Transcatheter arterial chemoembolisation combined with lenvatinib plus camrelizumab as conversion therapy for unresectable hepatocellular carcinoma: a single-arm, multicentre, prospective study.

Background: The synergistic effect of locoregional therapy in combination with systemic therapy as a conversion therapy for unresectable hepatocellular carcinoma (uHCC) is unclear. The purpose of this study was to evaluate the efficacy and safety of transcatheter arterial chemoembolisation (TACE) combined with lenvatinib and camrelizumab (TACE + LEN + CAM) as conversion therapy for uHCC. Methods: This single-arm, multicentre, prospective study was conducted at nine hospitals in China. Patients (aged 18-75 years) diagnosed with uHCC, an Eastern Cooperative Oncology Group performance score (ECOG-PS) of 0-1 and Child-Pugh class A received camrelizumab (200 mg, every 3 weeks) and lenvatinib (bodyweight ≥60 kg: 12 mg/day; <60 kg: 8 mg/day) after TACE treatment. Surgery was performed after tumour was assessed as meeting the criteria for resection. Patients who did not meet the criteria for surgery continued to receive triple therapy until disease progression or intolerable toxicity. Primary endpoints were objective response rate (ORR) according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) and safety. Secondary endpoints included the surgical conversion rate, radical (R0) resection rate, and disease control rate (DCR). This study was registered with Chinese Clinical Trial Registry (ChiCTR2100050410). Findings: Between Oct 25, 2021, and July 20, 2022, 55 patients were enrolled. As of the data cutoff on June 1, 2023, the median follow-up was 13.3 months (IQR 10.6-15.9 months). The best tumour response to triple therapy was complete response (CR) in 9 (16.4%) patients, partial response (PR) in 33 (60.0%) patients, stable disease (SD) in 5 (9.1%) patients, or progressive disease (PD) in 7 (12.7%) patients. The ORR was 76.4% (42/55, 95% CI, 65.2-87.6%), and the DCR was 85.5% (47/55, 95% CI, 76.2-94.8%) per mRECIST. Twenty-four (43.6%) of the 55 patients suffered from grade 3-4 treatment-related adverse events (TRAEs). No grade 5 TRAEs occurred. A total of 30 (30/55, 54.5%) patients were converted to resectable HCC and 29 (29/55, 52.7%) patients underwent resection. The R0 resection rate was 96.6% (28/29). The major pathologic response (MPR) and pathologic complete response (pCR) rates in the surgery population were 65.5% (19/29) and 20.7% (6/29), respectively. Only one patient developed a Clavien-Dindo IIIa complication (abdominal infection). No Clavien-Dindo IIIb-V complications occurred. The median OS and median PFS were not reached. Interpretation: The triple therapy (TACE + LEN + CAM) is promising active for uHCC with a manageable safety. Moreover, triple therapy has good conversion efficiency and the surgery after conversion therapy is feasible and safe. To elucidate whether patients with uHCC accepting surgical treatment after the triple therapy can achieve better survival benefits than those who receive triple therapy only, well-designed randomised controlled trials are needed. Funding: This study was funded by the Natural Science Foundation of Fujian Province, China (2022J01691) and the Youth Foundation of Fujian Province Health Science and Technology Project, China (2022QNA035).

Construction of an immune-related lncRNA signature pair for predicting oncologic outcomes and the sensitivity of immunosuppressor in treatment of lung adenocarcinoma.

