions and pathways. Statistical differences were not shown between both groups, in the aspect of immune landscape, response to immune therapy, and tumor mutation. Knocking down TNFRSF4 expression significantly reduced the proliferation ability and increased the apoptosis ability. On the basis of the costimulatory molecule expression in HCC, a novel risk model was constructed and had an excellent value to predict prognosis, immune microenvironment, and response to immune therapy. TNFRSF4 was identified as an underlying oncogene in HCC and deserves further exploration.

Microwave ablation combined with lipiodol-microsphere mixed or conventional transarterial chemoembolization for the treatment of colorectal liver metastases: A retrospective study.

PURPOSE: To investigate the clinical outcomes of microwave ablation (MWA) combined with lipiodol-microsphere mixed transarterial chemoembolization (mTACE) or conventional TACE (cTACE) for patients with colorectal liver metastases (CRLM). MATERIALS AND METHODS: This retrospective study evaluated the medical records of patients with CRLM who underwent MWA combined with mTACE or cTACE from January 2018 to September 2021. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were evaluated during the follow-up. In addition, prognostic factors affecting survival were analyzed by univariate and multivariate methods. RESULTS: A total of 79 patients with CRLM were enrolled in the study (MWA-mTACE group, n = 38; MWA-cTACE group, n = 41). The patients who underwent MWA-mTACE had higher DCR (86.8% vs. 65.9%, P = 0.029) and better PFS (median, 8.1 vs. 5.5 months, P = 0.018) than those who underwent MWA-cTACE, but no significant difference was found in ORR (34.2% vs. 22.0%, P = 0.225) and OS (median, 15.7 vs. 13.0 months, P = 0.231). Further univariate and multivariate analyses indicated that MWA-mTACE was an independent positive factor for PFS, and abnormal carcinoembryonic antigen level was a hazard factor for OS. The postoperative laboratory tests and complications in patients who underwent MWA-mTACE were similar to those who underwent MWA-cTACE. CONCLUSION: Lipiodol-microsphere mixed TACE might be an effective and safe treatment to combine with microwave ablation for patients with colorectal liver metastases.

The Impact of Socioeconomic Status on Staging, Prognosis in Hepatocellular Carcinoma.

PURPOSE: We conducted this large population-based study to evaluate the impact of socioeconomic status (SES) factors on cancer-specific survival (CSS) of patients with hepatocellular carcinoma (HCC). We further assessed the value of a novel TNM-SES staging system, which incorporated these SES factors with TNM stage on staging and prognosis. METHODS: A total of 13,791 patients diagnosed with HCC from 2012 to 2016 were retrieved from one large population database. Cox proportional hazards regression model and Harrell's concordance index (C-index) were used to identify the SES factors associated with CSS and analyze the prognostic value of TNM-SES stage. Kaplan-Meier curves and Log rank test were performed to evaluate CSS. RESULTS: Four SES factors (marital status, insurance status, education, household income) were identified as the prognostic factors associated with CSS. The SES-2 (lower SES) stage was significantly correlated to unfavorable CSS of the patients with HCC, with a 32.0% increased risk (HR = 1.32, 95% CI (1.26-1.39), P < 0.001), after adjusting for several confounders. The C-index of the TNM-SES stage was 0.735 (95% CI (0.729-0.741)) which was higher than that of the TNM stage (0.718, 95% CI (0.712-0.724)), indicating a high accuracy of prognostic prediction. CONCLUSION: Our comprehensive study revealed that SES was significantly associated with prognosis of patients with HCC after adjusting several confounders. The novel TNM-SES staging system which combined TNM stage and SES stage had more superior predictive value than the traditional TNM stage. Disparity on SES should receive more attention for patients with HCC in clinical management.

Identification of Epithelial Mesenchymal Transition-Related lncRNAs Associated with Prognosis and Tumor Immune Microenvironment of Hepatocellular Carcinoma.