BACKGROUND: Although immunotherapy has shown clinical activity in lung adenocarcinoma (LUAD), LUAD prognosis has been a perplexing problem. We aimed to construct an immune-related lncRNA pairs (IRLPs) score for LUAD and identify what immunosuppressor are appropriate for which group of people with LUAD. METHODS: Based on The Cancer Genome Atlas (TCGA)-LUAD cohort, IRLPs were identified to construct an IRLPs scoring system by Cox regression and validated in the Gene Expression Omnibus (GEO) dataset using log-rank test and the receiver operating characteristic curve (ROC). Next, we used spearman's correlation analysis, t-test, signaling pathways analysis and gene mutation analysis to explore immune and molecular characteristics in different IRLP subgroups. The "pRRophetic" package was used to predict the sensitivity of immunosuppressant. RESULTS: The IRLPs score was constructed based on eight IRLPs calculated as 2.12 × (MIR31HG|RRN3P2) + 0.43 × (NKX2-1-AS1|AC083949.1) + 1.79 × (TMPO-AS1|LPP-AS2) + 1.60 × (TMPO-AS1|MGC32805) + 1.79 × (TMPO-AS1|PINK1-AS) + 0.65 × (SH3BP5-AS1|LINC01137) + 0.51 × (LINC01004|SH3PXD2A-AS1) + 0.62 × (LINC00339|AGAP2-AS1). Patients with a lower IRLPs risk score had a better overall survival (OS) (Log-rank test P TCGA train dataset < 0.001, P TCGA test dataset = 0.017, P GEO dataset = 0.027) and similar results were observed in the AUCs of TCGA dataset and GEO dataset (AUC TCGA train dataset = 0.777, AUC TCGA test dataset = 0.685, AUC TCGA total dataset = 0.733, AUC GEO dataset = 0.680). Immune score (Cor = -0.18893, P < 0.001), stoma score (Cor = -0.24804, P < 0.001), and microenvironment score (Cor = -0.22338, P < 0.001) were significantly decreased in the patients with the higher IRLP risk score. The gene set enrichment analysis found that high-risk group enriched in molecular changes in DNA and chromosomes signaling pathways, and in this group the tumor mutation burden (TMB) was higher than in the low-risk group (P = 0.0015). Immunosuppressor methotrexate sensitivity was higher in the high-risk group (P = 0.0052), whereas parthenolide (P < 0.001) and rapamycin (P = 0.013) sensitivity were lower in the high-risk group. CONCLUSIONS: Our study established an IRLPs scoring system as a biomarker to help in the prognosis, the identification of molecular and immune characteristics, and the patient-tailored selection of the most suitable immunosuppressor for LUAD therapy.

MiR-4310 regulates hepatocellular carcinoma growth and metastasis through lipid synthesis.

Hepatocellular carcinoma (HCC), which is characterized by reprogrammed lipid metabolism, is a highly malignant tumor with a high incidence and mortality rate. While lipid metabolism is a promising target for HCC therapy, the regulation of lipid metabolism is not well elucidated. Through CRISPR/Cas9 screening, we show that miR-4310 inhibits lipid synthesis by targeting fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD1). In patients with HCC, miR-4310 is significantly downregulated, and its expression is negatively correlated with expressions of FASN and SCD1. Furthermore, low expression of miR-4310 is associated with poor prognosis. By suppressing SCD1-and FASN-mediated lipid synthesis, miR-4310 inhibits HCC cell proliferation, migration, and invasion in vitro and suppresses HCC tumor growth and metastasis in vivo. Our data indicate that miR-4310 plays an important role in HCC tumor growth and metastasis by regulating the FASN- and SCD1-mediated lipid synthesis pathways. Targeting the miR-4310-FASN/SCD pathway may provide a novel strategy for HCC treatment.

Clinical efficacy of endovascular radiofrequency ablation in the treatment of portal vein tumor thrombus of primary hepatocellular carcinoma.

OBJECTIVE: The objective of this study is to investigate the clinical efficacy and safety of Habib™ VesOpen, a new intravascular radiofrequency ablation (RFA) catheter in percutaneous puncture of portal vein tumor thrombus (PVTT) in patients with primary hepatocellular carcinoma. MATERIALS AND METHODS: Collected data of patients with primary hepatocellular carcinoma with portal vein trunk or main branch who were treated by the RFA of portal vein tumor ablation with Habib™ VesOpen, a new intravascular RFA catheter. The postoperative success rate, complications, liver and kidney function, alpha-fetoprotein (AFP), portal vein patency, and tumor thrombus were analyzed, and the survival status of patients was analyzed by Kaplan-Meier survival analysis, and the COX proportional hazards regression model was used to analyze the factors influencing the clinical prognosis of patients. RESULTS: All the 44 patients were operated successfully without complications such as vascular perforation, infection, liver abscess, and intraperitoneal hemorrhage. The liver function index, alanine aminotransferase, aspartate aminotransferase, and serum albumin (ALB) were significantly different before and after surgery at 2 weeks and 4 weeks after operation (P < 0.05); AFP before and after surgery, the difference was statistically significant (P < 0.05). Doppler ultrasonography showed blood flow through the original portal vein after 4 weeks of surgery; enhanced computed tomography examination or magnetic resonance examination on the abdomen suggested patients with varying degrees of tumor thrombosis or disappearance after 8 weeks of surgery. The overall survival time was 284.72 ± 27.20 days (95% confidence interval: 231.42-338.02 days). The cumulative survival rates of 90, 180, and 360 days were 97.7%, 72.7%, and 17.2%, respectively. Cox multivariate regression analysis showed that tumor size and the size of ALB before RFA treatment was an independent factor in the prognosis of hepatocellular carcinoma with PVTT ablation (P < 0.05). CONCLUSIONS: The use of Habib™ VesOpen intravascular RFA catheter percutaneous puncture of the portal vein tumor RFA has positive clinical effect which is safe and reliable, expected to become one of the effective means in treatment of primary hepatocellular carcinoma with PVTT.

Magnetic resonance imaging evaluation after radiofrequency ablation for malignant lung tumors.

OBJECTIVE: The objective of this study was to investigate magnetic resonance imaging (MRI) assessment of the therapeutic response in small lung malignancies (<3 cm) immediately after radiofrequency ablation (RFA). MATERIALS AND METHODS: This is a retrospective analysis of MRI performance in 24 cases of small lung tumors (16 primary, 8 metastatic; 20 patients) immediately, post-RFA, and at follow-up. Variables measured included maximum diameters of tumors on pre-RFA MRI, central areas of low signal intensity (SI) on post-RFA T2-weighted images (T2WIs), and central areas of high SI on post-RFA T1WIs. Additional post-RFA measurements included the maximum diameters for areas of ground-glass opacities (GGOs) on computed tomography (CT), high SI on T2WIs, and isointense SI on T1WIs. Mean values were used for statistical analysis. RESULTS: Before RFA, 16 primary and seven metastatic lung tumors showed isointense signals on T1WIs and hyperintense signals on T2WIs. Immediately after RFA, the ablated lesions showed central low signals and peripheral high annular signals on T2WIs and central high signals and peripheral annular isointense signals on T1WIs, with reduced SI on diffusion-weighted images. Significant differences were found between the preoperative MRI maximum tumor diameter and post-RFA diameters of central low SI areas on T2WIs and central high SI areas on T1WIs. Furthermore, there were significant differences between the post-RFA maximum diameter of circumferential high signals on T2WIs and the post-RFA maximum diameters of both GGOs on CT and circumferential isointense signals on T1WIs. There were three cases of local recurrence (two pulmonary metastases and one primary) during follow-up. CONCLUSIONS: MRI evaluation of the therapeutic response of RFA for small malignant lung tumors (<3 cm) was precise and reliable.

Effect of heat sink on the recurrence of small malignant hepatic tumors after radiofrequency ablation.

AIMS: The aim of this study was to investigate the effect of heat sink on the recurrence of hepatic malignant tumors <3 cm after percutaneous radiofrequency ablation (RFA). SUBJECTS AND METHODS: This study included 564 hepatic malignant tumors <3 cm in 381 patients. Preoperative images were used to determine whether these tumors were adjacent to vessels, and the diameter of adjacent vessels was measured. RFA was performed computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US) guidance, and postoperative imaging follow-up was then conducted. STATISTICAL ANALYSIS USED: SPSS software version 17.0 was used for data processing, and the χ2 test was used for comparative analysis. Two-sided P < 0.05 indicated statistical significance. RESULTS: A total of 33 recurrences were found: 15 in the MR group (15/468), 12 in the US group (12/53), and 6 in the CT group (6/43). Of the 101 lesions adjacent to blood vessels larger than 3 mm, 20 showed recurrence: 10 in the MR group (10/77), 7 in the US group (7/17), and 3 in the CT group (3/7). The recurrence rate of perivascular lesions was higher than that of nonperivascular lesions, and the rate in the MR group was lower those in the US and CT groups. CONCLUSIONS: The curative effect of MRI-guided RFA is better than those of US- and CT-guided ablation. The heat sink effect is an important factor affecting recurrence of hepatic malignant tumors after RFA.