PURPOSE: The long noncoding RNAs (lncRNAs) play the important role in tumor occurrence and progression, and the epithelial to mesenchymal transition (EMT) is the critical process for tumor migration. However, the role of EMT-related lncRNA in hepatocellular carcinoma (HCC) has not been elucidated. METHODS: In this study, we selected the EMT-related lncRNAs in HCC by using data from The Cancer Genome Atlas database (TCGA). Two prognostic models of the overall survival (OS) and relapse-free survival (RFS) were constructed and validated through Cox regression model, Kaplan-Meier analysis, and the receiver-operating characteristic (ROC) curves. The unsupervised clustering analysis was utilized to investigate the association between EMT-lncRNAs with tumor immune microenvironment. ESTIMATE algorithm and gene set enrichment analysis (GSEA) were used to estimate tumor microenvironment and associated KEGG pathways. RESULTS: Two EMT-related lncRNA prognostic models of OS and RFS were constructed. Kaplan-Meier curves showed the dismal prognosis of OS and RFS in the group with high-risk score. The ROC curves and AUC values in two prognostic models indicated the discriminative value in the training set and validation set. Patients with HCC were clustered into two subgroups according the unsupervised clustering analysis. Lnc-CCNY-1 was selected as the key lncRNA. GSVA analysis showed that lnc-CCNY-1 was negatively associated with peroxisome proliferator-activated receptor (PPAR) signaling pathway and positively correlated with CELL cycle pathway. CONCLUSION: Two EMT-related lncRNA prognostic models of OS and RFS were constructed to discriminate patients and predict prognosis of HCC. EMT-related lncRNAs may play a role on prognosis of HCC by influencing the immune microenvironment. Lnc-CCNY-1 was selected as the key EMT-related lncRNA for further exploration.

Combined iodine-125 seed strand, portal vein stent, transarterial chemoembolization, lenvatinib and anti-PD-1 antibodies therapy for hepatocellular carcinoma and Vp4 portal vein tumor thrombus: A propensity-score analysis.

Objective: To evaluate the safety and efficacy of interventional therapy (iodine-125[125I] seed strand and portal vein stent [PVS] implantation plus transarterial chemoembolization [TACE]) combined with systemic therapy (lenvatinib plus anti-PD-1 antibody) as first-line treatment for hepatocellular carcinoma (HCC) patients with Vp4 portal vein tumor thrombus (PVTT). Patients and methods: From December 2018 to October 2021, 87 HCC patients with Vp4 PVTT were included in this single-center retrospective study. Forty-seven patients underwent interventional therapy combined with lenvatinib and anti-PD-1 antibody (group A), while 40 cases underwent interventional therapy combined with lenvatinib only (group B). Overall response rate (ORR), stent occlusion rates (SOR), median overall survival (OS), median progression-free survival (PFS) and median stent patency time (SPT) were compared between the 2 groups. Results: The mean intended dose (r = 10 mm; z = 0; 240 days) was 64.9 ± 1.0 Gy and 64.5 ± 1.1 Gy in group A and B, respectively (p = 0.133). ORR and SOR were significantly different between group A and B (ORR, 55.3% vs 17.5%, p < 0.001; SOR, 12.8% vs 35.0%, p = 0.014). In the propensity-score matching (PSM) cohort, the median OS, median PFS and median SPT were significantly longer in group A compared with group B (32 PSM pairs; OS, 17.7 ± 1.7 vs 12.0 ± 0.8 months, p = 0.010; PFS, 17.0 ± 4.3 vs 8.0 ± 0.7 months, p < 0.001; SPT, not-reached vs 12.5 ± 1.1 months, p = 0.028). Conclusion: This interventional therapy combined with lenvatinib and anti-PD-1 antibody is safe and effective for HCC patients with Vp4 PVTT.

Microwave ablation and synchronous transarterial chemoembolization combined with PD-1 inhibitor in patients with hepatocellular carcinoma following tyrosine kinase inhibitor intolerance.

Purpose: To determine the safety and efficacy of microwave ablation (MWA) and synchronous transarterial chemoembolization (TACE) combined with or without PD-1 inhibitor in patients with hepatocellular carcinoma (HCC) following tyrosine kinase inhibitor (TKI) intolerance. Materials and methods: This study retrospectively enrolled TKI-intolerant HCC patients who underwent MWA-TACE combined with PD-1 inhibitor (MTP) or MWA-TACE (MT) from January 2019 to June 2021. MWA and TACE were performed simultaneously, and PD-1 inhibitor was administered intravenously at a dose of 200 mg once every three weeks after MWA-TACE. Adverse events (AEs) related to treatment were recorded during the follow-up. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. Results: A total of 87 patients were included and classified into the MTP group (n =42) and MT group (n=45). Complications related to MWA-TACE in the MTP group were similar to that in the MT group (21.4% vs. 24.4%, P = 0.738). Moreover, 35 (83.3%) patients had eighty-four AEs related to PD-1 inhibitor in the MTP group, and 8 (19.0%) patients developed grade 3. Patients who underwent MWA-TACE combined with PD-1 inhibitor had better PFS (median, 10.0 vs. 4.7 months, P < 0.001) and OS (median, 17.0 vs. 8.5 months, P < 0.001) than those who underwent MWA-TACE alone. Treatment method and Child-Pugh class were independent prognostic factors for survival in the univariate and multivariate analysis. Conclusion: MWA and synchronous TACE combined with PD-1 inhibitor might be a favorable treatment option in TKI-intolerant HCC patients.