The RNA-binding protein RBPMS1 represses AP-1 signaling and regulates breast cancer cell proliferation and migration.

The activator protein-1 (AP-1) transcription factor complex plays a crucial role in tumor growth and progression. However, how AP-1 transcriptional activity is repressed is not fully understood. Here, we show that RNA-binding protein with multiple splicing 1 (RBPMS1) physically and functionally interacts with AP-1 in vitro and in vivo. The RNA-recognition motif (RRM) and C-terminus of the RBPMS1 isoforms RBPMS1A and RBPMS1C, but not RBPMS1B, interacted with cFos, a member of the AP-1 family that dimerizes with cJun to stimulate AP-1 transcriptional activity. RBPMS1 did not associate with Jun proteins. RBPMS1A and RBPMS1C bound to the basic leucine zipper (bZIP) domain of cFos that mediates dimerization of AP-1 proteins. In addition, RBPMS1A-C interacted with the transcription factor Smad3, which was shown to interact with cJun and increase AP-1 transcriptional activity. RBPMS1 inhibited c-Fos or Smad3-mediated AP-1 transactivation and the expression of AP-1 target genes known to be the key regulators of cancer growth and progression, including vascular endothelial growth factor (VEGF) and cyclin D1. Mechanistically, RBPMS1 blocks the formation of the cFos/cJun or Smad3/cJun complex as well as the recruitment of cFos or Smad3 to the promoters of AP-1 target genes. In cultured cells and a mouse xenograft model, RBPMS1 inhibited the growth and migration of breast cancer cells through c-Fos or Smad3. These data suggest that RBPMS1 is a critical repressor of AP-1 signaling and RBPMS1 activation may be a useful strategy for cancer treatment.

Local curative effect of MRI-guided radiofrequency ablation on small hepatocellular carcinoma.

Radiofrequency ablation (RFA) is one of the treatment modes for liver cancer. The trauma caused by RFA is small, and its local curative effect is reliable. Computed tomography (CT) can only be used for axial scans, and parts of the lesion are unclear on plain scans. The aim of this study is to compare the local curative effect of RFA percutaneously guided by MRI and ultrasound for small hepatocellular carcinoma (HCC). This study is a retrospective study. In this study, we examined 60 cases of 88 liver lesions and 50 cases of 52 lesions, in which RFA was guided by MRI and ultrasound, respectively. All cases were clinically diagnosed. The therapeutic effect of ablation lesions was examined by postoperative imaging follow-up. The results indicated that there were 5 (5/88) recurrences of liver lesions with MRI-guided RFA and 14 (14/52) recurrences of liver lesions with ultrasound-guided RFA. The median time to recurrence in the case of recurrent lesions was 7 months. Postoperative ablation lesions showed a low-intensity signal surrounded by a thin high-intensity signal ring on T2WI images. On T1WI images, the ablation lesion showed a concentric pattern and the central area of the original lesion continued to show a low-intensity signal with a clear ring of high-intensity signal that had a clear boundary. In conclusion, the local curative effect of MRI-guided RFA for small HCC is superior to that of ultrasound-guided RFA.

Calculation of life-time death probability due malignant tumors based on a sampling survey area in China.

PURPOSE: To calculate the probability of one person's life-time death caused by a malignant tumor and provide theoretical basis for cancer prevention. MATERIALS AND METHODS: The probability of one person's death caused by a tumor was calculated by a probability additive formula and based on an abridged life table. All data for age-specific mortality were from the third retrospective investigation of death cause in China. RESULTS: The probability of one person's death caused by malignant tumor was 18.7% calculated by the probability additive formula. On the same way, the life-time death probability caused by lung cancer, gastric cancer, liver cancer, esophageal cancer, colorectal and anal cancer were 4.47%, 3.62%, 3.25%, 2.25%, 1.11%, respectively. CONCLUSIONS: Malignant tumor is still the main cause of death in one's life time and the most common causes of cancer death were lung, gastric, liver, esophageal, colorectal and anal cancers. Targeted forms of cancer prevention and treatment strategies should be worked out to improve people's health and prolong life in China. The probability additive formula is a more scientific and objective method to calculate the probability of one person's life-time death than cumulative death probability .